Transdermal therapeutic system for extended dosing of pramipexole in treating neurological disorders
09682068 ยท 2017-06-20
Assignee
Inventors
- Abhijit Mukund Deshmukh (Secundarabad, IN)
- Akhilesh Dixit (Nagpur, IN)
- Prasanna Kumar (Hyderabad, IN)
- Vikram Bindra (Panipat, IN)
Cpc classification
A61K9/7069
HUMAN NECESSITIES
A61F13/0259
HUMAN NECESSITIES
A61F13/0283
HUMAN NECESSITIES
A61F2013/0296
HUMAN NECESSITIES
International classification
A61K47/32
HUMAN NECESSITIES
Abstract
This disclosure relates to a transdermal therapeutic system (TTS) containing pramipexole or related compounds and methods of making the system as well as its use in administering such compounds as a single dose over an extended period, for example, one week. The system comprises an acrylic-based or silicone-based matrix layer containing pramipexole at concentrations of at least about 5 wt. % of the matrix, which is resistant to crystallizing and discoloration of the active ingredient even when stored over long periods.
Claims
1. A transdermal therapeutic system (TTS) for the administration of one or more active ingredients selected from the group consisting of pramipexole, pharmaceutically acceptable pramipexole salts, and pharmaceutically acceptable pramipexole derivatives, the system comprising: (i) a substantially active-ingredient-impermeable backing layer, (ii) at least one matrix layer which contains at least about 5% to 10% w/w active ingredient(s), and (iii) a substantially impermeable protective release liner layer which releasably contacts the matrix layer or other adhesive layer; wherein 1) the matrix layer comprises an adhesive selected from acrylate-based adhesive and silicone-based adhesive, 2) the transdermal therapeutic system provides a therapeutically effective administration of the active ingredient(s), at a flux rate ranging from 1 g/cm.sup.2/hr to 4.6 g/cm.sup.2/hr between the 96.sup.th and 168.sup.th hour after treatment is initiated, and 3) the matrix layer is color-stable and lacks crystal growth of the active ingredient, over an extended storage period of at least one of 30 or more days, 90 or more days, and 180 or more days.
2. The transdermal therapeutic system of claim 1, wherein the active-ingredient-containing matrix layer contains from about 5.5% to about 7% w/w active ingredient(s) and provides a therapeutically effective flux profile ranging from about 1 g/cm.sup.2/hr to 4.6 g/cm.sup.2/hr between the 96.sup.th hour and 168.sup.th hour after treatment is initiated.
3. The transdermal therapeutic system of claim 1, wherein the active-ingredient-containing matrix layer provides a therapeutically effective flux profile ranging from about 1.2 g/cm.sup.2/hr to 4.6 g/cm.sup.2/hr 168 hours after treatment is initiated.
4. The transdermal therapeutic system of claim 1, wherein the active ingredient comprises pramipexole free base.
5. The transdermal therapeutic system of claim 1, wherein the active ingredient comprises one or more salts of pramipexole comprising reaction products of pramipexole or a pramipexole derivative and an acid.
6. The transdermal therapeutic system of claim 1, wherein the matrix layer is self-adhesive.
7. The transdermal therapeutic system of claim 1, wherein the matrix layer comprises an acrylate-based adhesive comprising polyacrylate lacking a carboxylic acid functional group.
8. The transdermal therapeutic system of claim 7, wherein the matrix layer comprises a polymer material free of solubilizers and/or crystal growth inhibitors.
9. The transdermal therapeutic system of claim 7, wherein the matrix layer comprises 0 wt. % to about 20 wt. % of a solubilizer and/or crystal growth inhibitor.
10. The transdermal therapeutic system of claim 7, wherein the matrix layer comprises from about 2.5 wt. % to about 17.5 wt. % of a solubilizer and/or crystal growth inhibitor.
11. The transdermal therapeutic system of claim 7, wherein the matrix layer comprises about 10 wt. % of a solubilizer and/or crystal growth inhibitor.
12. The transdermal therapeutic system of claim 9, wherein the solubilizer and/or crystal growth inhibitor is selected from the group consisting of optionally saturated and/or unsaturated fatty alcohols each containing from 8 to 18 carbon atoms; tea tree oil; saturated and/or unsaturated cyclic ketones; alkyl methyl sulfoxides; saturated and/or unsaturated fatty acids each containing from 8 to 18 carbon atoms; esters and salts thereof; natural vitamin E; synthetic vitamin E and/or vitamin E derivatives; sorbitan fatty acid esters and/or ethoxylated sorbitan fatty acid esters; azones (laurocapram); 1-alkylpyrrolidone; polyvinylpyrrolidone; block copolymers of polyethylene glycol and dimethylsiloxane with a cationic group at one end; polysiloxanes; polyoxyethylene-10-stearyl ether; mixture of polyoxyethylene-10-stearyl ether and glyceryl dilaurate; dodecyl-2-(N,N-dimethylamino)-propanol tetradecanoate and/or dodecyl-2-(N,N-dimethylamino)-propionate; N-acetylprolinate esters with >8 carbon atoms; non-ionic surfactants, for example lauryl ethers and/or esters of polyoxyethylene; dimethyl(arylimino)sulfuran; mixture of oleic acid analogues and propylene glycol; mixture of octyl salicylate, isopropyl myristate, isopropyl palmitate, octylmethoxy cinnamate and laurocapram or a mixture of individual components; phospholipids; highly dispersed silicon dioxide; polyoxyethylene-7-glycerol monococoate; 2-octyldodecanol or a mixture of various individual components.
13. The transdermal therapeutic system of claim 9, wherein the solubilizer and/or crystal growth inhibitor is polyvinylpyrrolidone.
14. The transdermal therapeutic system of claim 1, wherein the active ingredient matrix layer contains from about 5.5% to about 7% w/w active ingredient(s).
15. A method for preparing a transdermal therapeutic system according to claim 1 which comprises: i) providing an active-ingredient containing matrix layer by: 1) forming a mixture comprising a) active ingredient pramipexole free base, b) a solvent selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol and tert-butanol, acetone, pentane, hexane, heptane, ethyl acetate, isopropanol, toluene, xylene, 2,4-pentanedione, and water, and c) an optional solubilizer and/or crystal growth inhibitor; 2) dissolving the mixture to provide a dissolved mixture; 3) combining the dissolved mixture with a matrix forming ingredient to form a pramipexole-containing matrix precursor mixture; and 4) optionally degassing the matrix precursor mixture to provide a degassed matrix precursor mixture; ii) coating one side of a release liner film with the matrix precursor mixture or optionally degassed matrix precursor mixture; and iii) laminating a backing film to the coated side of the release liner film.
16. The method of claim 15, wherein the solvent comprises ethanol, the dissolving step comprises sonication, the optional solubilizer and/or crystal growth inhibitor comprises polyvinylpyrrolidone, and the matrix forming ingredient comprises an adhesive selected from acrylate-based adhesive and silicone-based adhesive.
17. The method of claim 16, wherein the adhesive comprises polyacrylate lacking a carboxylic acid functional group.
18. The method of claim 15, wherein the optional solubilizer and/or crystal growth inhibitor comprises polyvinylpyrrolidone.
19. The method of claim 15, wherein the adhesive comprises silicone-based adhesive, silicone oil, and colloidal silicon dioxide.
20. A method for administering pramipexole to a human subject in need thereof, which method comprises: i) providing a transdermal dosage form according to claim 1; and ii) applying the dosage form onto an area of skin of the subject in an amount sufficient to provide a therapeutic concentration of pramipexole in the bloodstream or the subject.
21. The method according to claim 20, wherein the human subject is in need of pramipexole to treat a neurological disorder.
22. The method according to claim 21, wherein the human subject is in need of pramipexole to treat a condition selected from the group consisting of Parkinson's Disease, Restless Legs Syndrome, Tourette's Syndrome, Chronic Tic Disorder, Essential Tremor, and Attention Deficit Hyperactivity Disorder.
23. The method according to claim 20, which comprises applying up to about 10 grams of the dosage form daily to a skin surface area of about 50 to about 500 cm.sup.2.
24. The method according to claim 20, wherein the method comprises applying the dosage form in a weekly single dose.
25. A method for preparing a transdermal therapeutic system according to claim 1 which comprises: i) providing an active-ingredient containing matrix layer by: 1) forming a mixture comprising a) active ingredient pramipexole free base, b) a solvent and/or dispersant selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol and tert-butanol, acetone, pentane, hexane, heptane, ethyl acetate, isopropanol, toluene, xylene, 2,4-pentanedione, and water, and c) an optional solubilizer and/or crystal growth inhibitor; 2) dissolving and/or dispersing the mixture to provide a dissolved and/or dispersed mixture; 3) combining the dissolved and/or dispersed mixture with a matrix forming ingredient to form a pramipexole-containing matrix precursor mixture; and 4) optionally degassing the matrix precursor mixture to provide a degassed matrix precursor mixture; ii) coating one side of a release liner film with the matrix precursor mixture or optionally degassed matrix precursor mixture; and iii) laminating a backing film to the coated side of the release liner film.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
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DETAILED DESCRIPTION
(11) Current treatment options using pramipexole for Parkinsonism include conventional tablets and modified release tablets, as well as transdermal patches administered on a daily basis or more often. The present disclosure relates to the treatment of neurological disorders such as Parkinsonism using a dosage form delivering and maintaining the plasma concentration of drug over a prolonged period of time, typically two days or greater, e.g., two days, three days, four days, five days, six days, or seven days, without any need of frequent administration, using a non-invasive treatment.
(12) The current disclosure describes the method of treatment for neurological disorders such as Parkinsonism using a transdermal therapeutic system or patch comprising a formulation of pramipexole. The presently disclosed transdermal patch can be used for once a week, twice a week, or three times a week application for the patients in need of therapy.
(13) The components of the patch and the concentration of the drug in the patch and the dimensions of drug in adhesive layer are provided so that the patch can sustain the drug release for up to about 48 hours, about 72 hours, or about seven days or more to achieve a therapeutic plasma concentration. The treatment is non-invasive and non-irritating and ensures sufficiently constant plasma levels of the pramipexole for the intended period of treatment.
(14) The intended transdermal patch is a drug-in-adhesive matrix type having at least three layers. In one aspect, the composition of transdermal patch consists of three distinct layers: a) a backing membrane layer; b) a drug-containing adhesive matrix layer; and c) a release liner.
(15) The currently disclosed transdermal therapeutic system or patch contains an active ingredient in an adhesive matrix. Acrylate-based adhesives and silicone-based adhesives were found to provide both a suitable drug release profile, and a suitable stability for commercial use. Although a desirable drug release profile was observed for both acrylate- and silicone-based adhesives, the acrylate-based adhesive system was more acceptable, e.g., in terms of controlled delivery of the drug, especially for those systems in which the acrylate lacks a carboxylic acid functional group.
(16) The current disclosure also describes transdermal therapeutic systems for the treatment of Parkinson's disease by continuous transdermal delivery of pramipexole at therapeutically relevant rates over a seven day period, making possible once-weekly dosing.
(17) As noted, the present disclosure relates to a transdermal therapeutic system (TTS) for the administration of one or more active ingredients selected from the group consisting of pramipexole, pharmaceutically acceptable pramipexole salts, and pharmaceutically acceptable pramipexole derivatives. The system comprises: (i) a substantially active ingredient-impermeable backing layer, (ii) at least one matrix layer which contains at least about 5% w/w active ingredient(s), and (iii) a substantially impermeable protective release liner which releasably contacts the matrix layer or another adhesive layer; wherein 1) the matrix layer comprises an adhesive selected from an acrylate-based adhesive and a silicone-based adhesive, 2) the transdermal therapeutic system provides a rate of administration of the active ingredient(s) ranging from about 1 g to about 200 g per hour over seven days, and 3) the matrix layer is color-stable and does not promote crystal growth of the active ingredient, over an extended storage period of at least one of 30 or more days, 90 or more days, and 180 or more days.
(18) Backing Layer
(19) The substantially impermeable backing layer is a flexible substrate, e.g., a film or laminate, which provides support for the rest of the transdermal drug delivery device during storage, handling and wear. Any backing layer of sufficient strength and rigidity, which is substantially impermeable to the active pharmaceutical ingredient or ingredients present in the transdermal drug delivery device of the present disclosure can be used. For present purposes, substantially impermeable means that no substantial loss of active ingredient from the backing layer occurs under typical storage and usage conditions and periods which the device is expected to encounter during its lifetime. Typically, such losses are less than about 1 wt. %, preferably less than about 0.1 wt %, or even less than about 0.01 wt. %. The backing layer can be substantially moisture impermeable as well. Typically, a backing layer of the present disclosure has a moisture vapor transmission rate (MVTR) of less than 20 g/m.sup.2.Math.24 hr, less than about 17 g/m.sup.2.Math.24 hr, or less than about 15 g/m.sup.2.Math.24 hr, e.g., from about 1 g/m.sup.2.Math.24 hr to about 15 g/m.sup.2.Math.24 hr, in some embodiments.
(20) For present purposes, MVTR is defined as a measure of the passage of water vapor through a substance. It can be measured using suitable techniques. ASTM F1249 describes the procedure for MVTR testing using modulated infrared sensors which require use of a known calibration standard and determining the voltage-to-transmission-rate ratio for each sensor. Coulometric sensors for measuring oxygen transmission rates in flat films and packages, following ASTM D3985 and F1307 are also suitable and require no calibration. Typical rates in aluminum foil laminates may be as low as 0.001 g/m.sup.2/day, whereas the rate in fabrics can measure up to several thousand g/m.sup.2/day.
(21) In various embodiments of the present disclosure, the backing layer is composed of materials that are selected from polyesters, e.g., oriented or non-oriented polyethylene terephthalate, various nylons, polypropylenes, polyester/ethylene-vinyl acetates, metallized polyester films, polyvinylidene chloride, metal films such as aluminum foils, polyvinylidene fluoride films, and mixtures or copolymers thereof.
(22) Other non-limiting materials for the backing layer include ethylene vinyl acetate films laminated to a polyester, ethylene vinyl acetate films laminated to a metallized polyester, MEDIFLEX 1200, MEDIFLEX 1501, MEDIFLEX 1505, MEDIFLEX 1201, MEDIFLEX 1502 (with MEDIFLEX 1200 being especially preferred) (all five MEDIFLEX products being available from Mylan Technologies Inc., St. Albans, Vt., USA), DuPont polyester type S available from DuPont, Wilmington, Del., USA, Dow BLF 2050 available from The Dow Chemical Company, Midland, Mich., USA, and 3M Scotchpak 1109, 3M Scotchpak 9723, 3M Scotchpak 9733, 3M Scotchpak 9735 and 3M Scotchpak 9730, which Scotchpak products are available from 3M of Minneapolis, Minn., USA.
(23) Additional materials suited for the backing layer include polyethylene or polyolefin backings, such as MEDIFLEX 1000, 3M CoTran 9722, and 3M CoTran 9720. 3M CoTran products are available from 3M of Minneapolis, Minn., USA.
(24) In some embodiments of the disclosure, the backing layer comprises a film selected from MEDIFLEX 1501 (which has an MVTR of 14 g/m.sup.2.Math.24 hr), MEDIFLEX 1000 (which has an MVTR of 7 g/m.sup.2.Math.24 hr), available from Mylan Technologies Inc., Scotchpak 1109, Scotchpak 9730, Scotchpak 9732, Scotchpak 9733, Scotchpak 9735, as well as CoTran 9719, CoTran 9720, and CoTran 9726, available from 3M. The Scotchpak and CoTran films exhibit a relatively low MVTR range of from about 0.5 to about 17 g/m.sup.2.Math.24 hr.
(25) In certain embodiments, the backing layer is comprised of ethylene vinyl acetate or polyolefin films laminated to a polyester, such as MEDIFLEX 1501 from Mylan Technologies, Inc. MEDIFLEX 1501 is a three layer structure which can be described from its external surface inwardly as follows: peach-colored polyethylene/polyurethane adhesive/polyester.
(26) In some embodiments, the backing layer may be the same size as the adhesive drug-containing layer. In other embodiments, the backing layer may be oversized as compared with the adhesive drug-containing layer, i.e., the backing layer may be larger than the adhesive drug-containing layer.
(27) In certain embodiments of the present disclosure, the backing layer may range from about 0.01 mm to at least 10 mm larger than the matrix layer (adhesive drug-containing layer), from about 0.05 mm to about 5 mm larger than the adhesive drug-containing layer, or from about 0.1 mm to about 3 mm larger than the adhesive drug-containing layer. Without wishing to be bound by any particular theory, it is believed that the use of an oversized backing layer helps prevent the adhesive drug-containing layer and the remaining portions of the transdermal drug delivery device of the present disclosure from becoming distorted or relaxing during the handling and/or shipping processes.
(28) The backing layer should be thick enough to resist wrinkling which may arise upon prolonged periods in storage and through the movement of a subject's skin. Typically, the backing layer is from about 50 microns to about 100 microns in thickness.
(29) Active Ingredient-Containing Matrix Layer
(30) An active ingredient-containing matrix layersometimes referred to as an adhesive drug-containing layer or drug reservoir layercontaining a therapeutically effective amount of pramipexole, its salts, and/or its derivatives, is placed directly or indirectly (through an optional intermediate layer) on the front side of the backing layer, i.e., the side toward the wearer, in the transdermal drug delivery device of the present disclosure.
(31) For the matrix, the matrix formers customarily applied in medical applications are used, such as polyacrylates or silicone adhesives. Preferably, a self-adhesive matrix that is acrylic-based, more preferably a matrix that is based on acrylates lacking a carboxylic acid functional group, e.g., DuroTak 87-2287. The matrix formers and the adhesives may be one and the same.
(32) The matrix formers based on polyacrylates may be any desired homopolymer, copolymer or terpolymer consisting of various acrylic acid derivatives, where applicable with vinyl acetate.
(33) For example, the polyacrylates may be polymers of one or more monomers of acrylic acid and other copolymerizable monomers. In addition, the polyacrylates may include copolymers of alkyl acrylates and/or alkyl methacrylates and/or copolymerizable secondary monomers or monomers having functional groups. If the amount of any type added as monomer is altered, the cohesive properties of the resulting acrylate polymers can be altered. In general, the acrylate polymer consists of at least 50% by weight of an acrylate, methacrylate, alkyl acrylate or alkyl methacrylate monomer, from 0 to 20% by weight of a functional monomer copolymerizable with acrylate, and from 0 to 50% by weight of another monomer.
(34) Various acrylate monomers are mentioned hereinafter, such as, for example, acrylic acid, methacrylic acid, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, isooctyl acrylate, isooctyl methacrylate, glycidyl methacrylate, 2-hydroxyethyl acrylate, methyl acrylate, methyl methacrylate, 2-ethylhexyl acrylate and 2-ethylhexyl methacrylate, that may be polymerized individually or in admixture.
(35) In addition, functional monomers that are copolymerizable with the above-mentioned acrylates, such as, for example, acrylic acid, methacrylic acid, hydroxyethyl acrylate, vinyl acetate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, tert.-butylaminoethyl acrylate, tert.-butylaminoethyl methacrylate, methoxyethyl acrylate and methoxyethyl methacrylate, can be used for copolymerization.
(36) The content of adhesives in the matrix layer may be from 50 to 96% by weight, especially from 80 to 90% by weight, e.g., about 85% by weight, based on the total weight of the matrix layer.
(37) In certain embodiments, the acrylic adhesive can be selected from the group consisting of Duro-Tak 87-2352, Duro-Tak-387-2353, Duro-Tak 87-235A, Duro-Tak 387-235A, Duro-Tak 87-2516, Duro-Tak-387-2526, Duro-Tak-87-2287, Duro-Tak 387-2287, Duro-Tak 87-2194, Duro-Tak 387-2051, Duro-Tak 387-2052, Duro-Tak 387-2194, Duro-Tak 87-2196, GMS-9073, GMS-2873, GMS-9083, GMS-2883, GS-9067, GMS-9071, GMS-3083, GMS-3253, GMS-737, GMS-737-01, GMS-788, GMS-2999, GMS-2495, GMS-7883, GMS-1753, GMS-2893 and combinations thereof, or acrylic adhesives having substantially the same composition as these materials. The Duro-Tak products are available from Henkel of Dusseldorf, Germany and can be characterized as containing acrylic copolymers. GMS products are available from the Cytec Corporation, Germany.
(38) In certain embodiments, cross-linkable adhesives useful in making the matrix layer of the present disclosure include medical grade acrylic cross-linkable adhesives. As used herein, cross-linkable adhesive refers to an adhesive provided as a solvent-based solution that contains a cross-linking agent. As provided, the adhesive is uncross-linked; when the solution is dried to remove the solvent, the cross-linker is activated and the cross-linking of the adhesive occurs. Suitable acrylic adhesives include acrylate-vinylacetate self-curing pressure sensitive adhesives, such as Duro-Tak 387-2516/87-2516.
(39) In some embodiments, non-cross-linkable acrylic adhesive can be used to make the matrix layer. As used herein, a non-cross-linkable adhesive refers to an adhesive provided as a solvent-based solution that does not contain a cross-linking agent. Examples of non-cross-linkable adhesive are acrylate-vinylacetate non-curing PSAs Duro-Tak 387-2287 and Duro-Tak 87-2287, as well as mixtures thereof.
(40) In certain embodiments of the disclosure, a mixture of the above cross-linkable adhesive and non-cross-linkable adhesive may be used to make the matrix layer. Prior to drying, the cross-linkable acrylic adhesive is mixed with a second, non-cross-linkable adhesive. Preferably, the solution of non-cross-linkable adhesive comprises the same polymer as provided in the solution of the cross-linkable adhesive. Thus, if the cross-linkable adhesive comprises Duro-Tak 387-2516 and/or Duro-Tak 87-2516, then the non-cross-linkable adhesive comprises Duro-Tak 387-2287, Duro-Tak 87-2287. See, e.g., U.S. Published Application Number 2011/0106022 to Jackson et al.
(41) In certain embodiments of the disclosure, the acrylic pressure-sensitive adhesive can comprise a random copolymer of 2-ethylhexyl acrylate, butyl acrylate, t-octyl acrylamide and methyl methacrylate. In these embodiments, the adhesive may have a composition that is substantially the same as the composition of Duro-Tak 87-900 A (available from Henkel of Dusseldorf, Germany or National Adhesives, Bridgewater, N.J.). The term substantially the same as used herein refers to a composition that is a copolymer of 2-ethylhexyl acrylate, butyl acrylate, t-octyl acrylamide and methyl methacrylate and provides for the storage stable functionality as described above. In some embodiments, the acrylic pressure-sensitive adhesive is Duro-Tak 87-900 A itself.
(42) In various embodiments of the present disclosure, the acrylic adhesive comprises acrylate co-polymer, e.g. co-polymer of butyl acrylate, ethyl hexyl acrylate and vinyl acetate. The co-polymer can be cross-linked. A preferred acrylate polymer can be selected from the Duro-Tak brand, e.g. Duro-Tak 87-2353. Duro-Tak 87-235A is particularly advantageous inasmuch as it lacks the monomer glycidyl methacrylate component found in Duro-Tak 87-2353.
(43) The acrylic adhesive layer can be attached or adjacent to a backing film directly or through a suitable intermediate layer. In certain embodiments of the present disclosure, the acrylic adhesives used in the intermediate layer are selected from Duro-Tak 87-2352, Duro-Tak 387-2353, Duro-Tak 87-235A, Duro-Tak 387-2351, Duro-Tak 87-2516, Duro-Tak 387-2526, Duro-Tak 87-2287, Duro-Tak 387-2287, Duro-Tak 87-2194, Duro-Tak 387-2194, Duro-Tak 87-2196 and combinations thereof.
(44) In some embodiments, the matrix layer comprises suitable silicone adhesives alone or with the above-described acrylic adhesives. The silicone adhesives include pressure sensitive adhesives made from silicone polymer and resin. The polymer to resin ratio can be varied to achieve different levels of tack, which is useful where the matrix layer is the skin contact layer of a device of the present disclosure. Specific examples of useful silicone adhesives for this purpose which are commercially available include the standard Dow Corning BIO-PSA series (7-4400, 7-4500 and 7-4600 series) and the amine compatible (endcapped) Dow Corning BIO-PSA series (7-4100, 7-4200 and 7-4300 series) manufactured by Dow Corning. Preferred adhesives include Dow Corning BIO-PSA 7-4201, 7-4202, 7-4301, 7-4302, 7-4501, 7-4502 and 7-4602, with BIO-PSA 7-4201, BIO-PSA 7-4301, BIO-PSA 7-4302 or mixtures thereof, e.g., BIO-PSA 7-4201, BIO-PSA 7-4301 and/or BIO-PSA 7-4302 being especially preferred.
(45) In certain embodiments, the skin-contact layer contains an active pharmaceutical ingredient (API), where the API itself and degree of saturation of API in this layer is about the same as the degree of saturation in the adhesive layer.
(46) In some embodiments, the skin-contact layer contains one or more additives, e.g., a tackifier. A tackifier is added to provide a desired stickiness to the product, typically a stickiness sufficient to adhere the device to a patient's skin, without the patient feeling undue discomfort upon removal of the device. Tack can be measured by conventional techniques such as the Instron Peel Strength Test or the Tel-Tak test, employing a tackmeter sold by Monsanto Co., Testing Instruments Division.
(47) In various embodiments of the present disclosure, the optional tackifier can also be present in the adhesive drug-containing layer, typically in amounts ranging from about 10 wt. % to about 30 wt. %, e.g., from about 15 wt. % to about 25 wt. %, e.g., from about 17 wt. % to about 23 wt. %, typically, about 20 wt. %. The tackifier can be a suitable silicone oil, e.g., polydimethyl siloxane, such as Dow Corning Medical Fluid, 12,500 cSt.
(48) In some embodiments of the present disclosure, the matrix layer can contain one or more optional solubilizers and/or crystal growth inhibitors. Suitable active ingredient solubilizers and/or active ingredient crystal growth inhibitors can include optionally saturated and/or unsaturated fatty alcohols each containing from 8 to 18 carbon atoms; tea tree oil; saturated and/or unsaturated cyclic ketones; alkyl methyl sulfoxides; saturated and/or unsaturated fatty acids each containing from 8 to 18 carbon atoms; esters and salts thereof; natural vitamin E (Copherol F1300); synthetic vitamin E and/or vitamin E derivatives; sorbitan fatty acid esters and/or ethoxylated sorbitan fatty acid esters; azones (laurocapram); 1-alkylpyrrolidone; polyvinylpyrrolidone; block copolymers of polyethylene glycol and dimethylsiloxane with a cationic group at one end; polysiloxanes; polyoxyethylene-10-stearyl ether; mixture of polyoxyethylene-10-stearyl ether and glyceryl dilaurate; dodecyl-2-(N,N-dimethylamino)-propanol tetradecanoate and/or dodecyl-2-(N,N-dimethylamino)-propionate; N-acetylprolinate esters with >8 carbon atoms; non-ionic surfactants, for example lauryl ethers and/or esters of polyoxyethylene; dimethyl(arylimino)sulfuran; mixture of oleic acid analogues and propylene glycol; mixture of octyl salicylate, isopropyl myristate, isopropyl palmitate, octylmethoxy cinnamate and laurocapram or a mixture of individual components; phospholipids; highly dispersed silicon dioxide (Aerosil); polyoxyethylene-7-glycerol monococoate (Cetiol HE); 2-octyldodecanol (Eutanol G) or a mixture of various individual components. Povidone (polyvinylpyrrolidone) is preferred as the solubilizer and/or active ingredient crystal growth inhibitor in the transdermal therapeutic system according to the invention.
(49) In certain embodiments of the present disclosure, the transdermal drug delivery device comprises plural or multiple adhesive drug-containing layers, e.g., adhesive bilayers, trilayers, quadrilayer, pentalayers, etc., which include an acrylic adhesive matrix layer or silicone adhesive matrix layer, and a skin contact layer. The skin contact layer can be directly attached to the acrylic adhesive matrix layer or silicone adhesive matrix layer, or alternately, is attached to an intermediate membrane layer placed between the adhesive matrix layer and the skin contact layer. In plural or multiple adhesive drug-containing layer embodiments of the present disclosure, a skin contact layer is typically present in addition to a separate adhesive layer as described above. In some embodiments the skin contact layer itself contains an active pharmaceutical ingredient. In other embodiments, no active pharmaceutical ingredient is present in the skin contact layer.
(50) An optional skin contact layer adjacent to the adhesive drug containing layer or matrix layer comprises a skin contact layer adhesive, an optional drug component, usually of the type already present in the adhesive layer, and an optional tackifier. The adhesive is selected from silicones, including silicone oils, e.g., medical fluids, natural and synthetic rubbers, polyisobutylene (PIB) (HMW (High Molecular Weight) PIB, LMW (Low Molecular Weight) PIB, or mixtures of HMW and LMW PIB), neoprenes, polybutadienes, polyisoprenes, polysiloxanes, acrylic adhesives including cross-linked and uncross-linked acrylic copolymers, vinyl acetate adhesives, polyacrylates, ethylene vinyl acetate copolymers, styrene-isoprene copolymers, polyurethanes, plasticized polyether block amide copolymers, plasticized styrene-rubber block copolymers, and mixtures thereof.
(51) TABLE 1 below sets out desirable ranges of ingredients for the active ingredient-containing layer of the transdermal therapeutic system of the present disclosure which utilizes an acrylic matrix layer (Duro-Tak 87-287).
(52) TABLE-US-00001 TABLE 1 Acrylate PSA system - DuroTak 87-2287 Preferred Workable range Preferred Range composition Ingredients % w/w concentration Pramipexole Base 4.5-7.0 5.0-6.0 5.5 DuroTak 87-2287 65.0-96.0 80.0-95.0 84.5 PVP (Plasdone) K 0-15.0 2.5-10.0 10.0 90 Ethanol qs qs qs Thickness of Adhesive Layer: 70-100 gsm Patch size: 50 cm.sup.2
(53) TABLE 2 below sets out desirable ranges of ingredients for the active ingredient-containing layer of the transdermal therapeutic system of the present disclosure which utilizes an acrylic matrix layer (Duro-Tak 87-900A).
(54) TABLE-US-00002 TABLE 2 Acrylate PSA system - DuroTak 87-900 A Preferred Workable range Preferred Range composition Ingredients % w/w concentration Pramipexole Base 4.5-9.0 5.0-6.0 5.5 DuroTak 87-900 A 65.0-96.0 80.0-95.0 84.5 PVP (Plasdone) K 0-15.0 2.5-10.0 10.0 90 Ethanol qs qs qs Thickness of Adhesive Layer: 70-100 g/m.sup.2 Patch size: 50 cm.sup.2
(55) TABLE 3 below sets out desirable ranges of ingredients for the active ingredient-containing layer of the transdermal therapeutic system of the present disclosure.
(56) TABLE-US-00003 TABLE 3 Silicone BIO PSA Adhesive system - 4301 Preferred Workable range Preferred Range composition Ingredients % w/w concentration Pramipexole Base 4.5-9.0 6.0-7.0 6.0 Bio PSA 4301/4201 65.0-96.0 80.0-94.0 85.5 Silicone Oil 0-10.0 0-10.0 5.0 Colloidal silicone .sup.0-5.0 .sup.0-5.0 2.5 dioxide n- Heptane qs qs qs Thickness of Adhesive Layer: 70-100 g/m.sup.2 Patch size: 50 cm.sup.2
(57) Release Liner Layer
(58) Substantially impermeable protective release liners which are well known in the art can be used for the release liner layer of the present disclosure, especially where they exhibit adequate moisture impermeability. For present purposes, substantially impermeable means that no substantial loss of active ingredient from the release liner occurs under typical storage and usage conditions and periods which the device is expected to encounter during its lifetime. Typically, such losses are less than about 1 wt. %, preferably less than about 0.1 wt %, or even less than about 0.01 wt. %. The release liner layer can be substantially moisture impermeable as well. For present purposes, the substantially impermeable release liner layer is a flexible substrate, e.g., a film or laminate, which is releasably secured to the skin contact layer, e.g., a peelable layer. The release liner layer serves to protect the adhesive surface of the layer of the device which is to be applied to a subject's skin, e.g., during storage and any other time prior to use of the device. Any release liner layer of sufficient strength and rigidity, and which is substantially moisture impermeable, is suited for use in the present disclosure. Typically, such a release liner layer has a moisture vapor transmission rate (MVTR) of less than 20 g/m.sup.2.Math.24 hr, e.g., less than about 17 g/m.sup.2.Math.24 hr, e.g., from about 1 g/m.sup.2.Math.24 hr g/m.sup.2/24 hr to about 15 g/m.sup.2.Math.24 hr. MVTR can be measured for the release liner layer in the same way as earlier described in relation to the backing layer.
(59) Non-limiting examples of materials from which the release liner layer may be composed include polyethylene terephthalate/silicone (i.e. polydimethyl siloxane or PET/SI), polyethylene terephthalate/aluminized polyester coated with silicone (i.e. polydimethyl siloxane or PET/MET/SI), polyester or polyurethane liners with a silicone coating, polyester or polyurethane liners with a fluorocarbon or fluorosilicone coating, e.g., a polyfluoroalkylsiloxane, or polyester or polyurethane liners with a silicone coating.
(60) In various embodiments, the protective release liner layer comprises fluorosilicone coated polyester or silicone coated polyester. Suitable release liners include polyester film and polypropylene film coated with a fluoropolymer release agent. Such release liner layers include Scotchpak 1020, 1022, 9741, 9742, 9744 and 9755 available from 3M, of which Scotchpak 1022 is especially preferred. Other suitable release liner constituents include MEDIRELEASE 2500, MEDIRELEASE 2249 and MEDIRELEASE 2226, each of which is available from Mylan Technologies, Inc., of which MEDIRELEASE 2249 can be especially preferred. Still other suitable release liner layers can be made from CPFilms Inc. Clearsil UV5A and CPFilms Inc., Clearsil UV510, CPFilms Inc. Sil UV5A and CPFilms Inc. Sil UV510, which are available from CPFilms, Inc. of Fieldale, Va., USA.
(61) The release liner layer can, however, comprise other materials, including paper or paper-containing layers or laminates, various thermoplastics, polyester films, foil liners, and the like. The release liner is removed and discarded from the transdermal delivery device to expose the skin contact adhesive layer which functions as the means of adhering the composition to the patient and through which the drug passes as it is delivered to the patient. Suitable release liners include those known in the art for use with pressure sensitive adhesive compositions.
(62) In some embodiments, the release liner layer may be the same size as the matrix layer and/or may be the same size as the backing layer. In any event, the release liner should be at least coextensive with the surface of the matrix layer, in order to prevent migration of the active component prior to release liner removal. In other embodiments, the release liner layer may be larger than the adhesive matrix layer and/or may be larger than the backing layer. In yet other embodiments, the release liner may range from about 0.1 mm to at least about 20 mm larger than the margin of a backing layer or a matrix layer, preferably ranging from about 0.5 mm to about 10 mm larger than the backing layer or matrix layer, and most preferably ranging from about 1 mm to about 5 mm larger than the backing layer or matrix layer. It is believed that the use of an oversized release liner facilitates its removal by the user prior to application to the skin and also helps prevent the matrix from becoming distorted or relaxing during the handling and shipping processes. In certain embodiments, the release liner layer is of square or rectangular shape and can be attached to a smaller patch, e.g., one of circular shape.
(63) Methods of Preparing Transdermal Therapeutic System (Dosage Unit Forms)
(64) The transdermal therapeutic system drug delivery devices of this disclosure can be made by first preparing separate adhesive blends for each layer of the dosage unit, then dissolving or suspending the drug of choice in at least one of the blends, each of which has been made by mixing a suitable solvent with the pressure sensitive adhesive of choice. The drug reservoir layer can be coated first on a release liner, dried and then laminated to the desired backing film, according to predetermined parameters, such as temperature and dwell time (line speed), which yield minimal residual solvent levels. The optional skin contact layer can then be coated on a separate release liner and dried. The release liner can be removed from the drug reservoir layer and the adhesive side of the skin contact layer laminated onto the adhesive side of the drug reservoir layer so that the drug reservoir layer lies between the backing and the skin contact layer. If the drug initially is suspended or dissolved in only one of the two adhesive layers, it will, over time, equilibrate into the other adhesive layer until the degree of saturation is the same in both layers. It may be desirable to prepare the composition with the drug initially suspended or dispersed in only one of the two adhesive layers if for example, the other adhesive layer is prepared with a solvent which would be deleterious to the drug but which evaporates during processing (coating and drying).
(65) If more than two layers are to be provided, the third (middle) layer can be coated as a liquid onto a release liner, dried, laminated to either the adhesive side of the dried skin contact layer or the adhesive side of the dried drug reservoir layer once the release liner has been removed from the latter. Then the two parts of the dosage unit can be laminated to one another as above.
(66) Suitable solvents for use in preparing the adhesive blends include acetone, heptane, ethyl acetate, isopropanol, ethanol, hexane, toluene, xylene, 2,4-pentanedione, methanol and water. Short-chain alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol and tert-butanol are preferred, especially for use with acrylic-based matrix. Ethanol is especially preferred. Alkanes such as heptanes, e.g., n-heptane and hexanes, e.g., n-hexane, are especially preferred for use with silicone-based matrices.
(67) Alternative methods for producing or achieving a transdermal delivery dosage unit in accordance with this invention may be apparent to persons skilled in the art, and such alternative methods also fall within the scope of the present invention. For example, an adhesive blend can be coated onto the backing film rather than the release liner. Alternatively, an adhesive coating can be created without using a solvent, such as by heating a hot-melt adhesive to its melting temperature. With this technique, no drying of the adhesive is required, only cooling.
(68) There are many coating techniques for applying a continuous liquid coating onto a substrate, including using a gravure roll, reverse roll, falling film, inkjet, etc. All of these are well-known to persons of ordinary skill in the art and can be used to create pressure-sensitive adhesive layers from a fluid blend. Alternatively, a thin adhesive coating can be achieved by extrusion, in which the adhesive blend is forced through a die under pressure onto the substrate either as a continuous coating or as a printed (intermittent) pattern.
(69) The thickness of the adhesive drug-containing layer (drug reservoir layer) and optional skin contact layers of the compositions of this invention can vary, depending upon such factors as the amount of drug to be delivered from the composition and the desired wear period.
(70) Although such processes can be used for any sized patch, it is particularly suited for use in patches having a surface area ranging from between about 5 cm.sup.2 and about 100 cm.sup.2, and preferably ranging from between about 25 cm.sup.2 and about 75 cm.sup.2, e.g., a patch having a surface area of about 50 cm.sup.2.
(71) In various embodiments of the disclosure, the patches are of any suitable thickness, e.g., about 20 microns or greater in total thickness, including the release liner layer. Certain embodiments of the disclosure range from between about 20 microns to about 1,500 microns in total thickness. In some embodiments, the patches have a total thickness of about 250 microns.
(72) The dosage unit forms are made from the resulting multiple layer structure by die stamping to provide patches of desired shape and size.
(73) Once the dosage unit forms have been prepared, they are placed in an appropriate packaging system for storage and sealed therein in the substantial absence of oxidizing agents, e.g., air, until they are to be used in transdermal treatment. The packaging system can comprise a pouch, envelope, or any other suitable structure surrounding the dosage unit form. The structure is typically made from a plastic film or laminated film which is substantially impermeable to water vapor and air, including oxygen. In various embodiments the laminate can comprise a thermoplastic film which is heat sealable.
(74) In certain embodiments the packaging system comprises a pouch made from a multiple laminate film. The film typically exhibits an oxygen transmission rate of less than about 0.05 ml/100 in.sup.2/24 hr/bar measured at 22 C. (72 F.), e.g., less than about 0.04 ml/100 in.sup.2/24 hr/bar measured at 22 C. (72 F.), e.g., from about 0.01 to about 0.03 ml/100 in.sup.2/24 hr/bar.
(75) Once the dosage unit forms have been prepared, they are placed and sealed in appropriate packaging for storage until they are to be applied in transdermal treatment.
(76) The compositions of this disclosure possess sufficient adhesive properties that once the release liner is removed and the composition is applied to a patient's skin the composition can remain in place for a period of time sufficient to distribute the desired amount of the drug contained therein with a low incidence of debonding or delamination.
(77) In certain embodiments of the present disclosure, the thickness of the matrix layer or pharmaceutical composition layer in the transdermal device of the present disclosure ranges from about 20 to about 1000 microns, more preferably from about 60 to about 100 microns.
(78) In various embodiments of the present disclosure, the transdermal device is formed as a continuous sheet or web and may be cut into desired width and length, or separated along a frangible area dividing each device, into patches before use although such devices may be provided as discrete patches which are cut with a die into the desired shape, e.g., circular.
(79) The transdermal devices of the invention in general have, for example an effective contact area of pharmaceutical composition on the skin of from about 1 to about 80 cm.sup.2, preferably about 50 cm.sup.2, and are intended to be applied at intervals of about once every 2 to 7 days, preferably about every 7 days. The patch may be applied, for example on the abdomen, thigh, behind an ear, or on a shoulder or upper arm.
(80) Pharmaceutical compositions of the present disclosure formed as a transdermal device are useful for the same indications as for known compositions containing the active pharmaceutical ingredient or drug. The exact amounts of active pharmaceutical ingredient to be administered may depend on a number of factors, e.g. the drug release characteristics of the compositions, the drug penetration rate observed in vitro and in vivo, the duration of action required, the form of active pharmaceutical ingredient, and for transdermal compositions the size of the skin contact area, and the part of the body to which the unit is fixed. The amount of active pharmaceutical ingredient and surface area of the patch may be optimized through routine bioavailability tests measuring the blood levels of active agents after administration of the active pharmaceutical ingredient composition to intact skin and comparing those blood levels to those following oral administration of a therapeutically effective dose of the active pharmaceutical ingredient.
(81) With reference to the FIGURES, the transdermal device of the present disclosure can be further explained as follows:
(82)
(83)
(84)
(85)
(86) The invention will now be described in more detail by the following non-limiting EXAMPLES. In all the EXAMPLES, the polymer matrix contains the active pharmaceutical ingredient pramipexole free base in an amount of at least 5.5% w/w relative to the active-containing matrix. The EXAMPLES are presented to illustrate but a few embodiments of the invention. All parts are by weight unless otherwise indicated.
Examples 1-4 (Acrylic-Based Samples)
(87) Four samples of the transdermal therapeutic system of the present disclosure were prepared as follows, based on the batch compositions used in preparing the active ingredient-containing matrix layers (acrylic-based), two with Duro-Tak 87-900 A and two with Duro-Tak 87-2287 A as set out in TABLE 4 below.
(88) TABLE-US-00004 TABLE 4 Batch Batch compositions using Batch compositions using Duro-Tak 87-900 A Duro-Tak 87-2287 A Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ingredient % w/w % w/w % w/w % w/w Pramipexole free 5.5 6.0 5.5 6.0 base Plasdone K- 90 5.0 10.0 5.0 10.0 (Polyvinyl- pyrrolidone) Duro-Tak 89.5 84 87-2287 A Duro-Tak 89.5 84 900 A Ethanol q.s. q.s. q.s. q.s.
(89) Ethanol was added to a glass beaker to which polyvinylpyrrolidone (povidone) Plasdone K-90, available from Ashland, Inc. was added and dissolved. Pramipexole free base was then added to the beaker and dissolved by sonication to form a pramipexole mixture. The Duro-Tak component was then weighed in a glass jar to which was then added the pramipexole mixture with mixing for a suitable time using a stirrer and/or jar roller. The jar rolling was carried out as needed to effectively degas the resulting mixture. The resulting degassed matrix layer precursor mixture was then coated onto one side of a MEDIRELEASE 2249 film. The uncoated side was then laminated with MEDIFLEX 1200 backing layer.
Example 5 (Silicone-Based Sample)
(90) A sample of the transdermal therapeutic system of the present disclosure was prepared as follows, based on the batch composition used in preparing the active ingredient-containing matrix layer (silicone-based), made with Bio PSA 7-4301 as set out in TABLE 5 below.
(91) TABLE-US-00005 TABLE 5 Ex. 5 - Batch composition using Silicone Bio PSA Ingredient % w/w Pramipexole base 7.0 Silicone (Bio PSA 7-4301) 93.0
(92) DOW CORNING BIO-PSA 7-4301 SILICONE ADHESIVE was weighed out and added to a glass jar, to which a weighed portion of pramipexole free base was then added and dispersed to form a pramipexole mixture, followed by mixing for a suitable time using a stirrer and/or jar roller. The jar rolling was carried out as needed to effectively degas the resulting mixture. The resulting degassed matrix layer precursor mixture was coated onto one side of a Scotchpak 1022 release film layer. The uncoated side was then laminated with MEDIFLEX 1200 backing layer.
Example 6 (Comparative Polyisobutene-Based Sample)
(93) A sample of the transdermal therapeutic system of the present disclosure was prepared as follows, based on the batch composition used in preparing the active ingredient-containing matrix layer (silicone-based), made with Duro-Tak PIB 612 A as set out in TABLE 6 below.
(94) TABLE-US-00006 TABLE 6 Ex. 6 - Drug Composition Using Polyisobutene Adhesive Ingredient % w/w Pramipexole base 7.0 Duro-Tak PIB 612 A 93.0
(95) Duro-Tak PIB 612 A polyisobutene adhesive was weighed out and added to a glass jar, to which a weighed portion of pramipexole free base was then added and dispersed to form a pramipexole mixture, followed by mixing for a suitable time using a stirrer and/or jar roller. The jar rolling was carried out as needed to effectively degas the resulting mixture. The resulting degassed matrix layer precursor mixture was coated onto one side of a Scotchpak 1022 release film layer. The uncoated side was then laminated with MEDIFLEX 1200 backing layer.
Example 7 (Multi-Layer Adhesive Matrix without Polyvinylpyrrolidone)
(96) A sample of the transdermal therapeutic system of the present disclosure was prepared as follows, based on the batch composition used in preparing the active ingredient-containing matrix layers (including a skin contact layer without active ingredient), made with Duro-Tak 87-2287 A as set out in TABLE 7 below.
(97) TABLE-US-00007 TABLE 7 Ex. 7 - Drug Composition Using Multi-Layer Adhesive Matrix Ingredient % w/w Pramipexole base 7.0 Duro-Tak 87-2287 A 93.0 Ethanol q.s. Contact layer (Without Drug) Duro-Tak 87-2287 A 100.0
(98) Ethanol was weighed and added to a glass beaker. Pramipexole free base was then added to the beaker and dissolved to form a pramipexole mixture. The Duro-Tak component was then weighed in a glass jar to which was then added the pramipexole mixture with mixing for a suitable time using a stirrer and/or jar roller. The jar rolling was carried out for a suitable time as needed to effectively degas the resulting mixture. The resulting degassed matrix layer precursor mixture was then coated onto one side of a MEDIRELEASE 2249 film. The uncoated side was then laminated with MEDIFLEX 1200 backing layer. The contact layer was prepared by coating one side of a MEDIRELEASE 2249 film with Duro-Tak 87-2287 A. The release liner was then removed from the pramipexole-containing laminate and laminated with the contact layer, providing a multi-layer adhesive matrix having a skin contact layer.
Example 8 (Multi-Layer Adhesive Matrix with Polyvinylpyrrolidone)
(99) A sample of the transdermal therapeutic system of the present disclosure was prepared as follows, based on the batch composition used in preparing the active ingredient-containing matrix layers (including a skin contact layer without active ingredient), made with Duro-Tak 87-2287 A as set out in TABLE 8 below.
(100) TABLE-US-00008 TABLE 8 Ex. 8 - Drug Composition Using Multi-Layer Adhesive Matrix Pramipexole base 7.0 Duro-Tak 87-2287 A 88.0 Plasdone K- 90 5.0 (Polyvinylpyrrolidone) Ethanol q.s. Contact layer Duro-Tak 87-2287 A 100.0
(101) Ethanol was added to a glass beaker to which polyvinylpyrrolidone (povidone) Plasdone K-90, available from Ashland, Inc. was added and dissolved. Pramipexole free base was then weighed out, added to the beaker and dissolved by sonication to form a pramipexole mixture. The Duro-Tak component was then weighed in a glass jar to which was then added the pramipexole mixture with mixing for a suitable time using a stirrer and/or jar roller. The jar rolling was carried out for a suitable time as needed to effectively degas the resulting mixture. The resulting degassed matrix layer precursor mixture was then coated onto one side of a MEDIRELEASE 2249 film. The uncoated side was then laminated with MEDIFLEX 1200 backing layer. The contact layer was prepared by coating one side of a MEDIRELEASE 2249 film with Duro-Tak 87-2287 A. The release liner was then removed from the pramipexole-containing laminate and laminated with the contact layer, providing a multi-layer adhesive matrix having a skin contact layer.
Example 9 (Crystal Growth Observation for Batch Composition Using Duro-Tak 87-900A)
(102) A product of the disclosure made from a batch composition using Duro-Tak 87-900A was inspected for appearance, including color and crystal growth. It was then separately subjected to storage for six months at accelerated aging conditions (40 C.) and control room temperature conditions (20 C.) and then reinspected. Results are set out below in TABLE 9.
(103) TABLE-US-00009 TABLE 9 Batch Compositions Using Duro-Tak 87-900A Parameters Initial 6 Months Appearance Clear translucent patches Clear translucent patches No color change observed Crystal growth accelerated Clear translucent patches Clear translucent patches aging condition No crystal growth observed Control room Clear translucent patches Clear translucent patches temperature. No crystal growth observed
Example 10 (Crystal Growth Observation for Batch Composition Using Duro-Tak 87-2287 A)
(104) A product of the disclosure made from a batch composition using Duro-Tak 87-2287 A was inspected for appearance, including color and crystal growth. It was then separately subjected to storage for six months at accelerated aging conditions (40 C.) and control room temperature conditions (40 C.) and then reinspected. Results are set out below in TABLE 10.
(105) TABLE-US-00010 TABLE 10 Batch Compositions Using Duro-Tak 87-2287 A Parameters Initial 6 Months Appearance Clear translucent patches Clear translucent patches No color change observed. Crystal growth Accelerated Clear translucent patches Clear translucent patches aging condition No crystal growth observed. Control room Clear translucent patches Clear translucent patches temperature. No crystal growth observed.
Example 11 (Crystal Growth Observation for Batch Compositions Using Silicone Adhesive and Polyisobutene Adhesive)
(106) Products made from batch compositions using Dow Corning BIO-PSA 7-4301 (Silicone Adhesive) and Duro-Tak PIB 612 A (Polyisobutene Adhesive) were inspected for appearance, including color and crystal growth. They were then separately subjected to storage for six months at accelerated aging conditions (40 C.) and control room temperature conditions (20 C.) and then reinspected. The results are set out below in TABLE 11.
(107) TABLE-US-00011 TABLE 11 Batch compositions using Dow Corning BIO-PSA 7- 4301 (Silicone Adhesive) and Duro-Tak PIB 612 A (Polyisobutene Adhesive) Parameters Initial 6 Months Appearance Translucent patches with Translucent patches with drug dispersed in drug dispersed in adhesive matrix adhesive matrix. No color change observed. Crystal growth accelerated Translucent patches with Translucent patches with condition drug dispersed in drug dispersed in adhesive matrix adhesive matrix. No crystal growth or agglomerates observed. Control room Translucent patches with Translucent patches with temperature drug dispersed in drug dispersed in adhesive matrix adhesive matrix No crystal growth or agglomerates observed
Example 12 (Stability Testing for Batch Composition Using Duro-Tak 87-900A)
(108) A product of the disclosure made from a batch composition using Duro-Tak 87-900A was tested for initial stability including the presence of crystals and impurities associated with pramipexole manufacture and degradation. The product was then subjected to storage one month at room temperature (25 C.) for three months (with inspection at monthly intervals) and accelerated aging conditions (40 C.) for six months (with inspection at one, two, three and six month intervals). Results are set out below in TABLE 12.
(109) Oxidation, a prime cause of product instability resulting from adding oxygen or removing hydrogen, can be evinced by discoloration of the active ingredient or matrix layer in which it resides, e.g., as visible to the unassisted eye, or as determinable by conventional colorometric techniques known to the person of skill in the art.
(110) TABLE-US-00012 TABLE 12 Stability Data for Batch Composition with Duro-Tak 87-900A Initial RT 25 C./60 F. Accelerated Stability Time 1 Month 3 Month 6 Month 1 Month 2 Month 3 Month 6 Month Assay 103.2 97.7 103.1 100.0 100.9 96.9 101.3 (%) RELATED SUBSTANCES (% w/w) RT 25 C./60 F. Accelerated Impurity Initial 6 M 1 Month 2 Month 3 Month 6 Month Imp. A 0.031 0.130 0.048 0.083 0.078 0.098 Imp. B 0.0 0.014 0.0 0.0 0.0 0.016 Highest 0.033 0.327 0.239 0.260 0.228 0.334 unknown Total 0.090 0.644 0.333 0.401 0.352 0.624 Unknown Total 0.121 0.788 0.381 0.484 0.430 0.736
Example 13 (Determining Flux Rate Profiles of Examples 1-4)
(111) In vitro pramipexole flux rates from transdermal patches made according to Examples 1 and 2 (Using Duro-Tak 87-2287 A) and Examples 3 and 4 (Using Duro-Tak 87-900A) was determined and plotted as flux profiles (flux rate over time) in
(112) A flux profile was determined according to conventional methods known to those skilled in the art, using human cadaver skin (46) under the following conditions: phosphate buffer of 7.4 pH, temperature 32 C., 300 RPM paddle speed during dissolution, with complete decantations.
(113) A pramipexole transdermal delivery system having a drug releasing interface surface area of 1 cm.sup.2 may be used. In the test, the pramipexole transdermal delivery system can be held adhesively on a stainless steel holder, having the drug releasing surface of the patch facing up and immersable in release medium, and positioned at the center of a USP Dissolution Apparatus II with 1 L vessels. Accurately, 600 mL of degassed 0.005N sodium phosphate, pH 7.4 phosphate buffer solution is placed in the vessels and maintained at 32 C. and 300 rpm paddle speed during the dissolution experiment.
(114) At the preset time intervals of 1, 3, 6, 9, 12, 24, 48, 72, 96, 120, 144, and 168 hours, 1 mL portions of the dissolution medium can be withdrawn from the vessels and dispensed into HPLC vials.
(115) Release rates of pramipexole over time from the sample transdermal delivery systems were plotted and the resulting profiles are presented in
(116)
(117)
Example 14 (Determining Flux Rate Profiles of Examples 5-8)
(118) In vitro pramipexole flux rates from transdermal patches made according to Example 5 (using silicone Bio PSA 7-4301), Example 6 (using polyisobutene Duro-Tak PIB 612 A, and Examples 7 and 8 (using Duro-Tak 87-2287 A) were determined according to the procedures provided in EXAMPLE 13 and plotted as flux profiles in
(119)
(120) Average readings (taken by averaging three readings) used in preparing the flux profiles of
(121) TABLE-US-00013 TABLE 13 FLUX DATA For FIG. 3 and FIG. 4 Label Claim/6.99 cm2 5.00 mg 4.10 mg 3.59 mg 3.17 mg Amount Permeated Ex. 5 Ex. 6 Ex. 7 Ex. 8 B. NO. VIB-0716-087 VIB-0716-089 VIB-0716-092 VIB-0716-095 CELL NO. microg/sq .Math. cm microg/sq .Math. cm microg/sq .Math. cm microg/sq .Math. cm HRS. Avg Avg Avg Avg 0 0 0 0 0 3 13.5 6.7 30.6 21.1 6 45.8 17.1 78.9 65.5 9 83.3 27.1 126.4 109 12 139.3 39.5 190.5 165.9 24 283.7 68 333 295.8 48 471.2 101.4 503.8 450.5 72 658.8 119.6 615.8 544.5 96 787.4 133.3 678.7 598.4 120 869.2 145 717.7 634.3 144 916.8 154.1 740.8 657.6 168 957.3 164.1 760.8 677.3 Ex. 5 Ex. 6 Ex. 7 Ex. 8 B. NO. VIB-0716-087 VIB-0716-089 VIB-0716-092 VIB-0716-095 CELL NO. Flux g/cm2/hr Flux g/cm2/hr Flux g/cm2/hr Flux g/cm2/hr HRS. Avg Avg Avg Avg 0 0 0 0 0 3 4.5 2.2 10.2 7 6 10.8 3.4 16.1 14.8 9 12.5 3.3 15.8 14.5 12 18.6 4.1 21.4 19 24 12 2.4 11.9 10.8 48 7.8 1.4 7.1 6.4 72 7.8 0.8 4.7 3.9 96 5.4 0.6 2.6 2.3 120 3.4 0.5 1.6 1.5 144 2 0.4 1 1 168 1.7 0.4 0.8 0.8
Examples 15-18 (Batch Compositions Made with Duro-Tak 87-900 A and Varying Levels of Polyvinylpyrrolicone)
(122) Ethanol was added to a glass beaker to which polyvinylpyrrolidone (povidone) Plasdone K-90, available from Ashland, Inc. was added and dissolved. Pramipexole free base was then added to the beaker and dissolved to form a pramipexole mixture. The Duro-Tak component was then weighed in a glass jar to which was then added the pramipexole mixture with mixing for a suitable time using a stirrer and/or jar roller. The jar rolling was carried out as needed to effectively degas the resulting mixture. The resulting degassed matrix layer precursor mixture was then coated onto one side of a MEDIRELEASE 2249 film. The uncoated side was then laminated with MEDIFLEX 1200 backing layer. Crystal growth observations were made after 5 months of storage. Results are set out below in TABLE 14.
(123) TABLE-US-00014 TABLE 14 Drug in single adhesive matrix layer with higher levels of PVP in Duro-Tak 87-900 A system Ex. 15 Ex. 16 Ex. 17 Ex. 18 Batch No. 0956-151 0956-160 0956-163 0956-166 Pramipexole 5.0 5.0 5.0 5.0 base Plasdone 90 12.5 15.0 17.5 20.0 DT 900 A 82.50 80.0 77.5 75.0 Ethanol q.s q.s. q.s q.s. CRYSTAL GROWTH OBSERVATIONS 25/60 Crystal Crystal Crystal Crystal Not Not Not Not Observed Observed Observed Observed 5 Months 5 Months 5 Months 5 Months 40/75 Crystal Crystal Crystal Crystal Not Not Not Not Observed Observed Observed Observed 5 months 5 Months 5 months 5 Months
Examples 19-23 (Batch Compositions Made with Drug Dispersion Reservoir Layer of BIO PSA-4201 and Contact Layer of Duro-Tak 87-900 A with and without Polyvinylpyrrolicone)
(124) SILICONE (BIO-PSA 4201) was weighed out in a glass jar. Pramipexole free base was then weighed out, added to the jar and dispersed to form a pramipexole dispersion which was mixed for a suitable time using a stirrer and/or jar roller. The jar rolling was carried out for a suitable time as needed to effectively degas the resulting mixture. The resulting degassed matrix layer precursor mixture was then coated onto one side of an intermediate release liner (Scotchpak 1022) to provide a silicone-coated film. Duro-Tak 87-900A coating prepared with and without added Plasdone K-90, polyvinylpyrrolidone available from Ashland, Inc., and coated onto one side of an intermediate release liner (Scotchpak 1022) to form a Duro-Tak 87-900A coated material. The release liner was then removed from the silicone-coated film and the resulting product was then laminated with the Duro-Tak 87-900A coated material. Additional information is set out below in TABLE 15.
(125) TABLE-US-00015 TABLE 15 MULTI LAYER SYSTEM WITH DRUG DISPERSION RESERVOIR LAYER of SILICONE (BIO-PSA 4201) and CONTACT LAYER (Duro-Tak 900 A) Ex. 19 Ex. 20 Ex. 21 Ex. 22 Ex. 23 Batch No. 0956-195 1087-001 1087-006 1087-043 1087-096 Drug Layer (DL) Pramipexole 5.0 5.0 5.0 7.0 15.0 base Silicone Bio- 95.0 95.0 95.0 93.0 85.0 PSA 4201 Skin Contact layer (SC) Durotak 900 A Contact Layer Contact Layer Contact Layer Contact Layer Contact Layer 100.0 90.0 100.0 90.0 90.0 Povidone K 90 10.0 10.0 10.0 Ethanol q.s q.s q.s GSM (g/m.sup.2) 100 + 40 100 + 40 100 + 40 100 + 40 100 + 40
Example 24 (Determining Flux Rate Profiles of Examples 16, 19, and 22)
(126) In vitro pramipexole flux rates from transdermal patches made according to EXAMPLES 16, 19 and 22 were determined according to the procedures provided in EXAMPLE 13 and plotted as flux profiles in
Examples 25-28 (Batch Compositions Made with Acrylic Drug Dispersion Reservoir Layer of Duro-Tak 87-900 A or DuroTak 87-2287 with Polyvinylpyrrolicone)
(127) Ethanol was added to a glass beaker to which polyvinylpyrrolidone Plasdone K-90 (povidone; PVP K90), available from Ashland, Inc., was added and dissolved. Pramipexole free base was then added to the beaker and dissolved to form a pramipexole mixture. The Duro-Tak component was then weighed in a glass jar to which was then added the pramipexole mixture with mixing for a suitable time using a stirrer and/or jar roller. The jar rolling was carried out as needed to effectively degas the resulting mixture. The resulting degassed matrix layer precursor mixture was then coated onto one side of a MEDIRELEASE 2249 film at a coating weight of either 70 g/m.sup.2 or 100 g/m.sup.2. The uncoated side was then laminated with MEDIFLEX 1200 backing layer, as shown in TABLE 16.
(128) TABLE-US-00016 TABLE 16 Drug in single adhesive matrix layer with higher levels of PVP in Duro-Tak 87-900 A system Ex. 25 Ex. 26 Ex. 27 Ex. 28 Batch No. 0956-001 0956-016 0956-031 0716-194 Pramipexole 5.5 5.5 6 6 base PVP K90 5 5 10 10 DT 2287 89.5 84 DT 900 A 89.5 84 Ethanol q.s. q.s. q.s. q.s
(129) Formulations 0716-194 and 0956-031 were coated onto a backing, and formulated into transdermal dosage forms having an area of 7 cm.sup.2, containing 2.94 mg pramipexole base per dosage form (2.94 mg/7 cm.sup.2). Formulations 0956-001 and 0956-016 were coated onto a backing, and formulated into transdermal dosage forms having an area of 7 cm.sup.2, containing 3.85 mg pramipexole base per dosage form (2.94 mg/7 cm.sup.2).
Example 29 (Comparative Multi-Layer Adhesive Matrix with Polyvinylpyrrolidone)
(130) A comparative example of the transdermal therapeutic system of the present disclosure was prepared as follows, based on the batch composition used in preparing the active ingredient-containing matrix layers including a reservoir layer and a skin contact layer, made with Duro-Tak 87-2287 A as set out in TABLE 17 below. The reservoir layer and the skin contact layer each contain less than 5% w/w of the active ingredient.
(131) TABLE-US-00017 TABLE 17 Ex. 29 - Drug Composition Using Multi-Layer Adhesive Matrix (Batch No. 1087-031) Ingredient % w/w Reservoir Layer Pramipexole base 4 PVP K90 12.5 Duro-Tak 87-900 A 83.5 Ethanol q.s. Contact layer Pramipexole base 2 PVP K90 12.5 Duro-Tak 87-900 A 85.5 Ethanol q.s.
(132) Ethanol was weighed and added to a glass beaker. Pramipexole free base was then added to the beaker and dissolved to form a pramipexole mixture. The Duro-Tak component was then weighed in a glass jar to which was then added the pramipexole mixture with mixing for a suitable time using a stirrer and/or jar roller. The jar rolling was carried out for a suitable time as needed to effectively degas the resulting mixture. The resulting degassed matrix layer precursor mixture was then coated onto one side of a MEDIRELEASE 2249 film at a coating weight of 90 g/m.sup.2. The uncoated side was then laminated with MEDIFLEX 1200 backing layer.
(133) The formulation for the contact layer was prepared in the same manner as the reservoir layer formulation, and coated onto one side of a MEDIRELEASE 2249 film at a coating weight of 40 g/m.sup.2. The release liner was then removed from the pramipexole-containing laminate and laminated with the contact layer, providing a multi-layer adhesive matrix having a skin contact layer.
Example 30 (Determining Flux Rate Profiles of Examples 16, 19, 22, and 29)
(134) In vitro pramipexole flux rates from transdermal patches made according to Examples 19 and 22 (using a silicone reservoir layer and a Duro-Tak contact layer), Example 16 (using a Duro-Tak monolayer), and comparative Example 29 (using a drug-containing Duro-Tak reservoir layer and a drug-containing Duro-Tak contact layer) were determined according to the procedures provided in EXAMPLE 13 and plotted as flux profiles in
(135)
(136) Average readings (taken by averaging three readings) used in preparing the flux profiles of
(137) TABLE-US-00018 TABLE 18 FLUX DATA For FIG. 7 and FIG. 8 Amount Permeated Ex. 29 Ex. 22 Ex. 16 Ex. 19 B. NO. 1087-031 1087-043 0956-160 0956-195 microg/sq .Math. cm microg/sq .Math. cm microg/sq .Math. cm microg/sq .Math. cm HRS. 0 0.0 0.0 0.0 0.0 3 0.1 0.1 0.1 0.0 6 0.2 0.2 0.3 0.0 9 0.5 0.5 1.4 0.0 12 1.0 1.2 4.5 0.2 24 6.2 20.5 48.8 4.0 48 18.4 122.3 159.0 41.6 72 29.8 240.9 248.2 102.9 96 38.5 350.9 318.1 172.2 120 45.9 443.2 375.4 242.4 144 52.4 509.5 420.1 300.9 168 74.5 554.9 461.9 336.6 Ex. 29 Ex. 22 Ex. 16 Ex. 19 B. NO. 1087-031 1087-043 0956-160 0956-195 Flux g/cm2/hr Flux g/cm2/hr Flux g/cm2/hr Flux g/cm2/hr HRS. 0 0.0 0.0 0.0 0.0 3 0.0 0.0 0.0 0.0 6 0.0 0.0 0.1 0.0 9 0.1 0.1 0.4 0.0 12 0.2 0.2 1.0 0.0 24 0.4 1.6 3.7 0.3 48 0.5 4.2 4.6 1.6 72 0.5 4.9 3.7 2.6 96 0.4 4.6 2.9 2.9 120 0.3 3.8 2.4 2.9 144 0.3 2.8 1.9 2.4 168 0.9 1.9 1.7 1.5
Example 31 (Determining Flux Rate Profiles of Examples 25, 26, 27, and 28)
(138) In vitro pramipexole flux rates from transdermal patches made according to Examples 25, 26, 27, and 28 (using a Duro-Tak monolayer) were determined according to the procedures provided in EXAMPLE 13 and plotted as flux profiles in
(139)
(140) Average readings (taken by averaging three readings) used in preparing the flux profiles of
(141) TABLE-US-00019 TABLE 19 FLUX DATA For FIG. 9 and FIG. 10 Label Claim/6.99 cm2 5.00 mg 4.10 mg 3.59 mg 3.17 mg Amount Permeated Ex. 25 Ex. 26 Ex. 27 Ex. 28 B. NO. 0956-001 0956-016 0956-031 0716-194 microg/sq .Math. cm microg/sq .Math. cm microg/sq .Math. cm microg/sq .Math. cm HRS. 0 0.0 0.0 0.0 0.0 3 1.3 0.6 1.3 0.9 6 3.3 1.8 3.0 2.2 9 5.3 3.8 4.8 3.4 12 8.0 7.7 7.0 5.0 24 26.0 41.2 23.4 11.8 48 104.3 147.2 91.3 41.2 72 189.9 247.5 170.5 93.4 96 263.6 328.3 236.2 139.2 120 345.2 411.1 303.7 191.4 144 380.6 446.3 339.5 216.7 168 426.6 481.8 381.0 250.1 Ex. 25 Ex. 26 Ex. 27 Ex. 28 B. NO. 0956-001 0956-016 0956-031 0716-194 Flux g/cm2/hr Flux g/cm2/hr Flux g/cm2/hr Flux g/cm2/hr HRS. 0 0.0 0.0 0.0 0.0 3 0.4 0.2 0.4 0.3 6 0.7 0.4 0.6 0.4 9 0.7 0.7 0.6 0.4 12 0.9 1.5 0.7 0.5 24 1.5 2.8 1.4 0.6 48 3.3 4.4 2.8 1.2 72 3.6 4.2 3.3 2.2 96 3.1 3.4 2.7 1.9 120 3.4 3.5 2.8 2.2 144 1.5 1.5 1.5 1.1 168 1.9 1.5 1.7 1.4
(142) Although various exemplary embodiments have been described in detail with particular reference to certain exemplary aspects thereof, it should be understood that the subject matter disclosed herein is capable of other different embodiments, and its details are capable of modifications in various obvious respects. As is readily apparent to those skilled in the art, variations and modifications can be affected while remaining within the spirit and scope of the disclosure. Accordingly, the foregoing disclosure, description, and figures are for illustrative purposes only, and do not in any way limit the invention, which is defined only by the claims.