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.

 

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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).

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     “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.

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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.

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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).

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     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

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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.

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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.

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     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”).

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     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
[***]

     
 
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     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.

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          (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.

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          (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

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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.

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     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.

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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.

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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.

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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

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          (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

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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

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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

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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]

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[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    

 

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CONFIDENTIAL
SCHEDULE A
DVR Patent Applications

 

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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.

 

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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

 

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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.

 

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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

 

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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.

 

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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.

 

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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.

 

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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.

 

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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.

 

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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

 

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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

 

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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.

 

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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

 

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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

 

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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

 

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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

 

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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

 

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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

 

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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:

 

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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.

 

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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.