Source: https://patents.google.com/patent/US20110118206A1/en
Timestamp: 2018-07-16 11:13:48
Document Index: 496795795

Matched Legal Cases: ['application No. 61', 'application No. 61', 'application No. 61', 'application No. 61', 'application No. 61', 'application No. 61']

US20110118206A1 - Hyaluronic acid based formulations - Google Patents
Hyaluronic acid based formulations Download PDF
US20110118206A1
US20110118206A1 US12970707 US97070710A US2011118206A1 US 20110118206 A1 US20110118206 A1 US 20110118206A1 US 12970707 US12970707 US 12970707 US 97070710 A US97070710 A US 97070710A US 2011118206 A1 US2011118206 A1 US 2011118206A1
US12970707
This application claims priority to and the benefit of PCT application No. PCT/1B2010/002846, filed Nov. 8, 2010, and PCT application No. PCT/IB2010/003008, filed Nov. 23, 2010, and is a continuation in part of U.S. patent application Ser. No. 12/393,768, filed Feb. 26, 2009, which claims priority to U.S. provisional patent application No. 61/085,956, filed Aug. 4, 2008, U.S. provisional patent application No. 61/087,934, filed Aug. 11, 2008, and U.S. provisional patent application No. 61/096,278, filed Sep. 11, 2008, and is a continuation in part of U.S. patent application Ser. No. 12/393,884, filed Feb. 26, 2009, which claims priority to U.S. provisional application No. 61/085,956, filed on Aug. 4, 2008, U.S. provisional application No. 61/087,934, filed Aug. 11, 2008, and U.S. provisional application No. 61/096,278, filed September 11, 2008,the disclosure of each of which is hereby incorporated by reference in its entirety.
HA, also known as hyaluronan, has excellent biocompatibility and, unlike collegan, does not require any skin testing before implantation. In addition, HA has the ability to bind to large amounts of water, making it an excellent volumizer of soft tissues.
The uncrosslinked HA component is a relatively high molecular weight HA material, for example, a HA having a molecular weight of at least about 1.0MDa, and may be present in the composition in an amount of less than about 10%, for example, less than 5.0%, for example, less than about 2.0%, for example, less than about 1.0%, for example, about 0.95% w/w.
The crosslinking agent may be any suitable crosslinking agent, but in a particular embodiment, the crosslinking agent is selected from the group consisting of 1,4-butanediol diglycidyl ether (BDDE), 1,4-bis(2,3-epoxypropoxy)butane, 1,4-bisglycidyloxybutane, 1,2-bis(2,3-epoxypropoxy)ethylene and 1-(2,3-epoxypropyI)-2,3-epoxycyclohexane, and 1,4-butanediol diglycidyl ether.
In yet another embodiment, the composition has a complex viscosity of between about 50 Pa*s and about 450 Pa*s, for example, when measured at about 5 Hz with a rheometer using a cone/plate geometry)(4 cm/2° at 25° C.
Intrinsic Viscosity (m3/kg)=9.78×10−6×Mw0.690
The intrinsic viscosity is measured according to the procedure defined European Pharmacopoeia (HA monograph N° 1472, January/2009).
High molecular weight HA as used herein describes a HA material having a molecular weight of at least about 1.0 million Daltons (mw≧106 Da or 1 MDa) to about 4.0 MDa. For example, the high molecular weight HA in the present compositions may have a molecular weight in the range about 1.5 MDa to about 3.0 MDa, or the high molecular weight HA may have a weight average molecular weight of about 2.0 MDa. In another example, the high molecular weight HA may have a molecular weight of about 3.0 MDa.
Low molecular weight HA as used herein describes a HA material having a molecular weight of less than about 1.0 MDa. Low molecular weight HA can have a molecular weight of between about 200,000 Da (0.2 MDa) to less than 1.0 MDa, for example, between about 300,000 Da (0.3 M Da) to about 750,000 Da. (0.75 MDa), up to but not exceeding 0.99 MDa.
Degree of crosslinking as used herein refers to the intermolecular junctions joining the individual HA polymer molecules, or monomer chains, into a permanent structure, or as disclosed herein the soft tissue filler composition. Moreover, degree of crosslinking for purposes of the present disclosure is further defined as the percent weight ratio of the crosslinking agent to HA-monomeric units within the crosslinked portion of the HA based composition. It is measured by the weight ratio of crosslinker to HA monomers (crosslinker : HA monomers).
In certain embodiments, the HA concentration in the crosslinked component of the present compositions is no greater than about 25 mg/g, for example, about 20.0 mg/g, for example, about 18.0 mg/g, about 17.0 mg/g, about 16.0 mg/g, about 15.0 mg/g, about 13.0 mg/g, about 12.0 mg/g, about 11.0 mg/g or about 10.0 mg/g. In one embodiment, the HA concentration in the crosslinked component is about 17.5 mg/g. In another embodiment the HA concentration in the crosslinked component is 15.0 mg/g. In another embodiment, the HA concentration in the crosslinked component is about 25.5 mg/g.
In addition, in embodiments with anesthetics, the concentration of one or more anesthetics is in an amount effective to mitigate pain experienced upon injection of the composition. The at least one local anesthetic can be selected from the group of ambucaine, amolanone, amylocaine, benoxinate, benzocaine, betoxycaine, biphenamine, bupivacaine, butacaine, butamben, butanilicaine, butethamine, butoxycaine, carticaine, chloroprocaine, cocaethylene, cocaine, cyclomethycaine, dibucaine, dimethysoquin, dimethocaine, diperodon, dycyclonine, ecgonidine, ecgonine, ethyl chloride, etidocaine, beta-eucaine, euprocin, fenalcomine, formocaine, hexylcaine, hydroxytetracaine, isobutyl p-aminobenzoate, leucinocaine mesylate, levoxadrol, lidocaine, mepivacaine, meprylcaine, metabutoxycaine, methyl chloride, myrtecaine, naepaine, octacaine, orthocaine, oxethazaine, parethoxycaine, phenacaine, phenol, piperocaine, piridocaine, polidocanol, pramoxine, prilocaine, procaine, propanocaine, proparacaine, propipocaine, propoxycaine, psuedococaine, pyrrocaine, ropivacaine, salicyl alcohol, tetracaine, tolycaine, trimecaine, zolamine, and salts thereof. In one embodiment, the at least one anesthetic agent is lidocaine, such as in the form of lidocaine HCl. The compositions described herein may have a lidocaine concentration of between about 0.1% and about 5% by weight of the composition, for example, about 0.2% to about 1.0% by weight of the composition. In one embodiment, the composition has a lidocaine concentration of about 0.3% by weight (w/w %) of the composition. The concentration of lidocaine in the compositions described herein can be therapeutically effective meaning the concentration is adequate to provide a therapeutic benefit without inflicting harm to the patient.
In one aspect of the invention, the ratio of low molecular weight to high molecular weight of the HA in the compositions is at least about 2 (w/w≧2), with the low molecular weight HA having a molecular weight of between about 0.20 MDa and no greater than about 0.99 MDa.
In this aspect of the invention, the added uncrosslinked HA solution has a HA concentration of between about 10 mg/g and about 50 mg/g, for example, about 10 mg/g, about 20 mg/g, about 30 mg/g, about 40 mg/g, about 50 mg/g. The HA in the uncrosslinked solution is a high molecular weight HA, having a molecular weight of at least about 1.0 MDa up to about 4.0 MDa, for example, a molecular weight of about 1.2
MDa, about 1.4 MDa, about 1.6 MDa, about 1.8 MDa, about 2.0 MDa, about 2.2 MDa about 2.4 MDa, about 2.6 MDa, about 2.8 MDa, about 3.0 MDa, about 3.2 MDa, about 3.4 MD about 3.6 MDa, about 3.8 The uncrosslinked HA solution is added to the crosslinked HA component, to produce a dermal filler composition having a final weight percent of between 0.5% and 10% uncrosslinked HA.
(1) a crosslinked hyaluronic acid (HA) component comprising a crosslinked mixture of (i) a first, low molecular weight HA material having a weight average molecular weight of between 0.20 about MDa and about 0.99 MDa and (ii) a second high molecular weight HA material having a weight average molecular weight of between about 1.0 MDa and about 4.0 MDa;
wherein the weight average molecular weight of the second, high molecular weight HA material is at least twice that of the first, low molecular weight HA material;
wherein the HA materials are hyaluronic acid or one or more salts thereof;
wherein the crosslinked HA component has a HA concentration of between about 15.0 mg/g and about 20.0 mg/g; and
wherein the crosslinking is achieved by use of a crosslinking agent; and
(2) an uncrosslinked HA component which is HA or a salt thereof, and which has a weight average molecular weight of at least about 1.0 MDa and is present in the composition in an amount of less than about 5.0% w/w
2. The composition of claim 1 wherein the uncrosslinked HA component has a weight average molecular weight of at least about 2.0 MDa.
3. The composition of claim 1 wherein the weight average molecular weight of the first, low molecular weight HA material is at least about 500,000 Da.
4. The composition of claim 1 wherein the weight average molecular weight of the second, high molecular weight HA material is at least about 1.0M Da.
5. The composition of claim 1 wherein the weight average molecular weight of the first, low molecular weight HA material is about 800,000 Da.
6. The composition of claim 1 wherein the mixture contains about 50% by weight of the first, low molecular weight HA material.
7. The composition of claim 1 wherein the mixture contains at least about 70% by weight of the first, low molecular weight HA material.
8. The composition of claim 1 wherein the mixture contains about 90% by weight of the first, low molecular weight HA material.
9. The composition of claim 1 wherein the crosslinking agent is selected from the group consisting of 1,4-butanediol diglycidyl ether (BDDE), 1,4-bis(2,3-epoxypropoxy)butane, 1,4-bisglycidyloxybutane, 1,2-bis(2,3-epoxypropoxy)ethylene and 1-(2,3-epoxypropyl)-2,3-epoxycyclohexane, and 1,4-butanediol diglycidyl ether.
10. The composition of claim 1 wherein the crosslinked HA component has a HA concentration of about 15.0 mg/g.
11. The composition of claim 1 wherein the crosslinked HA component has a HA concentration of about 17.5 mg/g.
12. The composition of claim 1 wherein the uncrosslinked HA component is present in an amount of less than about 1.0% w/w.
13. The composition of claim 1 wherein the uncrosslinked HA component has a HA concentration of between about 10.0 mg/g and about 50.0 mg/g.
14. The composition of claim 1 further comprising at least one anesthetic agent combined with said crosslinked HA component.
15. A soft tissue filler composition comprising:
a crosslinked hyaluronic acid (HA) component comprising a mixture of a first, low molecular weight HA material and a second, high molecular weight HA material, the materials being hyaluronic acid or salts thereof and being crosslinked with a crosslinking agent, the crosslinked HA component having a HA concentration of between about 15 mg/g and about 20 mg/g, and the mixture containing at least 50% by weight of the low molecular weight HA material;
the weight average molecular weight of the second, high molecular weight HA material being at least twice that of the weight average molecular weight of the first, low molecular weight HA material;
an uncrosslinked hyaluronic acid component or salt thereof, having a weight average molecular weight of at least about 2.4 M Da and an HA concentration of between about 10 mg/g and about 50 mg/g;
the uncrosslinked HA component being present in an amount of less than about 5.0% w/w; and
16. The composition of claim 15 wherein the mixture contains at least 70% by weight of the first, low molecular weight HA material.
17. The composition of claim 15 wherein the mixture contains about 90% by weight of the first, low molecular weight HA material.
18. A method of making a soft tissue filler composition comprising the steps of:
preparing a crosslinked hyaluronic acid (HA) gel comprising a mixture of a first, low molecular weight HA material and a second, high molecular weight HA material, the second, high molecular weight HA material having a weight average molecular weight of at least twice that of the first, low molecular weight material, the mixture comprising more than about 50% by weight of the first, low molecular weight HA material, wherein the HA materials are hyaluronic acid or one or more salts thereof;
adjusting the HA concentration in the crosslinked HA gel to a HA concentration of between about 15.0 mg/g and about 20.0 mg/g;
preparing a solution comprising an uncrosslinked HA material or a salt thereof having a weight average molecular weight of between at least about 1.0 MDa and about 4.0 MDa and a concentration of between about 10 mg/g and about 50 mg/g; and
combining the gel with the solution.
19. The method of claim 18 wherein the mixture comprises more than about 70% by weight of the first, low molecular weight HA material.
20. The method of claim 18 wherein the mixture comprises more than about 90% by weight of the first, low molecular weight HA material.
21. The method of claim 18 further comprising the step of combining at least one anesthetic agent with the gel.
22. The method of claim 21 wherein the step of combining at least one anesthetic agent with the gel is performed prior to the step of combining the gel with the solution.
US12970707 2008-08-04 2010-12-16 Hyaluronic acid based formulations Abandoned US20110118206A1 (en)
IBPCT/IB2010/002846 2010-11-08
IB2010002846 2010-11-08
IB2010003008 2010-11-23
IBPCT/IB2010/003008 2010-11-23
US14170310 Continuation US20140148406A1 (en) 2008-08-04 2014-01-31 Hyaluronic acid based formulations
US20110118206A1 true true US20110118206A1 (en) 2011-05-19
ID=44011773
US12970707 Abandoned US20110118206A1 (en) 2008-08-04 2010-12-16 Hyaluronic acid based formulations
US14170310 Pending US20140148406A1 (en) 2008-08-04 2014-01-31 Hyaluronic acid based formulations
US14523641 Abandoned US20150045321A1 (en) 2008-08-04 2014-10-24 Hyaluronic acid based formulations
US (3) US20110118206A1 (en)
CN104225677A (en) * 2013-06-13 2014-12-24 山东省生物药物研究院 Cross-linked hyaluronic acid cell-scaffold material and preparation method and application
WO2014044808A3 (en) * 2012-09-21 2014-12-24 Labo Cosprophar Ag Fast-penetration cosmetic dermal filler for topical application
CN105878051A (en) * 2015-01-26 2016-08-24 华熙福瑞达生物医药有限公司 Honeycomb hyaluronic acid and preparation method thereof
US20150045321A1 (en) 2015-02-12 application
US20140148406A1 (en) 2014-05-29 application
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