exv10w15






Exhibit 10.15




CONFIDENTIAL




EXECUTION VERSION




DEVELOPMENT, LICENSE AND SERVICES AGREEMENT

([***]/METHSCOPOLAMINE PRODUCT)




     This Development, License and Services Agreement (including all Schedules hereto, this
“Agreement) is made and dated as of March 19, 2008 (the “Effective Date”), by and
between Cornerstone BioPharma, Inc., a Delaware corporation (“Cornerstone”), and Neos
Therapeutics, L.P., a Texas limited partnership (“Neos” and together with Cornerstone, the
“Parties”).



     WHEREAS, Neos is engaged in providing development and manufacturing services to pharmaceutical
companies and owns dynamic variable release technologies that result in products that show
controlled release characteristics in vitro (the “DVR Technology”), which technologies are
in part the subject of the pending patent application[s] set forth in Schedule A hereto
(the “DVR Patent Application[s]”);



     WHEREAS, Cornerstone is engaged in research, development, marketing and sale of human
pharmaceutical products, wishes to utilize the DVR Technology to develop the Product (as defined
below) for Commercialization (as defined below) in the Territory (as defined below), and wishes to
engage Neos to perform the Development Work (as defined below), including the production of
quantities of GMP Product for use as clinical material;



     WHEREAS, Neos has the capabilities and is willing to provide such development activities and
manufacturing services and to license rights under the DVR Technology and the DVR Patent
Applications in the Territory to Cornerstone, subject to the terms and conditions set forth herein;



     NOW, THEREFORE, in consideration of the premises and the mutual covenants and agreements
contained herein, the Parties hereto agree as follows:



ARTICLE 1.




DEFINITIONS




     In addition to the other terms defined elsewhere herein, the following terms and phrases shall
have the following meanings when used in this Agreement.



     “Affiliate” shall mean, with respect to any person, any person that directly or
indirectly through stock ownership or through other arrangements either controls, or is controlled
by or is under common control with, such person. The direct or indirect ownership of over 50% of
the outstanding voting securities of an entity, or the right to receive over 50% of the profits or
earnings of an entity, and such other relationships as in fact results in actual control over
the management of an entity, each shall be deemed to constitute control.



     “Clinical Product” means active and placebo batches of Product produced for use in
connection with Cornerstone’s clinical trials of the Product.





 





[***] Confidential portions of the exhibit have been omitted and filed separately with the
Securities and Exchange Commission.





 









 








CONFIDENTIAL




     “CMC” means the chemistry, manufacturing and controls section(s) and data in the NDA.



     “Commercialization” (or “Commercialize”) means developing, conducting
preclinical or clinical studies or trials, seeking regulatory approvals, manufacturing, marketing,
distributing, importing, offering for sale or selling the Product.



     “Development Work” means all the activities specified to be performed by Neos under
this Agreement including without limitation work related to formulation of the Product, developing
and documenting the manufacturing process related to the Product, preparing the CMC section of the
NDA for the Product, and manufacturing the Product for use in connection with the NDA submission.



     “FDA” means the United States Food and Drug Administration or any successor entity
thereto.



     “Force Majeure” has the meaning set forth in Section 11.7.



     “GLP” means the FDA’s current good laboratory practices, as specified in Title 21,
Code of Federal Regulations, Part 58, and applicable FDA guidance documents, as the same shall be
amended from time to time.



     “GMP” means the FDA’s current good manufacturing practices, as specified in Title 21,
Code of Federal Regulations, Part 210, and applicable FDA guidance documents, as the same shall be
amended from time to time.



     “ICH” means the International Conference on Harmonization of Technical Requirements
for Registration of Pharmaceuticals for Human Use.



     “Joint Invention” has the meaning set forth in Section 2.5(c).



     “Insolvency Event” has the meaning set forth in Section 10.2(d).



     “Know-How” means any and all product specifications, processes, product designs,
plans, trade secrets, know-how, ideas, concepts, manufacturing, engineering and other manuals and
drawings, standard operating procedures, flow diagrams, chemical, pharmacological, toxicological,
pharmaceutical, physical and analytical, safety, quality assurance, quality control and clinical
data, technical information, data, research records, supplier lists and similar data and
information, and all other confidential or proprietary technical and business information.



     “Laws” means any and all federal, state, and local laws, rules, regulations, orders
and requirements applicable to the Parties in performance of this Agreement including without
limitation the following: the Prescription Drug Marketing Act of 1987, the Federal Food, Drug and
Cosmetic Act, and all regulations and other guidance or requirements of the FDA or any equivalent
agency.



     “Manufacturing Site” means Neos’ facilities where the Product formulation and
manufacturing process are developed and the Product is manufactured, stored and handled.



     “Materials” has the meaning set forth in Section 2.1(b).



2









 





CONFIDENTIAL




     “NDA” means, in respect of the Product, a New Drug Application filed by Cornerstone
with the FDA and all subsequent related submissions thereto.



     “Neos Intellectual Property” means (i) the DVR Patent Applications, (ii) the Neos
Know-How related to the DVR Technology, (iii) the general Know-How of Neos related to manufacturing
processes or procedures utilized by Neos, its Affiliates or the Manufacturing Site in manufacturing
pharmaceutical products, (iv) any Neos Sole Inventions, and (v) Neos’ rights in any Joint
Inventions.



     “Net Sales” means the gross amounts invoiced by Cornerstone, any of its Affiliates or
any of its sublicensees for sales of Product in the Territory to third parties, less the total of
the following deductions to the extent actually and reasonably allowed or incurred in connection
with such sales:



     (a) reasonable and customary trade, cash and quantity discounts off the invoiced price;



     (b) excise, sales and other consumption taxes and custom duties to the extent included in the
invoice price;



     (c) freight, insurance and other transportation charges to the extent included in the invoice
price;



     (d) amounts repaid, credited or accrued, or allowances or adjustments made, by reason of
returns, rejections, or recalls, or because of chargebacks, retroactive price reductions, or
billing errors;



     (e) reasonable and customary rebates and chargebacks to pharmacy benefit managers, federal,
state, or local governments (or their agencies or purchasers), and managed health organizations
(including without limitation Medicaid rebates); and



     (f) any amounts actually written off or specifically identified as uncollectible in accordance
with GAAP;


solely to the extent the above deductions are taken in accordance with GAAP applicable to the
particular selling entity.



Use of Product for promotional, sampling or compassionate use purposes or for use in clinical
trials (but excluding post-approval clinical trials for which compensation is received by the
selling entity) shall not be considered in determining Net Sales. In the case of any sale of
Product between a Party and its Affiliates or sublicensees for resale, Net Sales shall be
calculated as above only on the first arm’s length sale thereafter to a third party.




     “Product” means a [***]/Methscopolamine [***] capsule that the Parties intend will
[***]. If the Parties agree as a result of the Development Work that the Product shall have a
different active pharmaceutical ingredient strength or other release charactistics, “Product” shall





 





[***] Confidential portions of the exhibit have been omitted and filed separately with the
Securities and Exchange Commission.




3









 








CONFIDENTIAL



mean such other combination pharmaceutical product for human use in the Territory containing [***]
and Methscopolamine as so agreed.




     “Registration Product” means Product produced for use in connection with Cornerstone’s
submission of its NDA to the FDA.



     “Sole Invention” has the meaning set forth in Section 2.5(b).



     “Territory” means the United States of America, including the states, territories and
possessions thereof, the District of Columbia, and the Commonwealth of Puerto Rico.



     “Valid Claim” means a claim of an issued and unexpired patent or a good faith claim in
a patent application, which claim has not been held invalid, unpatentable or unenforceable by a
court or other government agency of competent jurisdiction from which no appeal can be further
taken, and has not been held or admitted to be invalid, unpatentable or unenforceable through
abandonment, re-examination or disclaimer, opposition procedure, nullity suit or otherwise, which
claim covers the Product or its manufacture or use.



ARTICLE 2.




FORMULATION AND MANUFACTURING PROCESS DEVELOPMENT




     2.1 General.



          (a) Neos shall, at its expense, establish the Manufacturing Site as an FDA certified and
approved GMP facility by the date specified in the Development Plan and promptly shall provide
Cornerstone with a copy of the written GMP facility approval it receives from the FDA.




          (b) Neos shall use commercially reasonable efforts to perform the Development Work by the date
or dates specified in the plan of action and milestones attached hereto as Schedule B (as
the same may be amended in writing by the Parties from time to time, the “Development
Plan”). Neos shall, at its expense, provide all equipment necessary or advisable to complete
the Development Work. Neos also shall acquire raw materials, components, active pharmaceutical
ingredients or other materials necessary or advisable to complete the Development Work
(“Materials”), which shall be acquired only from approved suppliers where applicable, and
Cornerstone shall reimburse Neos for the costs of such items.




          (c) Except as set forth in this Agreement, Neos shall have no responsibility for clinical or
regulatory work associated with gaining FDA approval of the NDA for the Product.




     2.2 Formulation of Product and Development and Documentation of Manufacturing Process.



          (a) Neos shall use commercially reasonable efforts to develop a formulation of, and
manufacturing process for, the Product and shall, in consultation with Cornerstone’s development
staff, prepare and provide regulatory data and documentation and draft CMC






 





[***] Confidential portions of the exhibit have been omitted and filed separately with the
Securities and Exchange Commission.




4









 








CONFIDENTIAL



respecting the manufacture of the Product, all in compliance with applicable FDA guidelines and any
other applicable Laws. The project timeline for, and the Parties’ respective responsibilities with
respect to, such manufacturing process development and documentation are described in greater
detail in the Development Plan. Neos shall draft the CMC section of the NDA, and Cornerstone shall
cooperate with Neos to provide information reasonably requested by Neos in support of Neos’
drafting of the CMC. Cornerstone shall critically review and provide corrections to the CMC
section in a timely fashion. Neos shall use commercially reasonable efforts to be prepared for any
FDA pre-approval inspection of the Manufacturing Site. Neos agrees that Cornerstone may reference
Neos as the manufacturer of the Product in Cornerstone’s NDA and any other documentation required
under any regulatory filings for the Product, and Neos will provide Cornerstone with all required
documentation, including development and analytical reports to support such filings.




          (b) The Parties understand and agree that the Development Work and the manufacture of Product
contemplated by this Agreement are: to support Cornerstone’s product, clinical and regulatory
development plans respecting the Product; to support Cornerstone’s obtaining clearance from the FDA
for marketing of the Product; and to establish facilities, manufacturing processes and quality
control/quality assurance procedures and systems that will be found in compliance with GMP and
other Laws in the event of a related inspection by the FDA. Neos will comply with all applicable
GLP, GMP and other applicable U.S. regulations in order for the Development Work and the supplied
Product to meet all applicable Laws for the conduct and completion of validation runs. Without
limiting the foregoing, Neos will implement and maintain the policies and procedures and take the
other actions set forth in the Development Plan, and as may be requested by Cornerstone from time
to time. Neos will cooperate with Cornerstone to respond to any FDA information requests relating
to the CMC section that may arise during the NDA submission, regulatory agency review and approval
processes and, upon Cornerstone’s reasonable request, will provide other assistance related to
obtaining NDA approval.




          (c) Cornerstone will use commercially reasonable efforts to fulfill its responsibilities
described in greater detail in the Development Plan to develop the Product. Cornerstone shall
prepare the NDA submission and diligently pursue NDA approval from the FDA. Upon receipt of NDA
approval, Cornerstone shall use commercially reasonable efforts to fully Commercialize the Product
in the Territory.




     2.3 Development Schedule. Neos shall provide sufficient staffing for the Development
Work and use commercially reasonable efforts to perform and complete the Development Work, and the
various components thereof, according to the milestone schedule set forth in the Development Plan,
in order that the Product shall be available for supply to Cornerstone in compliance with all
applicable Laws in connection with the NDA submission, it being understood that Cornerstone has a
strategic objective to complete GMP manufacture of Clinical Product by August 2008. During the
Term, Neos shall provide monthly reports within ten (10) days following the last day of each month
regarding its progress in relation to the milestones set forth in the Development Plan, such
reports to be in form and substance reasonably satisfactory to Cornerstone. The Parties agree that
time is of the essence in this Agreement. Nevertheless, Cornerstone may abandon development of the
Product at any time in its sole discretion, subject to Section 10.3(d).



5









 





CONFIDENTIAL




     2.4 Project Coordination; Senior Executive Resolution. Cornerstone appoints its Chief
Medical Officer, Brian Dickson, and Neos appoints its Vice President, Research and Development,
Russ McMahen to serve as their respective primary contact persons with regard to the Development
Work (the “Project Managers”). The Project Managers will meet, by phone or in person, as
necessary (but not less than twice per month) to review, coordinate, and discuss issues and
progress regarding the Development Work. The Project Managers shall to the extent practicable seek
to operate by consensus in coordinating and facilitating the activities of the Parties under this
Agreement. For the avoidance of doubt, the Project Managers shall have no authority to amend or
waive compliance with the terms and conditions of this Agreement, to resolve differences of opinion
between the Parties regarding the interpretation of this Agreement or to approve actions of the
Parties that are inconsistent with this Agreement. In the event that a dispute of any kind arises
pertaining in any manner to activities of the Parties under this Agreement (a “Dispute”),
prior to the initiation of any formal legal action, the Dispute will be submitted to the Presidents
of Cornerstone and Neos. For all Disputes referred to the Presidents, the Presidents shall use
their good faith efforts to meet at least two times in person and to resolve the Dispute within ten
(10) business days after such referral. If the Presidents are unable to resolve the Dispute, the
Parties agree to refer the Dispute for non-binding mediation within ten (10) days of either Party
making a request to the other by notice hereunder. Any such mediation will be conducted by the
American Arbitration Association in the State of New York. The Parties agree to share the cost of
any mediation equally.



     2.5 Ownership of Intellectual Property and Regulatory Files in Connection with Development
Work.



          (a) Existing Inventions and Know-How. Ownership of existing inventions and Know-How of either
Party or future inventions and Know-How of either Party made outside the scope of this Agreement
shall remain the sole property of such Party, subject to any licenses granted in this Agreement.




          (b) Inventions and Know-How Developed Under this Agreement by a Party. Any and all inventions
(including all results and Know-How), whether or not patentable, that is conceived, reduced to
practice, or otherwise developed within the scope of this Agreement solely by a single Party’s
officers, employees, contractors and agents shall be owned solely by such Party along with all
related intellectual property rights (“Sole Inventions”), subject to any licenses granted
in this Agreement.




          (c) Inventions and Know-How Developed Jointly Under this Agreement. All other inventions
(including all results and Know-How), whether or not patentable, that is jointly conceived, reduced
to practice, or otherwise developed by officers, employees, contractors and agents of both Parties
under the scope of this Agreement shall be owned jointly by the Parties along with all related
intellectual property rights (“Joint Inventions”).




          (d) Joint Invention Rights. Patent applications on Joint Inventions may be filed only if the
Parties agree to file jointly on them. If the Parties agree to file for and obtain patents on
Joint Inventions, all expenses incurred therein shall be shared equally, except that the







6









 








CONFIDENTIAL



employer of each inventor, if applicable, will pay the inventor’s compensation. If a patent is
obtained on a Joint Invention, no Party shall transfer its interest in such patent to a Third Party
unless both Parties agree to do so. Notwithstanding the foregoing, the Parties shall be entitled
to transfer their respective rights to their respective Affiliates and successors in interest as
set forth in Section 11.3 hereof. Subject to the exclusivity arrangements in Section 2.6, each
Party is free to use and sublicense Joint Inventions to third parties without any further
obligations or accounting to the other Party; provided, however, that nothing in this Section
2.5(d) gives either Party any rights with respect to intellectual property that is owned solely by
the other Party.




          (e) Assignments of Inventions. Each Party shall, and shall cause its officers, employees,
contractors and agents to, (i) execute, all documents, including, without limitation, assignments
of inventions and discoveries and all related intellectual property rights, and (ii) perform such
acts as may be necessary, useful or convenient to secure or enforce for the other Party statutory
protection including patent, trademark, trade secret or copyright protection throughout the world
for all intellectual property assigned to it pursuant to this Section 2.5.




          (f) Regulatory Files. Cornerstone shall own all regulatory files with respect to the Product
including without limitation regulatory data and documentation prepared by Neos under Section 2.2
respecting the manufacture of the Product, including without limitation the CMC section of any NDA
filing with the FDA related to the Product.




     2.6 Exclusivity. Commencing upon the Effective Date, and extending for a period
ending on the later of (a) the fifth (5th) anniversary of (a) initial NDA submission,
(b) the fifth (5th) anniversary of the expiration of the Term, or (c) the expiration of
termination of the Supply Agreement Term (as defined in Section 5.2(a)), Neos agrees not to utilize
or permit the utilization of the Manufacturing Site, nor to perform services, nor to permit the use
of the Neos Intellectual Property, for or on behalf of any third party in connection with or
related to the development, manufacture or Commercialization of any combination pharmaceutical
product for human use in the Territory containing [***] and Methscopolamine (a “Competing
Product”), without Cornerstone’s prior written consent. Neos represents and warrants to
Cornerstone that, as of the Effective Date, Neos has not contracted with, is not collaborating with
and is not negotiating with any third party to perform services with respect to any Competing
Product.



ARTICLE 3.




PRODUCT MANUFACTURE




     3.1 Product Manufacture for NDA and Clinical Trials.



          (a) During the Term, provided that the Product has been successfully developed to
Cornerstone’s reasonable satisfaction through the Development Work, Neos agrees to manufacture and
supply Registration Product and Clinical Product that complies with Laws and GMP and that conforms
to the specifications set forth in the Development Plan (the “Specifications”) in the
quantities, at the times and at the locations designated by Cornerstone in the Development Plan.
Neos shall notify Cornerstone if there is any issue with time lines and





 





[***] Confidential portions of the exhibit have been omitted and filed separately with the
Securities and Exchange Commission.




7









 








CONFIDENTIAL



delivery of Product under this Agreement. The Specifications may be amended from time to time by
written agreement of the Parties without the necessity of amending this Agreement.




          (b) Promptly following each manufacturing run, Neos shall (i) test each batch in accordance
with the protocols specified in the Development Plan (“Quality Control Testing Protocols”)
and as the same may be modified from time to time in accordance with the last sentence of this
Section 3.1(b), (ii) furnish Cornerstone (attention: Chief Medical Officer) with a certificate of
analysis, test result sheets, Product reconciliation and yield information, copies of label
specimens, all investigations and deviations, and test results (such test results due within three
business days of batch release) and other documents in form and content satisfactory to
Cornerstone, and (iii) retain all relevant records pertaining thereto as may be required by GMP and
other applicable Law. The Quality Control Testing Protocols may be modified in writing by
Cornerstone with Neos’ written consent, such consent not to be unreasonably withheld, and any
changes to the Quality Control Testing Protocols requested by Neos shall be subject to the prior
written approval of Cornerstone and all such changes must comply with all applicable Laws.




          (c) Neos shall (i) validate using relevant ICH guidelines all non-pharmacopeial analytical
methods required for Product release testing in accordance with the Specifications, (ii) furnish
Cornerstone (attention: Chief Medical Officer) with method validation reports in form and content
satisfactory to Cornerstone and in compliance with FDA requirements, (iii) perform suitability
testing of all pharmacopoeial analytical methods required for Product release testing in accordance
with the Specifications, and (iv) furnish Cornerstone (attention: Chief Medical Officer) with
method suitability reports in form and content satisfactory to Cornerstone and in compliance with
FDA requirements.




          (d) When storing and handling raw materials, components, active pharmaceutical ingredients,
Product, or Product-derived wastes, Neos shall comply with, and shall maintain all storage
facilities in compliance with, the Specifications, GMP, and applicable Laws.




          (e) Upon Cornerstone’s request, Neos shall ship Product as directed by Cornerstone F.O.B. the
Facility. Freight and insurance shall be for the account of Cornerstone, and the risk of loss,
delay or damage in transit shall be with Cornerstone from and after delivery to Cornerstone’s
designated carrier. Neos shall use commercially reasonable efforts to assist Cornerstone in
arranging any desired insurance. Neos shall package the Product for shipment in accordance with
Cornerstone’s instructions and its SOPs or customary practices therefor. In the event of any
conflict between Cornerstone’s packaging instructions and Neos’s SOPs or customary practices, the
Parties shall endeavor in good faith to resolve such conflict as quickly as practicable. Neos
shall include the following for each shipment of the Product: (i) the purchase order number; (ii)
the lot and batch numbers; (iii) the quantity of the Product; and (iv) the certificate of analysis.




     3.2 Failure to Meet Specifications. Without limiting any rights or remedies available
to Cornerstone hereunder, in the event that Product not meeting the Specifications or otherwise
defective is shipped by Neos, Neos and Cornerstone shall mutually determine in good faith that Neos
shall either (a) refund any Materials costs related to the non-conforming Product for which it was
reimbursed by Cornerstone or (b) promptly replace such non-conforming Product with conforming
Product.



8









 





CONFIDENTIAL




     3.3 Right to Audit. During the Term and for the two-year period following the Term,
Neos shall permit Cornerstone and its employees or third party designees access, during reasonable
business hours and after reasonable notice, to the Manufacturing Site and to manufacturing records
for Product manufactured by Neos so that Cornerstone may perform a quality assurance audit of such
facilities and related activities but no more than twice yearly. In the event that Cornerstone
observes a condition which causes it to believe that the Manufacturing Site, the Product or its
method of development and production, tests, record keeping or other matters is not in compliance
with GLP, GMP or other Laws applicable to the development and production of the Product and the
conduct of the validation process, the Project Managers shall meet to discuss the concerns and any
strategies to bring the facilities, procedures or other matters into compliance.



     3.4 Inspections. In the event the Manufacturing Site is inspected by representatives
of any federal, state or local regulatory agency in connection with the regulatory approval process
or manufacture of Product, Neos shall notify Cornerstone in writing within twenty-four (24) hours
upon learning of such inspection, and shall supply Cornerstone with copies of any correspondence or
portions of correspondence that relate to the Product. Neos will make all reasonable efforts to
cooperate with such regulatory agency to accommodate the inspection and shall provide Cornerstone
with daily updates of any such inspections. In the event Neos receives any regulatory letter or
comments from any federal, state or local regulatory agency in connection with its manufacture of
the Product including, but not limited to, receipt of a Form 483 (Inspectional Observations) or a
Warning Letter, Neos shall provide Cornerstone with a copy thereof and a copy of each response for
Cornerstone review prior to submission of such response and opportunity to comment where
practicable.



     3.5 Supply of Product After NDA Approval. Following NDA approval of the Product,
provided that this Agreement has not been terminated by Cornerstone pursuant to Sections 10.2(a) or
10.2(b), the Parties will negotiate diligently and in good faith to enter into a supply agreement
for Neos to provide finished Product to Cornerstone for sale to commercial customers. The Parties
agree that if they enter into a definitive supply agreement, which would constitute their final
binding agreement, the provisions set forth in Schedule C attached hereto (the “Supply
Terms”) will, without material modification but with such additional description and additional
customary commercial terms as the Parties agree to, be included in such definitive supply
agreement. The Supply Terms do not purport to include all of the essential terms of the
contemplated supply relationship and it is the intention of the Parties that neither shall be
obligated to enter into the supply relationship unless the definitive supply agreement is executed
and delivered by the Parties and then only in accordance with the terms of such definitive
agreement.



ARTICLE 4.




COMPENSATION




     4.1 Hourly Fees. Cornerstone shall pay Neos One Hundred Fifty Dollars ($150) per hour
for each hour of professional services rendered in performing the Development Work that is
reflected in the Development Plan or that has been otherwise approved by Cornerstone in writing in
advance (“Hourly Fees”).



9









 





CONFIDENTIAL




     4.2 [***] Payments for Development Work. In addition to the Hourly Fees, Cornerstone
shall pay Neos [***] payments [***] not to exceed One Million Seven Hundred Fifty Thousand Dollars
($1,750,000) in the aggregate for all such [***] Payments. Neos hereby acknowledges [***].
Subsequent [***] Payments shall be [***]



	 	 	 
	 

	 	[***]
	 

	 	[***]
	 

	 	[***]
	 

	 	[***]
	 

	 	[***]
	 

	 	[***]






     4.3 Invoicing; Payments.



          (a) Neos will render monthly invoices within five business days after the last day of each
month of the Term for the Hourly Fees due in respect of the total number of professional hours
(including any fraction thereof) performed during that month or Materials costs for which
Cornerstone is required to provide reimbursement to Neos under Section 2.1(b), which invoice shall
be submitted to Cornerstone (attention: Chief Medical Officer) at the address set forth in Section
11.2. If applicable, such monthly invoice may also include a billing for any [***] Payment that is
then due and payable under Section 4.2.




          (b) The Hourly Fees, Materials reimbursements, and [***] Payments invoiced under this Section
4.3, except for any amounts disputed in good faith by Cornerstone, shall be payable by Cornerstone
within thirty (30) days of Cornerstone’s receipt of each invoice. If any invoice is rejected by
Cornerstone, in whole or in part, for any reason, Cornerstone shall provide Neos with its reason(s)
for such rejection, in writing, within thirty (30) days of receipt of the invoice. All payments
provided for under the terms of this Agreement shall be made by check or wire payable to Neos.




     4.4 Taxes. Neos shall pay and otherwise be responsible for all applicable sales,
goods, services, and transfer taxes in connection with any payment made to Neos pursuant to this
Agreement. Any income or other tax that one Party is required to withhold and pay on behalf of the
other Party with respect to amounts payable under this Agreement shall be deducted from and offset
against said amounts prior to payment to the other Party; provided, however, that in each case such
Party shall furnish the other Party on whose behalf amounts were withheld, proper evidence of the
taxes paid on its behalf.






ARTICLE 5.




REPRESENTATIONS AND WARRANTIES








     5.1 Mutual Representations and Warranties. Each of the Parties hereby represents and
warrants to the other Party as follows:




 





[***] Confidential portions of the exhibit have been omitted and filed separately with the
Securities and Exchange Commission.




10









 





CONFIDENTIAL




          (a) This Agreement has been duly authorized by all necessary corporate action, has been duly
executed and delivered, and is a legal and valid obligation binding upon such Party and enforceable
in accordance with its terms. Such Party has the full power and authority to enter into this
Agreement and to carry out the obligations contemplated hereby.




          (b) Delivery and performance of this Agreement by such Party does not conflict with any
agreement, instrument or understanding, oral or written, to which it is a party or by which it is
bound, nor violate any Laws of any court, governmental body or administrative or other agency
having jurisdiction over it.




          (c) All of such Party’s officers, employees, contractors and agents that perform any
Development Work or work on Joint Inventions will have entered into agreements with such Party that
provide, among other things, that if they become the inventor of a patentable invention in the
course of their work on behalf of such Party, they will assign their rights with respect to such
invention to such Party or as otherwise directed by such Party.




     5.2 Neos Representations and Warranties. Neos hereby represents and warrants to
Cornerstone as follows:



          (a) As of the Effective Date, Neos has the right to license the Neos Intellectual Property to
Cornerstone for purposes of the Development Work and the Commercialization of the Product in the
Territory and has no knowledge it is violating the intellectual property rights or other rights of
any third party. Neos owns all right, title and interest in and to, or otherwise controls, the DVR
Technology and will continue to do so at all times throughout the Term and the term of the supply
agreement contemplated by Section 3.5 (the “Supply Agreement Term”).




          (b) Neos has not, and during the Term and the Supply Agreement Term will not, grant any right
to any third party relating to the Neos Intellectual Property in a manner, or pursue any other
activity, that would otherwise conflict with the rights granted to Cornerstone hereunder.




          (c) As of the Effective Date, Neos has no actual knowledge that (i) any third party is
infringing any of the DVR Patent Applications or misappropriating or using Neos Know-How related to
the DVR Technology, and (ii) the Neos Intellectual Property, as applied to the Product, infringes
any third party intellectual property rights. Neos has not received any written communication from
a third party claiming that intellectual property rights owned or controlled by such third party
would be misappropriated or infringed by the use of the DVR Technology.




          (d) As of the Effective Date, Neos has not been served with any interference action or
litigation with respect to the DVR Patent Applications, and Neos has not received any written
communication that expressly threatens interference actions or other litigation before any
patent office, court, or any other governmental entity in any jurisdiction in regard to the DVR
Patent Applications.




          (e) As of the time of release of Product to Cornerstone in accordance with this Agreement, all
Product released (i) will conform to the applicable Specifications, and (ii) will have been
manufactured in material accordance with GMP (if applicable) and all applicable Laws and in
accordance with the applicable certificates of analysis.




11









 








CONFIDENTIAL




          (f) Without limiting the generality of the foregoing, Neos represents and warrants that it has
the right to provide to Cornerstone the Product and information provided by Neos hereunder, and to
grant Cornerstone the right to use such Product and information for the conduct of Cornerstone’s
rights and obligations hereunder.




          (g) Neos will not use, in any capacity associated with or related to the manufacture of the
Product, the services of any persons who have been debarred under 21 U.S.C. § 335a(a) (or who
become the subject of new debarment proceedings commenced after the Effective Date) or (b) or any
comparable Law. Furthermore, neither Neos nor, to the knowledge of Neos, any of its officers,
employees, or consultants has been convicted of an offense under (i) either a federal or state law
that is cited in 21 U.S.C. § 335(a) as a ground for debarment, denial of approval, or suspension,
or (ii) any other Law cited in any comparable regulatory act as a ground for debarment, denial of
approval or suspension.




          (h) As of the date of this Agreement, Neos does not have all manufacturing governmental
consents necessary for the performance of its obligations hereunder but is diligently pursuing all
such consents. Following Neos’ receipt of the FDA’s approval of the Manufacturing Site as a GMP
manufacturing facility, Neos will use its commercially reasonable efforts to thereafter maintain
throughout the remainder of the Term all manufacturing Consents necessary for the performance of
its obligations hereunder.




          (i) Neos will not sell the Product in the Territory during the Royalty Term or the Supply
Agreement Term except for sales to Cornerstone permitted by this Agreement or the supply agreement
contemplated by Section 3.5.




          (j) The manufacture, packaging, processing, storage, disposal and other handling of the
Product by Neos until delivery to Cornerstone’s designated carrier or freight forwarder at the
Manufacturing Site shall be in material accordance with and conform to the Specifications, GMP, and
applicable Laws. Product shall not be adulterated or misbranded within the meaning of the Federal
Food, Drug and Cosmetic Act.




     5.3 Cornerstone Representations and Warranties. Cornerstone hereby represents and
warrants to Neos as follows:



          (a) Cornerstone is the owner or has the lawful right to use or grant the right to use any and
all trademarks and trademark rights, trade names and trade name rights, service marks and service
mark rights, service names and service name rights, brand names, copyrights and copyright rights,
trade dress, business and Product names, logos, slogans, other proprietary information and related
documentation, and all pending applications for and registrations of trademarks, service marks and
copyrights that (i) it provides to Neos in connection with the
manufacture of the Product, or (ii) it uses in connection with the marketing, sale or
distribution of Product.




          (b) Cornerstone will not make any claims in any packaging, labeling, advertising or
promotional material regarding the Product that it knows to be false.




          (c) As of the date hereof, Cornerstone has not been served with any interference action or
litigation with respect to the Product and Cornerstone has not received any written communication
that expressly threatens interference actions or other litigation before any




12









 








CONFIDENTIAL



patent office, court,
or any other governmental entity in any jurisdiction in regard to the Product. Cornerstone
represents and warrants that as of the date of this Agreement it is not aware of any prior art or
other information that would render any claim under the DVR Patent Applications invalid.
Cornerstone represents and warrants that as of the date of this Agreement it is not aware of any
patent or any other third party intellectual property right that would be infringed by Cornerstone
in fulfilling its obligations under this Agreement.




          (d) Cornerstone will not use, in any capacity associated with or related to the clinical
development, FDA submission, sale, marketing or distribution of the Product, the services of any
persons who have been debarred or who are currently under investigation for possible debarment
under 21 U.S.C. § 335a(a) or any comparable Law. Furthermore, neither Cornerstone nor, to the
knowledge of Cornerstone, any of its officers, employees, or consultants has been convicted of an
offense under (i) either a federal or state law that is cited in 21 U.S.C. § 335a as a ground for
debarment, denial of approval, or suspension, or (ii) any other Law cited in any comparable
regulatory act as a ground for debarment, denial of approval or suspension.




ARTICLE 6.




CONFIDENTIALITY AND NONDISCLOSURE




     6.1 Confidentiality Obligation. Except as permitted below, each of the Parties (the
“Receiving Party”) shall keep strictly confidential any information disclosed in writing,
orally, visually or in any other manner by the other Party (the “Disclosing Party”) or
otherwise made available to the Receiving Party which the Disclosing Party considers to be and
treats as proprietary or confidential (“Confidential Information”). Confidential
Information shall not include information (a) which is or becomes generally available to the public
other than as a result of disclosure thereof by the Receiving Party; (b) which is lawfully received
by the Receiving Party on a nonconfidential basis from a third party that is not itself under any
obligation of confidentiality or nondisclosure to the Disclosing Party or any other person with
respect to such information; (c) which by written evidence can be shown by the Receiving Party to
have been independently developed by or for the Receiving Party; (d) which the Receiving Party
establishes by competent proof was in its possession at the time of disclosure by the Disclosing
Party and was not acquired, directly or indirectly from the Disclosing Party; or (e) which is
required to be disclosed by applicable Laws.



     6.2 Nondisclosure of Confidential Information. The Receiving Party shall use
Confidential Information solely for the purposes of this Agreement and shall not disclose or
disseminate any Confidential Information to any third party at any time without the Disclosing
Party’s prior written consent, except for disclosure to those of its directors, officers,
employees,
advisors and agents whose duties reasonably require them to have access to such Confidential
Information, provided that such directors, officers, employees, advisers and agents are required to
maintain the confidentiality of such Confidential Information to the same extent as if they were
Parties hereto. Upon reasonable request of the Disclosing Party, the Receiving Party shall
promptly surrender and deliver to the Disclosing Party all Confidential Information of the
Disclosing Party.



13









 





CONFIDENTIAL




     6.3 Survival. The confidentiality and nondisclosure obligations of this Article 6
shall survive the expiration or termination of this Agreement and remain in effect for a period of
five (5) years following the expiration or termination of this Agreement.



ARTICLE 7.




LICENSE OF NEOS INTELLECTUAL PROPERTY




     7.1 Neos License to Cornerstone. Subject to the terms of this Agreement, Neos hereby
grants to Cornerstone, and Cornerstone hereby accepts, a exclusive, irrevocable license, with right
to sublicense, under the Neos Intellectual Property (a) for performance of Cornerstone’s rights and
obligations under this Agreement, and (b) to use, make, have made and otherwise Commercialize the
Product (as successfully developed under this Agreement) in the Territory; provided, however, that
Cornerstone shall only have the right under this Section 7.1 to make or have made such product by a
third party manufacturer (i) if Neos suffers an Insolvency Event, (ii) if following Neos’ receipt
of the FDA’s approval of the Manufacturing Site as a GMP manufacturing facility, the FDA revokes
such approval, or (iii) Neos is unable to manufacture such product for a period exceeding ninety
(90) days due to Force Majeure or other cause.



ARTICLE 8.




ROYALTIES




     8.1 Royalty Payments. As sole consideration for the license granted under Section
7.2, Cornerstone shall pay to Neos royalties in accordance with this Article 8
(“Royalties”) based on Net Sales of the Product in the Territory:



          (a) [***] percent ([***]%) of Net Sales of Product sold during the Royalty Term while the DVR
Technology used in the Product is not the subject of a Valid Claim in the Territory.




          (b)
[***] percent ([***]%) of Net Sales of Product sold during the Royalty Term while the DVR
Technology used in the Product is the subject of a Valid Claim in the Territory; or



The obligation to pay Royalties under this Article 8 shall be imposed only once (i) with respect to
any sale of the same unit of the Product, and (ii) with respect to a single unit of the Product.




     8.2 Royalty Term. The Royalties set forth in Section 8.1 shall be payable until the
later of (i) such date as there no longer exists a Valid Claim under a United States patent or





 





[***] Confidential portions of the exhibit have been omitted and filed separately with the




Securities and Exchange Commission.




14









 








CONFIDENTIAL



patent application, or (ii) the [***] anniversary of the Effective Date if no United States patent
with a Valid Claim has been issued with respect to any of the DVR Patent Applications by such date.
If, after the Royalty Term has ended pursuant to the preceding sentence, but a United States
patent with a Valid Claim is thereafter issued with respect to any of the DVR Patent Applications
or other applications applicable to the Product, then the Royalty Term shall recommence on the date
such patent is approved and Royalties shall again be payable based on Net Sales of Product sold
after the date such patent is approved.




     8.3 Reports and Payments. Cornerstone shall deliver to Neos, within forty-five (45)
days after the end of each calendar quarter, a report setting forth for such calendar quarter the
following information for Product: (i) Net Sales of the Product by Cornerstone, any of its
Affiliates or any of its sublicensees; and (ii) the Royalties due to Neos in respect of such Net
Sales. The total Royalties due in respect of Net Sales of Product during such calendar quarter
shall be remitted at the time such report is made by check payable to Neos.



     8.4 Maintenance of Records; Audit. For a period of two (2) years from the end of the
calendar quarter in which the particular sale occurred, Cornerstone shall maintain, and shall
require its respective Affiliates and sublicensees to maintain, complete and accurate books and
records in connection with the sale of Product by Cornerstone, its Affiliates and sublicensees, as
necessary to allow the accurate calculation consistent with GAAP of the Royalties due to Neos,
including any records required to calculate any royalty adjustments hereunder. Once per calendar
year, Neos shall have the right to engage an independent accounting firm reasonably acceptable to
Cornerstone, which shall have the right to examine in confidence the relevant records of
Cornerstone as may be reasonably necessary to determine or verify the amount of the Royalties due
hereunder. Such examination shall be conducted during normal business hours, after at least
fifteen (15) Business Days prior written notice to Cornerstone and shall take place at
Cornerstone’s facility(ies) where such records are maintained. Each such examination shall be
limited to pertinent books and records for any year ending not more than twenty-four (24) months
prior to the date of request; provided that Neos shall not be permitted to audit the same period of
time more than once. Before permitting such independent accounting firm to have access to such
books and records, Cornerstone may require such independent accounting firm and its personnel
involved in such audit, to sign a confidentiality agreement (in form and substance reasonably
acceptable to Cornerstone) as to any confidential information which is to be provided to such
accounting firm or to which such accounting firm will have access, while conducting the audit under
this Section 8.4. The independent accounting firm will prepare and provide to each Party a written
report stating whether the royalty reports submitted and Royalties paid are correct or incorrect
and the details concerning any discrepancies. Such accounting firm may not reveal to Neos any
information learned in the course of such audit other than the amount of any such discrepancies.
Neos agrees to hold in strict confidence all information disclosed to it by such accounting firm,
except to the extent necessary for Neos to enforce its rights under this Agreement or to the extent
disclosure is required by Law. In the event there was an underpayment by Cornerstone of amounts
owed under this Agreement, Cornerstone shall promptly (but in no event later than thirty (30) days
after Cornerstone’s receipt of the





 





[***] Confidential portions of the exhibit have been omitted and filed separately with the
Securities and Exchange Commission.




15









 








CONFIDENTIAL



independent auditor’s report) make payment to Neos of any shortfall. In the event that there was
an overpayment by Cornerstone hereunder, Neos shall promptly (but in no event later than thirty
(30) days after Neos’ receipt of the independent auditor’s report) refund to Cornerstone or credit
to future royalties, at Cornerstone’s election, the excess amount. Neos shall bear the full cost
of such audit unless such audit discloses an underreporting by
Cornerstone of more than [***] percent ([***]%) of the aggregate amount of Royalties in any twelve (12) month period, in which
case, Cornerstone shall bear the full cost of such audit.




     8.5 Reductions. If either Party determines in its good faith judgment that it is
commercially necessary to obtain license rights in the Territory from a third party (a “Third
Party License”) under patent rights owned or controlled by such third party that claim or cover
the Product or its manufacture or use and are required to Commercialize the Product in the
Territory (“Third Party Patent Rights”), then such Party shall notify the other Party and
promptly thereafter the Parties shall enter into discussions regarding the appropriate terms and
conditions of such Third Party License and the Parties agree to negotiate in good faith their
respective shares of any license fees payable to such third party in respect of such Third Party
License. Following such discussions, Cornerstone may enter into a Third Party License and may
reduce the Royalties owed to Neos by an amount not exceeding the amount the Parties agreed should
be Neos’ share of such Third Party License fees.



ARTICLE 9.




INDEMNIFICATION AND LIMITATION OF LIABILITY




     9.1 Indemnification by Neos. Except as may be otherwise provided herein, Neos shall
defend, indemnify and hold harmless Cornerstone, its directors, officers and employees
(collectively the “Cornerstone Indemnitees”) from and against all Losses incurred in
connection with any third party suits, claims or causes of action arising out of or resulting from
(a) Neos’ breach of any representation, warranty, covenant, or other obligation provided for in
this Agreement; (b) the manufacture, delivery, storage, handling and use of the Product or any of
its components by Neos; (c) any actual or alleged infringement or misappropriation of any patent,
copyright, trade secret or any actual or alleged violation of any other intellectual property
rights arising from or in connection with Neos’ performance of the Development Work; or (d) the
negligence, recklessness or willful misconduct of Neos any of its directors, officers or employees;
provided, however, that Neos shall not be required to indemnify the Cornerstone Indemnitees to the
extent that any Losses arise out of or result from: (i) the negligence, recklessness or willful
misconduct of any Cornerstone Indemnitee; or (ii) any breach by Cornerstone of this Agreement.



     9.2 Indemnification by Cornerstone. Except as may be otherwise provided herein,
Cornerstone shall defend, indemnify and hold harmless Neos, its directors, officers and employees
(collectively the “Neos Indemnitees”) from and against all Losses incurred in connection
with any third party suits, claims or causes of action arising out of or resulting from (a)
Cornerstone’s breach of any representation, warranty, covenant, or other obligation provided




 






[***] Confidential portions of the exhibit have been omitted and filed separately with the
Securities and Exchange Commission.




16









 








CONFIDENTIAL



for in this Agreement; or (b) the negligence, recklessness or willful misconduct of Cornerstone and
its directors, officers or employees; provided, however, that Cornerstone shall not be required to
indemnify the Neos Indemnitees to the extent that any Losses arise out of or result from: (i) the
negligence, recklessness or willful misconduct of any of the Neos Indemnitees, or (ii) any breach
by Neos of this Agreement.




     9.3 Insurance. Neos will maintain in full force and effect during the Term of this
Agreement and for a period of three (3) years thereafter, worker’s compensation and general
liability insurance coverage in amounts appropriate to the conduct of its business and sufficient
to cover its indemnification obligations hereunder. Neos shall provide evidence of such insurance
to Cornerstone and ensure that Cornerstone will receive no less than thirty (30) days notice of
cancellation, non-renewal or material change.



ARTICLE 10.




TERM AND TERMINATION




     10.1 Effective Date and Expiration Date. The term of this Agreement shall commence on
the Effective Date and, unless terminated sooner in accordance with Section 10.2, shall expire upon
the earlier of FDA approval of the NDA for the Product or the fifth (5th) anniversary of
the Effective Date (the “Term”).



     10.2 Termination. This Agreement may be terminated as follows:



          (a) either Party may terminate this Agreement upon sixty (60) days written notice upon the
material breach of any provision of this Agreement by the other Party if the breach is not remedied
prior to the expiration of such sixty (60)-day notice period;




          (b) Cornerstone may terminate this Agreement upon ninety (90) days written notice if Neos
fails to achieve any milestones or quality targets set forth in the Development Plan and such
failure is not remedied prior to the expiration of such ninety (90)-day notice period,




          (c) Cornerstone immediately may terminate this Agreement if following Neos’ receipt of the
FDA’s approval of the Manufacturing Site as a GMP manufacturing facility, the FDA revokes such
approval;




          (d) either Party may terminate this Agreement upon thirty (30) days written notice if the
other Party is unable to perform its obligations for a period of ninety (90) days due to a Force
Majeure event as described in Section 11.7;




          (e) either Party immediately may terminate this Agreement upon written notice if the other
Party shall: (i) file in any court pursuant to any statute a petition for bankruptcy or
insolvency, or for reorganization in bankruptcy, or for an arrangement or for the appointment of a
receiver, trustee or administrator of such Party or of its assets; (ii) be served with an
involuntary petition against it, filed in any insolvency proceeding, and such petition shall not be
dismissed within sixty (60) days after the filing thereof; (iii) propose or be a party to any
dissolution; or (iv) make an assignment for the benefit of its creditors (each, an “Insolvency
Event”); and




17









 





CONFIDENTIAL




          (f) Cornerstone may terminate this Agreement immediately by written notice to Neos if the
Product is unable to achieve a suitable pharmacokinetic profile as determined by the
bioavailability study in the Development Plan or if it receives a Not Approvable Letter from the
FDA pursuant to 21 CFR §314.120 with respect to the NDA for the Product.




     10.3 Effects of Termination.



          (a) Accrued Rights; Delivery of Development Work Materials. Termination or expiration of this
Agreement for any reason shall (a) be without prejudice to any rights that shall have accrued to
the benefit of either Party prior to the effective date of such termination or expiration,
including without limitation rights to be paid any amounts owed to such Party hereunder as of such
date, and (b) not relieve either Party from obligations that are expressly indicated to survive
termination or expiration of this Agreement under Section 10.3(b).




          (b) Survival.




               (i) If FDA approval of the NDA for the Product is received and this Agreement expires or is
terminated, all rights granted and obligations undertaken by the Parties hereunder shall terminate
immediately upon the event of any termination or expiration of this Agreement, except for rights
and obligations set forth in Sections 2.5, 3.5, 10.3, 11.2, 11.7, 11.8, and 11.9, and in Articles
4, 6, 7, 8, and 9, or rights or obligations in this Agreement that by their express terms are
intended to operate after any termination or expiration of this Agreement.



               (ii) If FDA approval of the NDA for the Product is not received and this Agreement expires or
is terminated, all rights granted and obligations undertaken by the Parties hereunder shall
terminate immediately upon the event of any termination or expiration of this Agreement, except for
rights and obligations set forth in Sections 2.5, 10.3, 11.2, and 11.9, and in Articles 4, 6, and
9, or rights or obligations in this Agreement that by their express terms are intended to operate
after any termination or expiration of this Agreement.



               (iii) Should Neos become a party to a bankruptcy proceeding and such proceeding is not
dismissed within sixty (60) days then, to the extent permitted by applicable Laws, this Agreement
and the licenses granted by Neos hereunder shall continue, subject to the terms and conditions set
forth in this Agreement, and shall be adopted by any bankruptcy trustee or relevant third party
charged with the disposition of same, and shall not be rejected by same, it being the Parties’
intent that, in such event, Cornerstone and its Affiliates and sublicensees shall be entitled to
retain the rights granted to them hereunder by Neos.



          (c) Technical Transfer. If Cornerstone has the right under Section 7.1 to make or have made
by a third party manufacturer the Product, then Neos agrees to use commercially reasonable efforts
to assist Cornerstone to transfer the manufacture of the Product, including delivery of copies of
manufacturing and technical documentation, to any other facilities of Cornerstone or other third
party manufacturer selected by Cornerstone in its sole discretion.




          (d) Cessation of Work; Final Invoice. Upon delivery of written notice of termination to Neos
by Cornerstone, Neos shall immediately cease to perform work for or on behalf of Cornerstone,
unless authorized in writing by Cornerstone. In the event of termination of this Agreement for
any reason, Neos shall render a final invoice, due and payable promptly





18









 








CONFIDENTIAL



following receipt by Cornerstone, for Development Work performed for which Neos has not received
payment.




ARTICLE 11.




MISCELLANEOUS




     11.1 Counterparts. This Agreement may be signed in counterparts, each and every one
of which shall be deemed an original, notwithstanding variations in format or file designation
which may result from the electronic transmission, storage and printing of copies of this Agreement
from separate computers or printers. The exchange of copies of this Agreement or amendments
thereto and of signature pages by facsimile transmission or by email transmission in portable
document format (PDF), or similar format, shall constitute effective execution and delivery of such
instrument(s) as to the Parties and may be used in lieu of the original Agreement or amendment for
all purposes. Signatures of the Parties transmitted by facsimile or by email transmission in
portable document format (PDF), or similar format, shall be deemed to be their original signatures
for all purposes.



     11.2 Notices. In any case where any notice or other communication is required or
permitted to be given hereunder, such notice or communication shall be in writing, and shall be
deemed effective (a) in the case of hand delivery, when received, (b) in the case of overnight
delivery service, on the next business day after being placed in the possession of such service,
(c) in the case of facsimile, when electronic indication of receipt is received, and (d) in the
case of certified or registered mail, on the third day after being placed in the postal system
first class postage prepaid, at the respective addresses or facsimile numbers set forth below (or
such other address as the applicable Party may designate from time to time in writing):



          If to Cornerstone:



Cornerstone BioPharma, Inc.

2000 Regency Parkway, Suite 255

Cary, North Carolina 27511

Facsimile: (919) 678-6599

Attention: President




          If to Neos:



Neos Therapeutics

2940 N. Hwy. 360, Ste. 100

Grand Prairie, TX 75050

Facsimile: (972) 408-1143

Attention: President




     11.3 Binding Effect; Assignment. Neither this Agreement nor any rights or obligations
hereunder may be assigned, in whole or in part, by either Party without the prior written consent
of the other Party, and any attempted assignment without such consent shall be null and void.
Notwithstanding the foregoing, this Agreement or any rights and obligations under this Agreement
may be assigned (a) by Cornerstone to any Affiliate; (b) by Cornerstone to any person that acquires
substantially all of Cornerstone’s rights in the Product; or (c) by either Party
to a purchaser of substantially all of the capital stock or assets (including, in the case of



19









 





CONFIDENTIAL



Neos, the Neos Intellectual Property) of such Party by merger, purchase or other business combination.
Subject to the foregoing, this Agreement shall inure to the benefit of and be binding upon each of
the Parties hereto and their respective successors and permitted assigns.




     11.4 Entire Agreement; Amendment. The terms and conditions contained herein
constitute the entire agreement between the Parties relating to the subject matter hereof and shall
supersede all previous communications between the Parties with respect to the subject matter
hereof. This Agreement may be varied, amended or extended only by the written agreement of the
Parties, specifically referring to this Agreement.



     11.5 Severability. In case any one or more of the provisions contained herein shall,
for any reason be held to be invalid, illegal or unenforceable in any respect, such invalidity,
illegality or unenforceability shall not affect any other provision of this Agreement, but this
Agreement shall be construed as if such invalid, illegal or unenforceable provision or provisions
had never been contained herein unless the deletion of such provision or provisions would result in
such a material change as to cause completion of the transactions contemplated herein to be
impossible and provided that the performance required by this Agreement with such clause deleted
remains substantially consistent with the intent of the Parties.



     11.6 Applicable Law. The Agreement shall be governed by the laws of the State of New
York applicable to contracts made and to be performed entirely within such jurisdiction and without
giving effect to its choice or conflict of laws rules or principles.



     11.7 Force Majeure. No Party shall be liable for any failure to perform or any delay
in performing its obligations hereunder, when such failure or delay is due to Force Majeure and
without the fault or negligence of the Party so failing or delaying. For purposes of this
Agreement, “Force Majeure” is defined as acts of God; newly interpreted or issued Laws of
any government; war; civil commotion; destruction of production facilities or materials by fire,
flood, earthquake, explosion or storm; labor disturbances; epidemic; failure of public utilities or
common carriers; and other similar extraordinary unforeseen events that are beyond the control of
the affected Party, but shall not include general market or economic conditions and other ordinary
risks of doing business. If, for any of the reasons set forth in this Section 11.7, either Party
shall be unable to perform its obligations hereunder, such Party shall immediately notify the other
Party of such inability and the specific causes thereof and of the period for which such inability
is expected to continue. The Party giving such notice shall thereupon be excused from such of its
obligations under this Agreement as it is thereby disabled from performing during the pendency of
such causes, provided that it uses commercially reasonable efforts to overcome such causes.



     11.8 No Waiver of Rights. No failure or delay on the part of either Party in the
exercise of any power or right hereunder shall operate as a waiver thereof. No single or partial
exercise of any right or power hereunder shall operate as a waiver of such right or of any other
right or power. The waiver by either Party of a breach of any provision of this Agreement shall
not operate or be construed as a waiver of any other or subsequent breach hereunder. The remedies
herein provided are cumulative and not exclusive of any remedies provided by law.



     11.9 Publicity. Neither Party shall use the other Party’s name in any press release,
publicity, advertising, or other disclosure without the other Party’s prior written consent. Any



20









 





CONFIDENTIAL



public announcements or similar publicity with respect to this Agreement shall be at such time
and in such manner as the Parties shall mutually agree, provided that nothing herein shall prevent
either Party from, upon notice to and opportunity to review and comment by the other, making such
public announcements as such Party’s legal obligations require.




     11.10 Independent Contractor. In making and performing this Agreement, the Parties
are acting, and intend to be treated, as independent entities and nothing contained in this
Agreement shall be construed or implied to create an agency, partnership, joint venture, or
employer/employee relationship between Neos and Cornerstone. Except as otherwise expressly
provided herein, neither Party may make any representation, warranty or commitment, whether express
or implied, on behalf of, or incur any charges or expenses for or in the name of the other Party.
No Party shall be liable for the act of any other Party.



[signature page follows]




21









 








CONFIDENTIAL




[Signature Page to Development, License and Services Agreement]




     IN WITNESS WHEREOF, the Parties hereto have caused this Agreement to be executed by their duly
authorized representatives as of the date first written above.



	 	 	 	 	 	 	 
	 	 	CORNERSTONE, INC.	 	 
	 
	 	 	 	 	 	 
	 

	 	By:
	 	/s/ Brian Dickson	 	 
	 

	 	Name:
	 	 

Brian Dickson
	 	 
	 

	 	Title:
	 	Chief Medical Officer	 	 






	 	 	 	 	 	 	 
	 	 	NEOS THERAPEUTICS, L.P.	 	 
	 
	 	 	 	 	 	 
	 

	 	By:
	 	/s/ Mark Tengler	 	 
	 

	 	Name:
	 	 

Mark Tengler
	 	 
	 

	 	Title:
	 	President	 	 






 









 






CONFIDENTIAL




SCHEDULE A




DVR Patent Applications





 












 





			
	United States Patent Application: 0050152967
	 	Page 1 of 20
	 	 	 





US PATENT & TRADEMARK OFFICE

PATENT APPLICATION FULL TEXT AND IMAGE DATABASE




( 5 of 5 )





			
	 	 	 
	United States Patent Application
	 	20050152967
	Kind Code
	 	A1
	Tengler, Mark; et al.
	 	July 14, 2005








Dynamic variable release




Abstract



The present invention relates to novel mixed release pharmaceutical formulations that include a
expectorant available for immediate release and a decongestant for extended release that provide
for the symptomatic relief of cough associated with respiratory tract conditions such as the common
cold, bronchial asthma, acute and chronic bronchitis.




	 	 	 
	Inventors:
	 	Tengler, Mark; (Colleyville, TX); Ryan, Darlene; (Fort Worth, TX)
	Correspondence
	 	CHALKER FLORES, LLP
	Name and
	 	12700 PARK CENTRAL, STE. 455
	Address:
	 	DALLAS
	 
	 	TX
	 
	 	75251
	 
	 	US
	Assignee Name PFab, LP
	and Address:
	 	Grand Prairie
	 
	 	TX
	 
	 	75050
	 
	 	 
	Serial No.:
	 	010944
	Series Code:
	 	11
	Filed:
	 	December 13, 2004






			
	 	 	 
	U.S. Current Class: 

U.S. Class at Publication: 

Intern’l Class:
	 	424/451; 424/464; 514/649

424/451; 424/464; 514/649

A61K 009/48; A61K 009/20; A61K 009/26; A61K 031/137








Claims



1. A pharmaceutical composition comprising: an expectorant packaged for release of over 90% within
about 90 minutes; and a decongestant packaged for extended release wherein between about 30 to 60%
of the decongestant is available after 90 minutes, between about 50 to 70 percent is available at
between 150 and 210 minutes and wherein between about 60 to 80 percent is available after 360 minutes.





 









 








			
	United States Patent Application: 0050152967
	 	Page 2 of 20
	 	 	 




2. The composition of claim 1, wherein the decongestant comprises phenylephrine.



3. The composition of claim 1, wherein the expectorant comprises guaifenesin.



4. The composition of claim 1, wherein the pharmaceutical formulation is packed into a capsule.



5. The composition of claim 1, wherein the decongestant and the expectorant are packed into a
capsule, caplet, softgel, gelcap, suppository, film, granule, gum, insert, pastille, pellet,
troche, lozenge, disk, poultice or wafer.



6. The composition of claim 1, wherein over 80% of the expectorant is released within about 60
minutes.



7. The composition of claim 1, wherein immediate release is defined further as comprising release
of over 90% of the expectorant within about 60 minutes.



8. The composition of claim 1, wherein the decongestant is packaged with PVPP and Povidone.



9. The composition of claim 1, wherein the decongestant is packaged with a talc and a stearate.



10. The composition of claim 1, wherein the expectorant comprises gauifenesin in a powder form.



11. The composition of claim 1, wherein the expectorant comprises 422 mg of 95% gauifenesin.



12. The composition of claim 1, wherein the decongestant comprises phenylephrine as a sustained
release bead, a layered sustained release bead or three or more layers of phenylephrine on a bead.



13. The composition of claim 1, wherein the expectorant is superposed on the decongestant.



14. The composition of claim 1, comprising further one or more inactives.



15. A pharmaceutical composition consisting essentially of: an expectorant packaged for release of
over 90% within about 90 minutes; a decongestant packaged for extended release wherein between
about 30 to 60% of the decongestant is available after 90 minutes, between about 50 to 70 percent
is available at between 150 and 210 minutes and wherein between about 60 to 80 percent is available
after 360 minutes; and one or more inactive agents.



16. A capsule consisting essentially of: an expectorant packaged for release of over 90% within
about 90 minutes; a decongestant packaged for extended release wherein between about 30 to 60% of
the decongestant is available after 90 minutes, between about 50 to 70 percent is available at
between 150 and 210 minutes and wherein between about 60 to 80 percent is available after 360
minutes; and one or more inactive agents.



17. A method of providing a dual-release formulation comprising: loading into a capsule an
expectorant in a powered form and a decongestant in an extended release form, wherein the capsule
comprises one or more excipients selected from a polymer, a cellulose, a stearate, a talc, a
lacquer and a pharmaceutical glaze.



18. A method of providing a dual-release formulation comprising: providing a expectorant packed
for immediate release in a powder form; providing a nasal decongestant packed for extended release




 









 





			
	United States Patent Application: 0050152967
	 	Page 3 of 20
	 	 	 




comprising, phenylephrine, PVP, cellulose and a pharmaceutical glaze, and loading the expectorant
and the decongestant into a capsule.



19. A pharmaceutical composition consisting essentially of: a guaifenesin packaged for release of
over 90% within about 90 minutes; a phenylephrine packed for extended release; and one or more
inactive agents selected from a polyvinyl polymer, microcrystalline cellulose, stearate, lacquer,
talc and a pharmaceutical glaze, wherein between about 30 to 60% of the decongestant is available
after 90 minutes, between about 50 to 70 percent is available at between 150 and 210 minutes and
wherein between about 60 to 80 percent is available after 360 minutes.



20. A pharmaceutical composition consisting essentially of: an expectorant packaged for release of
over 90% within about 90 minutes; a decongestant packaged for extended release wherein between
about 30 to 60% of the decongestant is available after 90 minutes, between about 50 to 70 percent
is available at between 150 and 210 minutes and wherein between about 60 to 80 percent is available
after 360 minutes; and one or more inactive agents.



21. The composition of claim 20, wherein the decongestant comprises phenylephrine.



22. The composition of claim 20, wherein the expectorant comprises guaifenesin.



23. The composition of claim 20, wherein the pharmaceutical formulation is packed into a capsule.



24. The composition of claim 20, wherein the decongestant and the expectorant are packed into a
capsule, caplet, softgel, gelcap, suppository, film, granule, gum, insert, pastille, pellet,
troche, lozenge, disk, poultice or wafer.



25. The composition of claim 20, wherein over 80% of the expectorant is released within about 60
minutes.



26. The composition of claim 20, wherein immediate release is defined further as comprising
release of over 90% of the expectorant within about 60 minutes.



27. The composition of claim 20, wherein the decongestant is packaged with a polyvinyl polymer and
Povidone.



28. The composition of claim 20, wherein the decongestant is packaged with a talc and a stearate.



29. A pharmaceutical composition comprising: a guaifenesin salt packaged for release of over 90%
within about 90 minutes; a phenylephrine salt packaged for extended release wherein between about
30 to 60% of the decongestant is available after 90 minutes, between about 50 to 70 percent is
available at between about 150 and 210 minutes and wherein between about 60 to 80 percent is
available after 360 minutes.



30. The composition of claim 29, wherein the decongestant comprises phenylephrine.



31. The composition of claim 29, wherein the expectorant comprises guaifenesin.



32. The composition of claim 29, wherein the pharmaceutical formulation is packed into a capsule.



33. The composition of claim 29, wherein the decongestant and the expectorant are packed into a
caplet, softgel, gelcap, suppository, film, granule, gum, insert, pastille, pellet, troche,
lozenge, disk, poultice or wafer.




 









 





			
	United States Patent Application: 0050152967
	 	Page 4 of 20
	 	 	 




34. The composition of claim 29, wherein over 80% of the expectorant is released within about 60
minutes.



35. The composition of claim 29, wherein immediate release is defined further as comprising
release of over 90% of the expectorant within about 60 minutes.



36. The composition of claim 29, wherein the decongestant is packaged with a polyvinyl polymer and
Povidone.



37. The composition of claim 29, wherein the decongestant is packaged with a talc and a stearate.






Description





FIELD OF INVENTION



[0001] The invention relates to novel mixed release pharmaceutical formulations having an
expectorant for immediate release and a decongestant for mixed release, wherein the release
profiles of the ingredients are controlled to maximize the effectiveness of their pharmacological
action.




BACKGROUND OF THE INVENTION



[0002] Without limiting the scope of the invention, its background is described in connection with
immediate and extended release formulations and combination drug therapy, as an example.
Heretofore, in this field, medications have been formulated so that they may be administered in a
reduced number of daily doses. These doses must also provide drug that is released uniformly over a
desired, extended period of time. Sustained or extended release pharmaceutical formulations provide
a significant advantage over immediate release formulations to both clinicians and their patients
because patients require fewer daily doses than their immediate release counterparts. In some
cases, extended release formulation may improve therapeutic efficiency due to more consistent drug
serum levels.



[0003] Various techniques have been developed to provide pharmaceutical preparations that include,
e.g., a drug-containing particle with a coating layer and a pharmaceutical preparation in a
continuous matrix with a drug dispersed therein, such as embedded into a rigid lattice of a resin.
To achieve extended release, some pharmaceutical preparations include generally, a partially or
completely insoluble matrix that in aqueous body fluids releases the drug. Alternatively,
pharmaceutical preparations made of particles may be coated to provide extended release. It is
believed that the release of the drug from such pharmaceutical preparations is driven by the
gradient of the drug concentration resulting from penetration of water by diffusion into the
formulation. The rate of the release decreases due to a decrease in the concentration gradient and
the increase in the distance of diffusion. A sustained release formulation is also believed to help
reduce side effects caused by a drug because they deliver the drug in slow, incremental amounts
versus the cyclic high and low concentrations of immediate release formulations. By providing more
consistent drug levels it is argued that the patient is better able to process the drug to avoid
undesirable side-effects. Sustained release formulations for the sequential or timed release of
medicaments are generally known in the art. Such formulations often contain drug particles mixed
with or covered by a polymer material, or blend of materials, which is resistant to degradation or
disintegration in the stomach and/or in the intestine for a selected period of time. Release of the
drug may occur by





 









 








			
	United States Patent Application: 0050152967
	 	Page 5 of 20
	 	 	 




leeching, erosion, rupture, diffusion or similar actions depending upon the nature of the polymer material or polymer blend used.



[0004] To improve the release profile of certain sustained release dosage forms, some formulations
include tablets and capsules that include a combination of an immediate release formulation and a
sustained release formulation. Although the inclusion of tablets and capsules improves control over
the dosing of drug levels in the blood stream in some formulations, the extended therapeutic effect
may not be improved or desired.



[0005] Furthermore, every active has different solubility properties and pH dependencies that
affect, e.g., its dissolution rate, and hence its bioavailability. Bioavailability may also be
affected by a number of factors such as the amounts and types of additives used, its granulation
and compression, surface area, mechanical shearing (e.g., by the stomach), pH, solubility of the
active agent in water, the presence of food, etc. Due to these numerous factors, the specific form
of the drug, its excipients, coating, pH, dissolution profile alone, and in combination, affect the
manner and formulation of actives to achieve the best bioavailability profile to achieve an optimum
therapeutic effect.



[0006] U.S. Pat. Nos. 4,309,404 and 4,248,857 to DeNeale, et al., disclose slow release
formulations formed of a core material containing the active drug, carboxypolymethylene, zinc
oxide, stearic acid, and mannitol; a seal coating surrounding the core; and a sugar coating
surrounding the seal coating. U.S. Pat. No. 4,309,405 to Guley, et al., discloses a sustained
release tablet similar to that disclosed by DeNeale, et al., except that the core contains a drug,
a mixture of a water-soluble polymer such as hydroxypropylmethylcellulose or hydroxypropylcellulose
and a water-insoluble polymer (ethylcellulose alone or in admixture with carboxypolymethylene,
hydroxypropylcellulose and the like). The DeNeale and Guley patents disclose that their
compositions provide substantially zero order release of the core contained drug for about 12 hours
following the first hour of administration. Thus, zero order release is only obtained after the
initial surge of release of drug in the first hour.



[0007] U.S. Pat. No. 4,695,467 to Uemura, et al., relates to a sustained release tablet that
includes easily disintegrable granules including: a drug, a disintegrating agent selected from the
group consisting of starch derivatives, gums, cellulose derivatives and ion-exchange resins, and a
water-soluble polymer selected from the group consisting of cellulose derivatives, synthetic water
soluble polymers and polysaccharides. The surfaces of the granules are treated with a wax selected
from the group consisting of plant or animal wax, hydrogenated oils and paraffin.



[0008] U.S. Pat. No. 6,372,252 to Blume, et al., relates to guaifenesin sustained release
formulation and tablets that require a hydrophilic polymer and a water-insoluble polymer. The
formulation is said to be capable of providing therapeutically effective bioavailability of
guaifenesin for at least twelve hours after dosing in a human subject. The invention also relates
to a modified release guaifenesin tablet that has two portions: the first portion comprises an
immediate release formulation of guaifenesin and the second portion comprises a sustained release
formulation of guaifenesin as described above. A two portion, or bi-layer, tablet has a maximum
serum concentration equivalent to that of an immediate release guaifenesin tablet, and is capable
of providing therapeutically effective bioavailability of guaifenesin for at least twelve hours
after dosing in a human subject.



[0009] U.S. Pat. No. 6,462,094 to Dang, et al., relates to decongestant/expectorant compositions
consisting essentially of phenylephrine tannate and guaifenesin that are effective when
administered orally for the symptomatic relief of cough associated with respiratory tract
conditions such as the common cold, bronchial asthma, acute and chronic bronchitis are disclosed.





 









 








			
	United States Patent Application: 0050152967
	 	Page 6 of 20
	 	 	 





SUMMARY OF THE INVENTION



[0010] It has been found, however, that the present methods fail to provide an efficacious amount
of an expectorant in an immediate release form and a decongestant that is provided as an extended
release formulation that takes advantage of the pharmacological effect of the immediate release active to
maximize the efficiency of the delivery and pharmacological action of the decongestant. Yet another
problem is that certain drugs affect the release profile of a second drug that is being provided in
a single dose. The present invention solves these problems in the art.



[0011] The present invention also addresses a growing concern for physicians as they write
prescriptions for drugs: cost. While pharmacists continue to substitute generics in order to reduce
cost to the patients or allow for greater insurance coverage, the effectiveness of dosing and
effect has become paramount. The present invention increases the effectiveness of the individual
components, thereby reducing the number of doses and increasing the therapeutic effectiveness. It
may also be used to decrease dose sizes, thereby reducing costs. In one example of the advantages
of the present invention, an expectorant (e.g., gauifenesin) is provided at lower doses and is made
available immediately for absorption, followed by a lower dose of a decongestant (e.g.,
phenylephrine) which is release slowly over, e.g., about 90 minutes to about 8 hrs. This release
profile makes the product more efficacious since the large amount of expectorant begins to break up
mucus and the time released decongestant provides long acting decongestant activity.



[0012] One embodiment of the present invention is a capsule that includes an expectorant available
for immediate release and a decongestant for extended release. The expectorant may be, e.g.,
gauifenesin that is compressed into a slug of between about 50, 200, 400, 500, 600 or more
milligrams and packaged for release of over 90% of the active within about 90 minutes. The
decongestant comprises a nasal decongestant, e.g., phenylephrine packaged as a sustained release
bead, e.g., from between about 1.5 to 30 mg. The term immediate release is defined as release of
over 90% within about 90 minutes. The decongestant for extended release provides between about 40
to 60% of the decongestant after 90 minutes, between about 50 to 70 percent at between 150 and 210
minutes and wherein between about 60 to 80 percent after 360 minutes.



[0013] In another embodiment, the present invention is a single pharmaceutical composition that
includes an expectorant that is packed for immediate release; and a decongestant that is a nasal
decongestant packed for extended release, wherein the expectorant provides productive coughs in the
short-term and the decongestant provides long-acting decongestant activity.



[0014] In yet another embodiment, the present invention provides a time released phenylephrine that
is formulated to provide maximum effective release over 2-8 hours using a combination of polymers
and/or pharmaceutical glaze. It was found that when the phenylephrine were overcoated with
immediate release gauifenesin the process was not only time consuming (since building up the bead
with gauifenesin had adhesion problems), but also that overcoating of the gauifenesin on the
phenylephrine slowed the release of the phenylephrine to an unacceptable level. Further attempts to
increase adhesion by sustain releasing both actives also resulted in a poor release profile for
gauifenesin. Nevertheless, overcoating the extended release active with an immediate release active
may be used with these or other actives, depending on the actives selected and the desired
efficacy. One embodiment of the present invention includes powder filling the gauifenesin and
extended release phenylephrine into a capsule. The solution provided herein addresses the problems
of dosing, effective pharmacological serum levels and cost. This process also reduces greatly the
already taxed capacity on the bead room since up to about 96% of the active load would not need to
go through the coating process.





 









 








			
	United States Patent Application: 0050152967
	 	Page 7 of 20
	 	 	 




[0015] In one embodiment, the present invention includes a pharmaceutical composition having an
expectorant packaged for release of over 90% within about 90 minutes; and a decongestant packaged
for extended release wherein between about 40 to 60% of the decongestant is available after 90
minutes, between about 50 to 70 percent is available at between 150 and 210 minutes and wherein between
about 60 to 80 percent is available after 360 minutes. In another embodiment, the present invention
is a method of providing a dual-release formulation that includes an expectorant packed for
immediate release in a powder form, a nasal decongestant packed for extended release, e.g.,
phenylephrine, PVP, cellulose and a pharmaceutical glaze, and loading the expectorant and the
decongestant into a capsule. Yet another embodiment is a pharmaceutical composition with an
expectorant (e.g., guaifenesin) packaged for release of over 90% within about 90 minutes and a
nasal decongestant (e.g., phenylephrine HCl) packed for extended release with PVP, microcrystalline
cellulose and a pharmaceutical glaze, wherein between about 40 to 60% of the decongestant is
available after 90 minutes, between about 50 to 70 percent is available at between about 150 and
210 minutes and wherein between about 60 to 80 percent is available after 360 minutes; and one or
more inactive agents.




BRIEF DESCRIPTION OF THE DRAWINGS



[0016] For a more complete understanding of the features and advantages of the present invention,
reference is now made to the detailed description of the invention along with the accompanying
figures and in which:



[0017] FIG. 1 is a graph that shows one embodiment of the present invention for immediate release
guaifenesin and delayed release phenylephrine HCl;



[0018] FIG. 2 is a graph that shows another embodiment of the present invention for immediate
release guaifenesin and delayed release phenylephrine HCl; and



[0019] FIG. 3 is a graph that shows another embodiment of the present invention for immediate
release guaifenesin and delayed release phenylephrine HCl.




DETAILED DESCRIPTION OF THE INVENTION



[0020] While the making and using of various embodiments of the present invention are discussed in
detail below, it should be appreciated that the present invention provides many applicable
inventive concepts which can be embodied in a wide variety of specific contexts. The specific
embodiments discussed herein are merely illustrative of specific ways to make and use the invention
and do not delimit the scope of the invention.



[0021] The present invention is based on the recognition that patients and physicians are looking
to simplify the number of doses that a patient takes, improving the efficacy of drug delivery and
reducing costs. The effectiveness of dosing and effect has become paramount in order to reduce cost
to the patients and allow for greater insurance coverage, while improving patient compliance.




[0022] Definitions



[0023] A number of definitions are provided herein to facilitate an understanding of the present
invention. As used herein, the term “enveloped pharmaceutical” means a capsule, a suppository, a
gel cap, a softgel, a lozenge, a sachet or even a fast dissolving wafer. As used herein the term
“carrier” is used to describe a substance, whether biodegradable or not, that is physiologically
acceptable for human or animal use and may be pharmacologically active or inactive.





 









 








			
	United States Patent Application: 0050152967
	 	Page 8 of 20
	 	 	 




[0024] The term “immediate release” as used herein is used to describe a release profile to effect
delivery of an active as soon as possible, that is, as soon as practically made available to an
animal, whether in active form, as a precursor and/or as a metabolite. Immediate release may also
be defined functionally as the release of over 80 to 90 percent (%) of the active ingredient within about 60, 90, 100 or 120
minutes or less. Immediate release as used herein may also be defined as making the active
ingredient available to the patient or subject regardless of uptake, as some actives may never be
absorbed by the animal. Immediate release formulations of the active on a carrier, such as rolled
or compressed beads, may be formulated such that the surface area is maximized on beads and the
active is exposed immediately. The immediate release formulations may also include effervescing
agents that cause the disintegration of the structure integrity of the active and carrier such that
release of the active is maximized. Various immediate release dosage forms may be designed readily
by one of skill in art to achieve drug delivery to the stomach and small intestine, depending upon
the choice of compression, adhesive materials and/or beading.



[0025] The terms “extended release” and “delayed release” as used herein is used to define a
release profile to effect delivery of an active over an extended period of time, defined herein as
being between about 60 minutes and about 2, 4, 6 or even 8 hours. Extended release may also be
defined functionally as the release of over 80 to 90 percent (%) of the active ingredient after
about 60 minutes and about 2, 4, 6 or even 8 hours. Extended release as used herein may also be
defined as making the active ingredient available to the patient or subject regardless of uptake,
as some actives may never be absorbed by the animal. Various extended release dosage forms may be
designed readily by one of skill in art as disclosed herein to achieve delivery to both the small
and large intestines, to only the small intestine, or to only the large intestine, depending upon
the choice of coating materials and/or coating thickness.



[0026] “Extended release” and “delayed release” formulations may be prepared and delivered so that
release is accomplished at some generally predictable location in the lower intestinal tract more
distal to that which would have been accomplished if there had been no delayed release alterations.
A method for delay of release is, e.g., a coating. Any coatings should be applied to a sufficient
thickness such that the entire coating does not dissolve in the gastrointestinal fluids at pH below
about 5, but does dissolve at pH about 5 and above. It is expected that any anionic polymer
exhibiting a pH-dependent solubility profile can be used as an enteric coating in the practice of
the present invention to achieve delivery to the lower gastrointestinal tract. Polymers and
compatible mixtures thereof may be used to provide the coating for the delayed or the extended
release of active ingredients, and some of their properties, include, but are not limited to:
shellac, also called purified lac, a refined product obtained from the resinous secretion of an
insect. This coating dissolves in media of pH>7.



[0027] The present pharmaceutical composition may also be provided in a variety of dosage forms,
e.g., solution, suspension, cream, ointment, lotion, capsule, caplet, softgel, gelcap, suppository,
enema, elixir, syrup, emulsion, film, granule, gum, insert, jelly, foam, paste, pastille, pellet,
spray, troche, lozenge, disk, magma, poultice, or wafer and the like.



[0028] For gelcap preparations, the pharmaceutical formulation may include oils, e.g.: (1) fixed
oils, such as peanut oil, sesame oil, cottonseed oil, corn oil and olive oil; (2) fatty acids, such
as oleic acid, stearic acid and isostearic acid; and fatty acid esters, such as ethyl oleate,
isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides; (3) alcohols, such
as ethanol, isopropanol, hexadecyl alcohol, glycerol and propylene glycol; (4) glycerol ketals,
such as 2,2-dimethyl-1,3-dioxolane-4-methanol; (5) ethers, such as poly(ethylene glycol) 450; (6)
petroleum hydrocarbons, such as mineral oil and petrolatum; and (7) water, or with mixtures
thereof; with or without the addition of a pharmaceutically suitable surfactant, suspending agent
or emulsifying agent.





 









 








			
	United States Patent Application: 0050152967
	 	Page 9 of 20
	 	 	 




[0029] For oral, buccal, and sublingual administration, the pharmaceutical composition of the
invention may be administered as either solutions or suspensions in the form of gelcaps, caplets,
tablets, capsules or powders. For rectal administration, the compounds of the invention may be administered in the form
of suppositories, ointments, enemas, tablets and creams for release of compound in the intestines,
sigmoid flexure and/or rectum. For example, when making a suppository a beeswax/glycerol
composition may be used to form a body meltable suppository for transrectal or transurethral
delivery.



[0030] It is contemplated that the “immediate release” active may be formulated as, e.g., freeze
dried, rotary dried or spray dried powders; amorphous or crystalline powders; granules,
precipitates or particulates. The immediate release active may be either free-flowing or
compressed. The pharmaceutical formulation may further include, e.g., water, aqueous solvents,
non-protic solvents, protic solvents, hydrophilic solvents, hydrophobic solvents, polar solvents,
non-polar solvent, emollients and/or combinations thereof. Other formulations may include,
optionally, stabilizers, pH modifiers, surfactants, perfumes, astringents, cosmetic foundations,
pigments, dyes, bioavailability modifiers and/or combinations thereof.



[0031] The immediate release actives of the present invention may be processed by agglomeration,
air suspension chilling, air suspension drying, balling, coacervation, coating, comminution,
compression, cryopelletization, encapsulation, extrusion, wet granulation, dry granulation,
homogenization, inclusion complexation, lyophilization, melting, microencapsulation, mixing,
molding, pan coating, solvent dehydration, sonication, spheronization, spray chilling, spray
congealing, spray drying, or other processes known in the art. The extended release actives may be
provided in the form of a minicapsule, a capsule, a tablet, an implant, a troche, a lozenge
(minitablet), a temporary or permanent suspension, a pellet, a bead, a pill, a strip or a sachet.



[0032] The pharmaceutical composition and/or the solid carrier particles may be coated with one or
more enteric coatings, seal coatings, film coatings, barrier coatings, compress coatings, fast
disintegrating coatings, or enzyme degradable coatings. Multiple coatings may be applied for
desired performance. For example, the pharmaceutical composition, e.g., phenylephrine may be mixed
with one or more agents that delay release until the proper pH, gel formation and/or timed-release
polymers and/or additives are provided. Further, some actives may be provided for immediate
release, pulsatile release, controlled release, extended release, delayed release, targeted
release, synchronized release, or targeted delayed release. For release/absorption control, solid
carriers can be made of various component types and levels or thicknesses of coats, with or without
an active ingredient. Such diverse solid carriers can be blended in a dosage form to achieve a
desired performance. The compositions may be formulated for oral, nasal, buccal, ocular, urethral,
transmucosal, vaginal, topical or rectal delivery, although oral delivery is used mostly.



[0033] For example, suitable mixed or extended release polymers for use with the present invention
include but are not limited to synthetic polymers such as poly(ethylene glycol), poly(ethylene
oxide), partially or fully hydrolyzed poly(vinyl alcohol), poly(vinylpyrrolidone),
poly(ethyloxazoline), poly (ethylene oxide)-co-poly(propylene oxide) block copolymers (poloxamers
and meroxapols), poloxamines, carboxymethyl cellulose, and hydroxyalkylated celluloses such as
hydroxyethyl cellulose and methylhydroxypropyl cellulose, and natural polymers such as
polypeptides, polysaccharides or carbohydrates such as Ficoll.RTM., polysucrose, hyaluronic acid,
dextran, heparan sulfate, chondroitin sulfate, heparin, or alginate, and proteins such as gelatin,
collagen, albumin, or ovalbumin or copolymers or blends thereof. As used herein, “celluloses”
includes cellulose and derivatives of the types described above; “dextran” includes dextran and
similar derivatives thereof.





 









 








			
	United States Patent Application: 0050152967
	 	Page 10 of 20
	 	 	 




[0034] The blend of polymers may form a hydrogel or matrix using a material such as a carbohydrate
polymer or polysaccharide (e.g., hyaluronic acid) in the presence of an initiator such as mono-,
di- or trivalent cations or anions in water, a radical, or a photoinitiator. The polymer blend may
be intrinsically biodegradable, biocompatible, or of sufficiently low molecular weight to allow
excretion. Some components of the polymer blend exhibit little to no ability to biologically degrade. Where there
are two or more water-soluble polymer blocks joined by other groups, the joining groups may include
biodegradable linkages, polymerizable linkages, or both.



[0035] Other polymer formulations for use with the present invention include scaffolds prepared
with the polymer of the present invention and one or more bioactive compounds or active species so
that the polymer or scaffold becomes a microcarrier for one or more active species. The active
species may be incorporated into the polymer or polymer solution (e.g., scaffold) or may be
attached to its surface using techniques readily apparent to those skilled in the art. In some
instances, it may be preferred to incorporate or attach a precursor of the active agent, e.g., an
inactive version of the species that can then be activated to the active species as needed and
required. The active species may be a drug or other biologically active compound; thus, the
scaffold may be a microcarrier for the delivery of drugs or other biologically active compounds
when used in the body. Examples of biologically active compounds are proteins, peptides,
polysaccharides, nucleic acids, oligonucleotides, natural and synthetic organic or inorganic
molecules, and those biologic molecules used for therapeutic, prophylactic or diagnostic purposes.
Drugs may include antibiotics, antivirals, chemotherapeutic agents, anti-angiogenic agents,
hormones, anti-inflammatory agents, drugs having an effect on vascular flow or that are effective
against one or more diseases, and combinations thereof.



[0036] When formulated as a capsule, the capsule can be a hard or soft gelatin capsule, a starch
capsule, or a cellulosic capsule. Although not limited to capsules, such dosage forms may be
further coated with, for example, a seal coating, an enteric coating, an extended release coating,
or a targeted delayed release coating. For example, the capsule may include one or more actives in
powder form. The term “powder” as used herein include, e.g., true powder, as well as truly
crystalline materials, microgranulated, nanosprayed, nanoprecipitated, microprecipitated and/or
granulated materials, agglomerates, adsorbates and the like. In addition, when these powders are
coated, the coating contemplated is a rapid release coating. For immediate release of an active,
suitable coatings (if any) will dissolve, disintegrate and/or become sufficiently porous to allow
the full release and dissolution of the coated drug in a manner consistent with the administration
of the same drug in a completely uncoated fashion. Certainly, the use of these “coated powders”
should not alter the dissolution rates of the drug in the digestive tract by more than an hour and
preferably by less than half an hour.



[0037] Dosage forms of the compositions of the present invention can also be formulated as enteric
coated delayed release oral dosage forms, i.e., as an oral dosage form of a pharmaceutical
composition as described herein that uses an enteric coating to effect release in the lower
gastrointestinal tract. The enteric coated dosage form may be a compressed or molded or extruded
tablet/mold (coated or uncoated) containing granules, pellets, beads or particles of the active
ingredient and/or other composition components, which are themselves coated or uncoated. The
enteric coated oral dosage form may also be a capsule (coated or uncoated) containing pellets,
beads or granules of the solid carrier or the composition, which are themselves coated or uncoated.



[0038] The coating may also contain a plasticizer and possibly other coating excipients such as
colorants, talc, and/or magnesium stearate, which are well known in the art. Suitable plasticizers
include: triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate
(Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate,
acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. In
particular, anionic carboxylic acrylic polymers





 









 








			
	United States Patent Application: 0050152967
	 	Page 11 of 20
	 	 	 




usually will contain 10-25% by weight of a plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin.
Conventional coating techniques such as spray or pan coating are employed to apply coatings. The
coating thickness must be sufficient to ensure that the oral dosage form remains intact until the
desired site of topical delivery in the lower intestinal tract is reached.



[0039] Colorants, detackifiers, surfactants, antifoaming agents, lubricants, stabilizers such as
hydroxy propyl cellulose, acid/base may be added to the coatings besides plasticizers to solubilize
or disperse the coating material, and to improve coating performance and the coated product.



[0040] Immediate release coating of solid carriers is commonly used to improve product elegance as
well as for a moisture barrier, and taste and odor masking. Rapid breakdown of the film in gastric
media is important, leading to effective disintegration and dissolution. Eudragit RD100 (Rohm) is
an example of such a coating. It is a combination of a water insoluble cationic methacrylate
copolymer with a water-soluble cellulose ether. In powder form, it is readily dispensable into an
easily sprayable suspension that dries to leave a smooth film. Such films rapidly disintegrate in
aqueous media at a rate that is independent of pH and film thickness.



[0041] Actives. Decongestants useful with the present invention (along with a salt form) are
phenylephrine (bitartrate, tannate, HBr, HCl), phenylpropanolamine (HCl) and pseudoephedrine (HCl).
Furthermore, a number of herbal and/or natural decongestants are known in the art, all of which may
be used with the present invention.



[0042] Expectorants for use with the present invention include, e.g., guaifenesin, terpin hydrate,
(glyceryl guaiacolate), potassium (iodide, citrate) and potassium guaicolsulfonate. Other
expectorants, whether individual ingredients or combinations of ingredients may be used with the
present invention. Furthermore, a number of herbal and/or natural expectorants are known in the
art, all of which may be used with the present invention, e.g., Oregano Leaf Extract 25-500 mg
(which may be a liquid extract), Red Clover 25-500 mg, Buckthorn Root 25-500 mg, or Fenugreek
25-500 mg, or mixtures thereof.



[0043] Examples of antihistamines for use with the present invention (e.g., in salt form) are
chlorpheniramine (maleate), brompheniramine (maleate), dexchlorpheniramine (maleate),
dexbrompheniramine (maleate), triprolidine (HCl), diphenhydramine (HCl), doxylamine (succinate),
tripelennamine (HCl), cyproheptatine (HCl), bromodiphenhydramine (HCl), phenindamine (tartrate),
pyrilamine (maleate, tannate) and azatadine (maleate). Antitussives that may be used with the
present invention (with salt form) include: caramiphen (edisylate), dextromethorphan (HBr) and
codeine (phosphate, sulfate). A number of herbal and/or natural antihistamines are known in the
art, all of which may be used with the present invention.



[0044] Other actives may also be included with the present invention, e.g., non-steroidal
anti-inflammatory drugs (NSAIDs) such as propionic acid derivatives; acetic acid derivatives;
fenamic acid derivatives; biphenylcarboxylic acid derivatives; and oxicams. Examples of propionic
acid derivatives include: ibuprofen, naproxen, ketoprofen, flurbiprofen, fenoprofen, suprofen,
fenbufen, and fluprofen may be mentioned as preferred compounds. Acetic acid derivatives include:
tolmetin sodium, zomepirac, sulindac and indomethacin. Fenamic acid derivatives include: mefenamic
acid and meclofenamate sodium. Diflunisal and flufenisal are biphenylcarboxylic acid derivatives,
while oxicams include piroxicam, sudoxicam and isoxicam. Other analgesics for use with the present
invention include acetaminophen and phenacetin.



[0045] Those skilled in the art will appreciate that any of the foregoing compounds may be used in
the form of their pharmaceutically acceptable salt forms, e.g.—carboxylic acids with potassium or
sodium




 









 








			
	United States Patent Application: 0050152967
	 	Page 12 of 20
	 	 	 




counter-ions, and the like. In one example of the present invention, an expectorant (e.g.,
Gauifenesin DC) is provided at lower doses and is made available immediately for absorption,
followed by a lower dose of a decongestant (e.g., phenylephrine) which is release slowly over,
e.g., about 1 to 8 hrs. This release profile makes the product more efficacious since the large
amount of expectorant begins to break up mucus prior to the time the decongestant is released to
provide long acting decongestant activity after mucus breakdown has begun. Generally, guaifenesin is present in amounts of about 10 to about 600
milligrams per capsule. Guaifenesin may be present in amounts of 100, 150, 200, 300, 400, 440, 500
or even 600 or more milligrams per capsule. In one example, guaifenesin is present in amounts of
about 100 to about 200 milligrams per capsule, with half or less of that amount used in a pediatric
form of the formulation.



[0046] In one example, 400 milligrams of gauifenesin are included as an active for immediate
release. Guaifenesin is an expectorant that increases the output of phlegm (sputum) and bronchial
secretions by reducing adhesiveness and surface tension. The increased flow of less viscous
secretions promotes cilliary action and facilitates the removal of mucus. Hence, expectorants such
as guaifenesin change a dry, unproductive cough to one that is more productive and less frequent.
Guaifenesin, known chemically as 3(2-methoxyphenoxy)-1,2-propanediol, is a crystalline powder
soluble in water and alcohol. It is indicated in the USP Drug information as an expectorant for the
symptomatic relief of cough due to colds and minor upper respiratory infections.



[0047] Phenylephrine may be present in amounts of between about 15 and about 60 milligrams per
capsule. Phenylephrine is generally in amounts of about 5 to about 30 milligrams per capsule, with
half or less of that amount used in a pediatric form of the formulation. In one example of the
present invention, phenylephrine is provided in the amount of about 15 mg for extended release.
Phenylephrine hydrochloride is an orally effective nasal decongestant. Chemically it is
(S)-3-hydroxy-.alpha. [(methylamino) methyl]benzenemethanol hydrochloride. Phenylepherine is a
synthetic, optically active sympathomimetic amine that has one hydroxyl group on the benzene ring.
The hydroxyl group is placed in the position meta to the aliphatic side chain. The meta position
affords optimal activity and phenylepherine (neo-synephrine) replaced an older preparation,
synephrine, in which the hydroxyl was in the para position. Phenylephrine hydrochloride is
available in the form of the levorotatory isomer, a white, odorless, non-hygroscopic, crystalline
compound possessing a bitter taste. Phenylephrine hydrochloride has a melting point of 140-145
degrees C and is freely soluble in water and alcohol. Decongestant compounds in the form of their
free bases as well as their salts, e.g., hydrochloride, citrate, maleate, tannate, etc., are well
known.



[0048] Excipients for use with the present invention are well known to those of skill in the art
and include humectants such as glycerin and propylene glycol, preservatives such as sodium benzoate
and paraben, sweeteners such as sodium saccharin, corn syrup and sorbitol solutions, menthol and
various flavoring and coloring agents. The pharmaceutically active compounds and excipients for
human use should be of N.F. or U.S.P. grade.



[0049] Sugar spheres may be used as inert cores in capsule and tablet formulations particularly
multiparticulate sustained release formulations and are provided in amounts sufficient to accept
the active ingredient for extended release, e.g., phenylephrine. Sugar spheres are generally of
relatively uniform diameter and contain 62.5%-91.5% sucrose with the remainder being starch.



[0050] Pharmaceutical Glaze: (4.5 mg) Shellac is a natural occurring material, consisting of a
complex mixture of constituents. The main component of shellac (.about.95%) is a resin that upon
mild basic hydrolysis gives a mixture of compounds of high plasticity. Shellac is used extensively
in the pharmaceutical industry as a film coating agent for beads and tablets.





 









 








			
	United States Patent Application: 0050152967
	 	Page 13 of 20
	 	 	 




[0051] Substrate(s) for use with the present invention may be a powder or a multiparticulate, such
as a granule, a pellet, a bead, a spherule, a beadlet, a microcapsule, a millisphere, a
nanocapsule, a nanosphere, a microsphere, a platelet, a minitablet, a tablet or a capsule. A powder
may be a finely divided (milled, micronized, nanosized, precipitated, sprayed) to form of an active
ingredient or additive molecular aggregates or a compound aggregate of multiple components or a
physical mixture of aggregates of an active ingredient and/or additives. Such substrates may be
formed of various materials known in the art, such as, for example: sugars, such as lactose, sucrose or dextrose; polysaccharides, such as
maltodextrin or dextrates; starches; cellulosics, such as microcrystalline cellulose or
microcrystalline cellulose/sodium carboxymethyl cellulose; inorganics, such as dicalcium phosphate,
hydroxyapitate, tricalcium phosphate, talc, or titania; and polyols, such as mannitol, xylitol,
sorbitol or cyclodextrin.



[0052] It should be emphasized that a substrate need not be a solid material, although often it
will be a solid. For example, the encapsulation coat on the substrate may act as a solid “shell”
surrounding and encapsulating a liquid, semi-liquid, powder or other substrate material. Such
substrates are also within the scope of the present invention, as it is ultimately the carrier, of
which the substrate is a part, which must be a solid.



[0053] Excipients. Solid pharmaceutical compositions may include optionally one or more additives,
sometimes referred to as excipients or additives. The excipients may be contained in an
encapsulation coat in compositions, which include an encapsulation coat, or can be part of the
solid carrier, such as coated to an encapsulation coat, or contained within the components forming
the solid carrier. Alternatively, the excipients can be contained in the pharmaceutical composition
but not part of the solid carrier itself.



[0054] Suitable excipients are those used commonly to facilitate the processes involving the
preparation of the solid carrier, the encapsulation coating, or the pharmaceutical dosage form.
These processes include agglomeration, air suspension chilling, air suspension drying, balling,
coacervation, comminution, compression, pelletization, cryopelletization, extrusion, granulation,
homogenization, inclusion complexation, lyophilization, nanoencapsulation, melting, mixing,
molding, pan coating, solvent dehydration, sonication, spheronization, spray chilling, spray
congealing, spray drying, or other processes known in the art. The excipients may also be
pre-coated or encapsulated, as are well known in the art.



[0055] The pharmaceutical compositions of the present invention may include optionally one or more
solubilizers, i.e., additives to increase the solubility of the pharmaceutical active ingredient or
other composition components in the solid carrier. It has been recognized by the present inventors
that guaifenesin, in fact, acts as a solubilizer for phenylephrine, and is used as such in the
examples provided herein. Other solubilizers are known in the art. Mixtures of solubilizers are
also within the scope of the invention and are readily available from standard commercial sources.



[0056] The amount of solubilizer that may be included in compositions of the present invention is
not particularly limited. Of course, when such compositions are administered to a patient, the
amount of a given solubilizer is limited to a bioacceptable amount, which is readily determined by
one of skill in the art. In some circumstances, it may be advantageous to include amounts of
solubilizers far in excess of bioacceptable amounts, for example, to maximize the concentration of
active ingredient, with excess solubilizer removed prior to providing the composition to a patient
using conventional techniques, such as distillation or evaporation.



[0057] Other additives conventionally used in pharmaceutical compositions may be included, which
are well known in the art. Such additives include, e.g.,: anti-adherents (anti-sticking agents,
glidants, flow promoters, lubricants) such as talc, magnesium stearate, fumed silica), micronized
silica, polyethylene





 









 








			
	United States Patent Application: 0050152967
	 	Page 14 of 20
	 	 	 




glycols, surfactants, waxes, stearic acid, stearic acid salts, stearic acid derivatives, starch, hydrogenated vegetable oils, sodium benzoate, sodium acetate, leucine,
PEG-4000 and magnesium lauryl sulfate.



[0058] Other additives include, binders (adhesives), i.e., agents that impart cohesive properties
to powdered materials through particle-particle bonding, such as matrix binders (dry starch, dry
sugars), film binders (polyvinylpyrrolidone (PVP), starch paste, celluloses, bentonite and
sucrose), and chemical binders (polymeric cellulose derivatives, such as carboxy methyl cellulose,
HPC and HPMC; sugar syrups; corn syrup; water soluble polysaccharides such as acacia, tragacanth, guar and alginates; gelatin;
gelatin hydrolysate; agar; sucrose; dextrose; and non-cellulosic binders, such as PVP, PEG, vinyl
pyrrolidone copolymers, pregelatinized starch, sorbitol, and glucose).



[0059] For certain actives it may be useful to provide buffering agents (or bufferants), where the
acid is a pharmaceutically acceptable acid, such as hydrochloric acid, hydrobromic acid, hydriodic
acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, acetic acid, acrylic acid, adipic
acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid,
butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid,
hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic
acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid,
stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid
and uric acid, and where the base is a pharmaceutically acceptable base, such as an amino acid, an
amino acid ester, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen
carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate,
synthetic aluminum silicate, synthetic hydrotalcite, magnesium aluminum hydroxide,
diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine,
triisopropanolamine, or a salt of a pharmaceutically acceptable cation and acetic acid, acrylic
acid, adipic acid, alginic acid, alkanesulfonic acid, an amino acid, ascorbic acid, benzoic acid,
boric acid, butyric acid, carbonic acid, citric acid, a fatty acid, formic acid, fumaric acid,
gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic
acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic
acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic
acid, and uric acid.



[0060] In some formulations additives may also include: chelating agents (such as EDTA and EDTA
salts); colorants or opaquants (such as titanium dioxide, food dyes, lakes, natural vegetable
colorants, iron oxides, silicates, sulfates, magnesium hydroxide and aluminum hydroxide); coolants
(e.g., trichloroethane, trichloroethylene, dichloromethane, fluorotrichloromethane);
cryoprotectants (such as trehelose, phosphates, citric acid, tartaric acid, gelatin, dextran and
mannitol); and diluents or fillers (such as lactose, mannitol, talc, magnesium stearate, sodium
chloride, potassium chloride, citric acid, spray-dried lactose, hydrolyzed starches, directly
compressible starch, microcrystalline cellulose, cellulosics, sorbitol, sucrose, sucrose-based
materials, calcium sulfate, dibasic calcium phosphate and dextrose).



[0061] Yet other additives may include disintegrants or super disintegrants; hydrogen bonding
agents, such as magnesium oxide; flavorants or desensitizers; ion-exchange resins, such as
styrene/divinyl benzene copolymers, and quaternary ammonium compounds; plasticizers, such as
polyethylene glycol, citrate esters (e.g., triethyl citrate, acetyl triethyl citrate,
acetyltributyl citrate), acetylated monoglycerides, glycerin, triacetin, propylene glycol,
phthalate esters (e.g., diethyl phthalate, dibutyl phthalate), castor oil, sorbitol and dibutyl
seccate; and preservatives, such as ascorbic acid, boric acid, sorbic acid, benzoic acid, and salts
thereof, parabens, phenols, benzyl alcohol, and quaternary ammonium compounds.



[0062] It should be appreciated that there is considerable overlap between the above-listed
additives in common usage, since a given additive is often classified differently by different
practitioners in the field, or is commonly used for any of several different functions. Thus, the
above-listed additives should be




 









 








			
	United States Patent Application: 0050152967
	 	Page 15 of 20
	 	 	 




taken as merely exemplary, and not limiting, of the types of additives that can be included in compositions of the present invention. The amounts of such
additives may be readily determined by one skilled in the art, according to the particular
properties desired.



[0063] The compositions of the present invention may be prepared by a variety of processes to apply
an encapsulation coat onto a substrate or to form a substrate-free solid carrier such as a
multiparticulate or a powder. The most commonly used coating and pelletization processes include:
balling, spheronization, extrusion, spray congealing, spray drying, pan coating, fluidized bed coating, melt extrusion,
crystallization, cryopelletization, nanoencapsulation, coacervation, spraying, precipitation, etc.
One skilled in the art will recognize that appropriate additives may also be introduced to the
composition or during the processes to facilitate the preparation of the solid carrier or the
dosage forms, depending on the need of the individual process.



[0064] A coating process frequently involves spraying a coating solution onto a substrate. The
coating solution can be a molten solution of the encapsulation coat composition free of a
dispersing medium. The coating solution may also be prepared by solubilizing or suspending the
composition of the encapsulation coat in an aqueous medium, an organic solvent, a supercritical
fluid, or a mixture thereof. At the end of the coating process, the residual dispersing medium can
be further removed to a desirable level using appropriate drying processes, such as vacuum
evaporation, heating, freeze drying, etc.



[0065] A pelletization process typically involves preparing a molten solution of the composition of
the solid carrier or a dispersion of the composition of the solid carrier solubilized or suspended
in an aqueous medium, an organic solvent, a supercritical fluid, or a mixture thereof. Such
solution or dispersion is then passed through a certain opening to achieve the desired shape, size,
and other properties. Similarly, appropriate drying processes may be used to control the level of
the residual dispersing medium, if necessary. The processes, the combination of the processes
and/or the modification of the processes described above are well known in the art. Some of the
processes are briefly described herein for reference.



[0066] Balling. In a broad sense, pellets are very much like granules and bead; the techniques for
producing pellets may also produce granules, beads, etc. Pellets, granules or beads are formed with
the aid of, e.g., a pelletizer, a spheronizer or an extruder. The pelletizer, spheronizer or
extruder is able to form approximately spherical bodies from a mass of finely divided particles
continuously, by a rolling or tumbling action on a flat or curved surface with the addition of a
liquid.



[0067] Pelletizers are generally classified based on the angle of their axis as a horizontal drum
or an inclined dish pelletizer. Rotary fluidized granulators may also be used for pelletization. A
standard fluidized drier bowl may be replaced with a rotating plate as an air distributor. For
granulation, a binder liquid is sprayed from via one or two binary nozzles located axially to the
rotational movement of the powder bed. The granulation results in rounding of the granules to
approximately spherical pellets. Such balling or agitation techniques are generally influenced by
operating conditions, e.g., the bridging/binding liquid requirements, the residence time of the
material in the pelletizer, the speed and angle of inclination of the pelletizer, the amount of
material fed to the pelletizer and the choice and levels of binder, etc. Those skilled in the art
may adjust readily such factors to produce a satisfactory product.



[0068] The choice of binder for a given application may also be determined readily by those skilled
in the art. Generally, the binder must be capable of wetting the surfaces of the particle being
pelletized or granulated. In general, binders must have sufficient wet strength to allow
agglomerates to be handled and sufficient dry strength to make them suitable for their intended
purposes. Each process, however, makes use of a different system of forces and may require a
different agglomerate strength. The final selection of




 









 








			
	United States Patent Application: 0050152967
	 	Page 16 of 20
	 	 	 




the binder is made generally based on the type of equipment used. Factors that affect the equipment and binder choices include: the size and
size distribution of pellets, bulk density, strength and flow properties. Other factors that affect
the performance of the pellets, which may be adjusted by one skilled in the art by the inclusion of
additives, choice of equipment and processing conditions.




EXAMPLES



[0069] Example 1



[0070] The amount of active dissolution over time, e.g., guaifenesin and/or phenylephrine in the
tablets or capsules disclosed herein below may be tested as follows. Briefly, in vitro guaifenesin
or phenylephrine release may be determined using an acid/base dissolution bath, e.g., a standard
USP 23/NF Drug Release Apparatus. Dissolution vessels of a USP calibrated dissolution bath,
equipped with shafts and paddles, are filled with 675 ml of 0.1N hydrochloric acid at 37.0 degrees
Centigrade. The bath and vessels are maintained at a temperature of 37.0.+-.0.5 degrees Centigrade
throughout a standard 7 hour dissolution test. The paddles were set to rotate at 50 RPM and slowly
lowered into the vessels. One tablet or capsule is dropped into each vessel.



[0071] At the testing intervals, e.g., 1 minute, 10, 10, 30, 45, 60 or 90 minutes, 2, 3, 4, 6, 7, 9
or 12 hour testing intervals, an aliquot, e.g., 5 mls of dissolution solution is withdrawn from
each vessel, filtered (e.g., through a 10-22 micron polyethylene filter) and tested using an HPLC.
To stop the dissolution a strong base may be added to the sample, e.g., 0.2M sodium phosphate
tribasic to increase the pH of the solution to about 6.8. The percent dissolution is determined
using HPLC.



[0072] Capsule shells and process: 7.5% phenylephrine immediate release beads where used as
starting material. A portion of this lot was transferred to a rotating pan. Phenylephrine was added
to the beads using of pharmaceutical glaze. The beads were then allowed to roll and cure for 6
hours before sustained release coating was added. In-order to develop the product, four different
levels of sustained release coating amounts were added. In one example, 10.93 Kgs of phenylephrine
were added to the beads using 4.32 Kgs of pharmaceutical glaze. The beads were then allowed to roll
and cure for 6 hours before sustained release coating was added.



[0073] In order to develop the product four different levels of sustained release coating amounts
were added. The first was 7.15 kg’s of SR mix #1 and 4.96 kg’s of pharmaceutical glaze. Once this
loading was complete 5.0 kg’s were removed for drying and testing. The second load consisted of
4.75 kg’s of SR mix #1 and 2.68 kg’s of pharmaceutical glaze. Again 5.0 kg’s of beaded material was
removed for drying at 40.degree. C. and testing. The third load consisted of 5.92 kg’s SR mix #1
and 3.43 kg’s of glaze. After application another 5.0 kg’s of beaded material was removed from the
pan for drying at 40.degree. C. and testing. The fourth and final load consisted of 7.78 kg’s of SR
mix #1 and 4.56 kg’s of pharmaceutical glaze. The entire pan was allowed to roll and cure under
heat lamps for 6 hours before sampling for study.



[0074] Table 1 is a list of all theoretical percentages and actual assay results for the, above,
described material.



1 SR Mix Theoretical PEH % Actual PEH % Diss. 90 min, 3 hr, 6 hr #1 21.6% 20.8% 4.6%, 18.6%, 59.3%
#2 19.8% 19.3% 0.2%, 0.8%, 11.0% #3 17.8% 17.3% 0.16%, 0.4%, 2.7% #4 15.5% 15.4% 0.6%, 0.8%, 2.6%



[0075] Based on assay and dissolution profile load #1 was selected for use in further development.
The moisture content in load #4 may be higher than those loads dried in the tray drier. This may
have






 









 








			
	United States Patent Application: 0050152967
	 	Page 17 of 20
	 	 	 




contributed to why load #3 and #4 have essentially the same dissolution profile despite the
increased SR mix. The gauifenesin DC 95% was compressed into slugs using a bb2 type tablet press
with standard 1/4” cup tooling. GRA001 was pressed into slugs weighing 220 mg each. Capsules were
filled using 75 mg of Load #1 beads (15 mg phenylephrine). Then two 220 mg slugs of Gauifenesin DC.
These capsule were then placed in a 75 cc bottle and conditioned at 35.degree. C. for 24 hours.
Dessicant was then added. The material was capped and the induction seal was activated. The
material was placed on accelerated stability.



[0076] Dissolution: The present inventors found that the dissolution rate of the phenylephrine is
accelerated when combined with Gauifenesin DC. Due to this effect the testing of the dissolution
rate is achieved by first making a mock-up of the finished product. By doing so the suitability of the
phenylephrine beads was determined more accurately. Direct specifications for dissolution were
determined once data was collected to accurately predict this rate change.



[0077] Stability: Capsules were studied for stability. Accelerated stability indicates that the
product is stable. Gauifenesin DC released 100% immediately with stable potency. The phenylephrine
exhibited a first order release profile consistent with an 8 hour product and was consistent from
month to month. Results are summarized below in Table 2.



2 Lot # Count Container Closure Desiccant DEV 191 100 CON014 CLO452 DES101 GFN PEH Diss. PEH Time
Diss. 90 min/Assay 90 min/3 hr/6 hr Assay Initial 103.7%/99.8% 30.1%/43.5%/70.5% 105.2% 4 week
103.5%/98.5% 33.8%/49.4%/78.7% 105.7% 6 week 104.2%/98.7% 20.8%/38.3%/70.6% 100.4% 8 week
102.6%/99.5% 26.8%/44.5%/78.7% 107.3% 10 week 103.9%/99.4% 31.5%/46.2%/73.1% 97.8% 12 week
104.1%/98.8% 33.7%/51.0%/85.5% 107.7%



[0078] Equipment: Bosch GKF 700 and GKF 2000 machines were used for the pellet and powder
functions. The GKF 700 runs the 400/15 product that requires the beads to be dosed prior to powder.
The GKF 2000 runs product 200/7.5 and is capable of filling powder followed by beads. The reason
for this is that the 400/15 product is in a size 0 elongated capsule that is overfilled. If the
beads are added after the powder slug they will tend to roll off the slug during capsule closure.
This would result in poor closure and poor content uniformity.




Example 2



[0079] Phenylephrine for delayed release may be prepared using pharmaceutical glaze,
polyvinylpyrrolidone and/or microcrystalline cellulose in combination with one or more inactive
agents. For example, the phenylephrine may be allowed to roll and cure for 1-6 hours in the
presence of the polyvinylpyrolidone and microcrystalline cellulose. Optionally, a sustained release
coating may be added to infuse and/or coat the active-polymer (phenylephrine-polyvinylpyrrolidone).
Different levels of sustained release coating amounts may be added, with or without intervening
layers of active and/or polymer. In one example, 10.93 Kgs of phenylephrine may be added to
polyvinylpyrrolidone and pharmaceutical glaze. The phenylephrine-polyvinylpyrrolidone is allowed to
roll and cure for 1-6 hours before sustained release coating (pharmaceutical glaze) is added.



[0080] Table 3 is a list of all percentages of actual assay results for the above described
formulation for extended release phenylephrine.



3 PHFB DVR II Phenylephrine 90 min 3 hours 6 hours ELA 30 mg 41.5 58.0 80.3 GFD 30 mg 57.6 69.9
86.4 EER 30 mg 36.2 51.2 74.6





 









 








			
	United States Patent Application: 0050152967
	 	Page 18 of 20
	 	 	 




[0081] Table 4 shows the release profile for guaifenesin immediate release.



4 PHFB DVR II Guaifenesin 90 min 3 hours 6 hours ELA 400 mg 100.9 N/A N/A GFD 400 mg 99.7 N/A N/A
EER 400 mg 101.4 N/A N/A



[0082] The results from the formulations are summarized in FIGS. 1-3, which demonstrate the
percentage release of the three different formulations and packaging of actives over time. The
gauifenesin DC 95% may be compressed into slugs using, e.g., a bb2 type tablet press with standard
1/4” cup tooling. GRA001 was pressed into slugs weighing 220 mg each. Capsules may be filled with
phenylephrine and two 220 mg slugs of Gauifenesin DC. These capsules are placed in a 75 cc bottle and conditioned at 35.degree.
C. for 24 hours. Dessicant was then added. The material was capped and the induction seal was
activated. The material was placed on accelerated stability.



[0083] Dissolution: The present inventors found that the dissolution rate of the phenylephrine is
accelerated when combined with Gauifenesin DC. Due to this effect the testing of the dissolution
rate is achieved by first making a mock-up of the finished product. By doing so the suitability of
the phenylephrine was determined more accurately. Direct specifications for dissolution were
determined once data was collected to accurately predict this rate change.



[0084] Stability: Capsules were studied for stability. Accelerated stability indicates that the
product is stable. Gauifenesin DC released 100% immediately with stable potency. The phenylephrine
exhibited a first order release profile consistent with an 8 hour product and was consistent from
month to month. Results are summarized below.



[0085] Formula I. A batch of immediate release expectorant, e.g., guaifenesin for use with the
enveloped formulation was prepared with the following components:



5 Components Weight Guaifenesin DC 421 mg Talc 5 mg



[0086] Formula II. A batch of immediate release guaifenesin for use with the enveloped formulation
was prepared with the following components:



6 Components Weight Guaifenesin DC 632 mg Talc 3 mg Stearic Acid 2 mg



[0087] Formula III. A batch of immediate release guaifenesin for use with the enveloped formulation
was prepared with the following components:



7 Components Weight Guaifenesin DC 211 mg Talc 3 mg Magnesium Stearate 2 mg



[0088] Formula IV. A batch of immediate release guaifenesin for use with the enveloped formulation
was prepared with the following components:



8 Components Weight Guaifenesin DC 421 mg Magnesium Stearate 3 mg Ludipress 50 mg



[0089] Formula IV. A batch of effervescent expectorant for immediate release, e.g., guaifenesin for
use with the enveloped formulation was prepared with the following components:



9 Components Weight Guaifenesin DC 421 mg Talc 5 mg Sodium bicarbonate 25 mg





 









 








			
	United States Patent Application: 0050152967
	 	Page 19 of 20
	 	 	 




[0090] When combining the first and the second active, these may be formulated as follows. A
capsule for immediate release of a first active and extended release of a second active in an
enveloped formulation, in a single capsule:



10 First Active Weight Second Active Weight Guaifenesin DC 421 mg Phenylephrine 15 mg Talc 5 mg
Bead 44 mg Lacquer 6 mg Talc 5 mg Calcium Stearate 5 mg Capsule 1



[0091] A formulation for immediate release of a first active and extended release of a second
active in an enveloped formulation, in a gelcap:



11 First
Active Weight Second Active Weight Guaifenesin DC 421 mg Phenylephrine 15 mg Talc 0 mg Bead 44 mg Lacquer 6 mg Talc 5 mg Calcium Stearate 5 mg Gelcap 1



[0092] A formulation for immediate release of a first active and extended release of a second
active in an enveloped formulation, in a suppository:



12 First Active Weight Second Active Weight Guaifenesin DC 421 mg Phenylephrine 5 mg Talc 5 mg Bead
15 mg Lacquer 2 mg Talc 1.5 mg Calcium Stearate 1.5 mg Stearic Acid 2 mg beeswax/glycerol 1- 2 gr



[0093] An effervescent tablet for immediate release of a first active and extended release of a
second active in an enveloped formulation, in an effervescent tablet:



13 First Effervescent Active Weight Second Active Minicap Weight Guaifenesin DC 421 mg
Phenylephrine 15 mg Talc 5 mg Bead 44 mg Lacquer 6 mg Talc 5 mg Calcium Stearate 5 mg Monosodium
citrate 10 mg Sodium bicarbonate 10 mg



[0094] For immediate release of a first active and extended release of a second active in an
enveloped formulation one may add the following ingredients, in a caplet:



14 First Active Weight Second Active Weight Guaifenesin DC 421 mg Phenylephrine 15 mg Talc 3 mg
Bead 44 mg Lacquer 6 mg Talc 5 mg Calcium Stearate 5 mg



[0095] When combining the first active and the decongestant, these may be formulated as follows. A
capsule for immediate release of an expectorant and extended release of a decongestant in an
enveloped formulation, in a single capsule:



15 Expectorant Weight Decongestant Weight Guaifenesin DC 421 mg Phenylephrine HCl 30 mg Talc 5 mg
PVPyrrole 44 mg Povidone 6 mg Talc 5 mg Calcium Stearate 5 mg Capsule 1



[0096] When combining the first active and the decongestant, these may be formulated as follows. A
capsule for immediate release of an expectorant and extended release of a decongestant in an
enveloped formulation, in a single capsule:



16 Expectorant Weight Decongestant Weight Guaifenesin DC 421 mg Phenylephrine HCl 30 mg Talc 5 mg
PVPyrrole 44 mg Povidone 6 mg Microcrystalline Cellulose 5 mg Magnesium Stearate 5 mg Gelatin
Capsule 1



[0097] A formulation for immediate release of an expectorant and extended release of a decongestant
in an enveloped formulation, in a gelcap:





 









 








			
	United States Patent Application: 0050152967
	 	Page 20 of 20
	 	 	 




17 Expectorant Weight Decongestant Weight Guaifenesin DC 421 mg Phenylephrine 30 mg
Microcrystalline Cellulose 44 mg Magnesium Stearate 5 mg Gelcap 1



[0098] A formulation for immediate release of an expectorant and extended release of a decongestant
in an enveloped formulation, in a suppository:



18 Expectorant Weight Decongestant Weight Guaifenesin DC 421 mg Phenylephrine 15 mg Talc 5 mg
PVPyrrole 44 mg Povidone 6 mg Microcrystalline Cellulose 5 mg Magnesium Stearate 5 mg Stearic Acid
2 mg beeswax/glycerol 1-2 gr



[0099] An effervescent tablet for immediate release of an expectorant and extended release of a decongestant in an enveloped formulation, in an effervescent tablet:



19 First Effervescent Active Weight Decongestant Minicap Weight Guaifenesin DC 421 mg Phenylephrine
15 mg Talc 5 mg PVPyrrole 44 mg Povidone 6 mg Microcrystalline Cellulose 5 mg Magnesium Stearate 5
mg Monosodium citrate 10 mg Sodium bicarbonate 10 mg



[0100] For immediate release of an expectorant and extended release of a decongestant in an
enveloped formulation one may add the following ingredients, in a caplet:



20 Expectorant Weight Decongestant Weight Guaifenesin DC 421 mg Phenylephrine 15 mg Talc 3 mg
PVPyrrole 44 mg Povidone 6 mg Microcrystalline Cellulose 5 mg Magnesium Stearate 5 mg



[0101] While this invention has been described in reference to illustrative embodiments, this
description is not intended to be construed in a limiting sense. Various modifications and
combinations of the illustrative embodiments, as well as other embodiments of the invention, will
be apparent to persons skilled in the art upon reference to the description. It is therefore
intended that the appended claims encompass any such modifications or embodiments.




 









 





CONFIDENTIAL




SCHEDULE B




Development Plan




	 	 	 	 	 
	1.

	 	Determine formulation for combination product
of [***] and methscopolamine [***] to be a [***]
dosing for allergic rhinitis
	 	[***]
	 
	 	 	 	 
	2.

	 	Method development – prevalidation
	 	[***]
	 
	 	 	 	 
	3.

	 	Method development – including degredants
and impurities
	 	[***]
	 
	 	 	 	 
	4.

	 	Formulation development protocol
	 	[***]
	 
	 	 	 	 
	5.

	 	Perform cleaning validation studies
	 	[***]
	 
	 	 	 	 
	6.

	 	Write clinical lot MBR
	 	[***]
	 
	 	 	 	 
	7.

	 	Write feasibility protocol
	 	[***]
	 
	 	 	 	 
	8.

	 	Write stability protocol
	 	[***]
	 
	 	 	 	 
	9.

	 	Manufacture GMP batch
	 	[***]
	 
	 	 	 	 
	10.

	 	Commence stability studies
	 	[***]
	 
	 	 	 	 
	11.

	 	Pre-IND meeting with FDA
	 	[***]
	 
	 	 	 	 
	12.

	 	Submit IND
	 	[***]
	 
	 	 	 	 
	13.

	 	Conduct single dose PK study
	 	[***]
	 
	 	 	 	 
	14.

	 	Conduct multiple dose study
	 	[***]
	 
	 	 	 	 
	15.

	 	Conduct Phase III clinical study
	 	[***]
	 
	 	 	 	 
	16.

	 	Prepare NDA
	 	[***]
	 
	 	 	 	 
	17.

	 	Submit NDA
	 	[***] 2010








 




			
	[***]	 	Confidential portions of the exhibit have been omitted and filed separately with the Securities and Exchange Commission.





 









 





CONFIDENTIAL



SCHEDULE C




Supply Terms



Requirements Contract. Neos to supply all of Cornerstone’s requirements for Product for
commercial sale and promotional samples of Product in the United States except as set forth in the
next paragraph.



Alternate Third Party Supplier. Neos to assist Cornerstone to qualify an alternate third
party supplier selected by Cornerstone in its sole discretion, which shall be permitted to supply a
quantity up to the greater of (i) one lot of bottles with the same number of capsules per bottle as
supplied by Neos to Cornerstone under the definitive supply agreement, or (ii) [***] percent
([***]%) of Cornerstone’s requirements for Product in the United States. However, if Neos is
unable to supply 100% of the quantities of Product ordered for sixty (60) days or more, then
Cornerstone may increase its purchases of Product from the alternate third party supplier to
address any shortfall.



Term. Five year initial term, with a Cornerstone option to renew for an additional five
year renewal term.




Pricing.





	 	•	 	Initial pricing shall be set by the Parties based on [***] of Neos’ direct
manufacturing costs
	 
	 	•	 	Prices may be increased on January 1st of each year during the Term based
on Neos’ demonstrating increased costs but any price increase shall not exceed
increases in the Producer Price Index for manufactured goods for that same period and
provided further that such increase shall not increase the Product Price by more than
[***] from the previous calendar year.




Intellectual Property. All intellectual property relating to the Product, excluding
Process Developments (as defined below), conceived, reduced to practice, authored, or otherwise
generated or developed in the course of activities under the supply agreement, whether patentable
or not, and any authorship of works relating to a Product, including any trademarks, trade dress,
trade secrets or copyrights (“Product Developments”), shall be owned by Cornerstone without
payment to Neos. Such Product Developments shall not include any intellectual property, including,
without limitation, know-how or improvements relating to the manufacture of pharmaceutical products
generally or relating to the DVR Technology generally, conceived, reduced to practice or otherwise
developed by or on behalf of Neos, in connection with the performance of its obligations under the
supply agreement (“Process Developments”).



Representations and Warranties. Customary for agreements of this type, including regarding
maintenance of all manufacturing regulatory approvals and GMP facility status, and manufacture of
Product to Specifications, GMP, Neos manufacturing SOPs, and applicable Laws.






 




			
	[***]	 	Confidential portions of the exhibit have been omitted and filed separately with the
Securities and Exchange Commission.