CA1163559A - Polymeric diffusion matrix for administration of drugs - Google Patents
Polymeric diffusion matrix for administration of drugsInfo
- Publication number
- CA1163559A CA1163559A CA000380505A CA380505A CA1163559A CA 1163559 A CA1163559 A CA 1163559A CA 000380505 A CA000380505 A CA 000380505A CA 380505 A CA380505 A CA 380505A CA 1163559 A CA1163559 A CA 1163559A
- Authority
- CA
- Canada
- Prior art keywords
- weight
- patient
- diffusion matrix
- sustained release
- polyvinylalcohol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 239000011159 matrix material Substances 0.000 title claims abstract description 62
- 238000009792 diffusion process Methods 0.000 title claims abstract description 52
- 229940079593 drug Drugs 0.000 title claims abstract description 40
- 239000003814 drug Substances 0.000 title claims abstract description 40
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 57
- 239000004372 Polyvinyl alcohol Substances 0.000 claims abstract description 25
- 229920002451 polyvinyl alcohol Polymers 0.000 claims abstract description 25
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims abstract description 25
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims abstract description 21
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 21
- 238000013268 sustained release Methods 0.000 claims abstract description 19
- 239000012730 sustained-release form Substances 0.000 claims abstract description 19
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 claims abstract description 18
- 239000004014 plasticizer Substances 0.000 claims abstract description 18
- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229960000195 terbutaline Drugs 0.000 claims abstract description 12
- 229960001802 phenylephrine Drugs 0.000 claims abstract description 10
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 claims abstract description 10
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229960002179 ephedrine Drugs 0.000 claims abstract description 9
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 claims abstract description 8
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229940046978 chlorpheniramine maleate Drugs 0.000 claims abstract description 8
- 229960002896 clonidine Drugs 0.000 claims abstract description 8
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 claims abstract description 8
- -1 e.g. Substances 0.000 claims abstract description 8
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 claims abstract description 8
- 229960000395 phenylpropanolamine Drugs 0.000 claims abstract description 8
- 150000002159 estradiols Chemical class 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims description 18
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 15
- 230000000694 effects Effects 0.000 claims description 12
- 239000002202 Polyethylene glycol Substances 0.000 claims description 10
- 230000002035 prolonged effect Effects 0.000 claims description 10
- 229920001223 polyethylene glycol Polymers 0.000 claims description 9
- 229960005309 estradiol Drugs 0.000 claims description 8
- 229930182833 estradiol Natural products 0.000 claims description 8
- 229940124630 bronchodilator Drugs 0.000 claims description 5
- 239000000850 decongestant Substances 0.000 claims description 4
- 230000001225 therapeutic effect Effects 0.000 claims description 4
- 238000012423 maintenance Methods 0.000 claims description 3
- 230000001387 anti-histamine Effects 0.000 claims description 2
- 230000003276 anti-hypertensive effect Effects 0.000 claims description 2
- 230000037317 transdermal delivery Effects 0.000 claims 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 12
- 239000003071 vasodilator agent Substances 0.000 abstract 1
- 229940068984 polyvinyl alcohol Drugs 0.000 description 12
- 229920000642 polymer Polymers 0.000 description 6
- 229920000936 Agarose Polymers 0.000 description 5
- 229920001817 Agar Polymers 0.000 description 4
- 239000008272 agar Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 238000013019 agitation Methods 0.000 description 3
- 238000005266 casting Methods 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 239000008240 homogeneous mixture Substances 0.000 description 3
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- VQHQLBARMFAKSV-AANPDWTMSA-N [(8r,9s,13s,14s,17s)-3-acetyloxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1CC2=CC(OC(C)=O)=CC=C2[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)C)[C@@]1(C)CC2 VQHQLBARMFAKSV-AANPDWTMSA-N 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- NZJXADCEESMBPW-UHFFFAOYSA-N 1-methylsulfinyldecane Chemical compound CCCCCCCCCCS(C)=O NZJXADCEESMBPW-UHFFFAOYSA-N 0.000 description 1
- OMIGHNLMNHATMP-UHFFFAOYSA-N 2-hydroxyethyl prop-2-enoate Chemical compound OCCOC(=O)C=C OMIGHNLMNHATMP-UHFFFAOYSA-N 0.000 description 1
- GNSFRPWPOGYVLO-UHFFFAOYSA-N 3-hydroxypropyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCCCO GNSFRPWPOGYVLO-UHFFFAOYSA-N 0.000 description 1
- QZPSOSOOLFHYRR-UHFFFAOYSA-N 3-hydroxypropyl prop-2-enoate Chemical compound OCCCOC(=O)C=C QZPSOSOOLFHYRR-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 229920002799 BoPET Polymers 0.000 description 1
- DSEKYWAQQVUQTP-UHFFFAOYSA-N Cerin Natural products CC12CCC3(C)C4CC(C)(C)CCC4(C)CCC3(C)C2CCC2(C)C1CC(O)C(=O)C2C DSEKYWAQQVUQTP-UHFFFAOYSA-N 0.000 description 1
- HSRJKNPTNIJEKV-UHFFFAOYSA-N Guaifenesin Chemical compound COC1=CC=CC=C1OCC(O)CO HSRJKNPTNIJEKV-UHFFFAOYSA-N 0.000 description 1
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 description 1
- 229920002845 Poly(methacrylic acid) Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 239000012790 adhesive layer Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 239000000306 component Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000001879 gelation Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000133 nasal decongestant Substances 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 210000000707 wrist Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
- A61K9/0036—Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Reproductive Health (AREA)
- Urology & Nephrology (AREA)
- Gynecology & Obstetrics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
ABSTRACT
A polymeric diffusion matrix for administering a drug is provided comprising from about 2 to about 60% of a polar plasticizer, e.g., glycerol, from about 6 to about 20% of polyvinylalcohol, from about 2 to about 10% of polyvinylpyr-rolidone, and a pharmaceutically effective amount of drug, yielding a matrix capable of sustained release of a vasodila-tor drug dispersed therein, and the balance water, the per-centages being by weight The drugs include terbutaline, ephedrine, clonidine, phenylephrine, estradiol esters, phenyl-propanolamine, and chlorpheniramine maleate.
A polymeric diffusion matrix for administering a drug is provided comprising from about 2 to about 60% of a polar plasticizer, e.g., glycerol, from about 6 to about 20% of polyvinylalcohol, from about 2 to about 10% of polyvinylpyr-rolidone, and a pharmaceutically effective amount of drug, yielding a matrix capable of sustained release of a vasodila-tor drug dispersed therein, and the balance water, the per-centages being by weight The drugs include terbutaline, ephedrine, clonidine, phenylephrine, estradiol esters, phenyl-propanolamine, and chlorpheniramine maleate.
Description
~ 3 B3~59 POLYMERIC DIFFUSION MATRIX
FOR ADMINISTR~TION OF D~UGS
SUMMARY OF THE INVENTION
The present invention relates to a polymeric diffusion matrix containing one or more drugs suitable for transdermal administration to a patient. More particularly, the invention xelates to a polymeric diffusion matrix containing one or more of such drugs characterized by a sustained relase o-E such drugs. Among the drugs suitable for administration in the polymeric diffusion matrix of this invention are terbutaline, ephedrine, clonidine, phenylephrine, estradiol esters, phenyl-propanolamine, and chlorpheniramine maleate.
A self-supporting polymeric diffusion matrix is provided for the sus-tained release of a drug or drugs in order to transdermally deliver said drug to a patient, and provide said patient with a therapeutic effect, said matrix comprising from about 2 to about 60% by weight of a polar plasticizer; from about 6 to about 20% by weight polyvinylalcohol; from about 2 to about 10% by weight polyvinylpyrrolidone; and a pharmaceu-tically effective amount of drug to provide a sustained release of sa;d drug over a prolonged period.
In one embodiment the polar plasticizer is glycerol pre-sent in an amount of from about 2 to about 60~ by weight. In another embodiment -the polar plasticizer is polyethylene gly-col present in an amount of from about 2 to about 15% by weight. ~ still further embodiment contemplates a mixture of glycerol and polyethylene glycol wherein the la-tter is present in an amount by weight of from about 1 to about 5 parts per weight glycerol.
The self-suppor-ting polymeric diffusion matrix generally '~ .
355g contains a mixture of polyvinylalcohol and polyvinylpyrroli-done, although it will be understood that other polymeric mix-tures may be used provided they yield the desired sustained release effect. For example, both the polyvinylalcohol and the polyvinylpyrrolidone may be completely replaced with from about 1 to ahout 9% agar or agarose, and preferably from about 1.5 to 3% agar or agarose, 2% agar or agarose being particu-larly preferred.
As the polyvinylalcohol used in the present invention there is generally contemplated one having a molecular weight from about 50,000 to about 150,000, and more preferably about 100,000 to about 150,000, 115,000 having been used in related systems of the present inven-tors with success. The polyvinyl-alcohol should be hydrolyzed, generally at least to the extent of 90%, with a preferred embodiment being at least ~5% hydro-lyzed. Polyvinylpyrrolidone should have a molecular weigh-t of from about 15,000 to about ~5,000, and more preferably from about 20,000 to about 60,000. Polyvinylpyrrolidone with a molecular weight of 40,000 is a particularly preferred embodiment.
The amount by weight of the ingredients other than the polar plasticizer generally should be in the following ranges:
polyvinylalcohol is generally present in an amount of -from about 6 to about 20% by weight, with 10% being a preferred embodiment; polyvinylpyrrolidone is present generally in an amount of from about 2 to about 10% by weight.
~ he water-soluble polymer can be replaced with (in addi-tion to agar~ yum arabic, gum tragacanth t polyacrylic acid, polymethacrylic acid, polyvinyloxazolidone, polyvinylmorpho-linone, and polyvinylpiperidone.
Polyalkylene glycols such as polyethylene glycol andpolypropylene glycol may replace all or part of the glycerol.
It is possible to replace the polyvinylalcohol with poly-mers of hydroxyethylacrylate, polymers of hydroxyethylmetha-crylate, polymers of hydroxypropylacrylate, and polymers of ~ ~ ~;3~59 hydroxypropylmethacrylate.
In forming the matrix, excess water is not required. In accordance with a preferred aspect o.E the present invention, about 2~ by weigh-t of any of the drugs listed above are inclu-ded in the difEusion matrix. The resultant homogeneous mix-ture is poured into forms preferably made of glass or stain~
less steel, these forms or templates producing a diffusion matrix having a thickness of about 1 to about 3 mm. in accor-dance with a preferred aspect of the present invention~ This diffusion is either cast or cut into pieces of the desired size.
The following methods may be used for preparing the dif-fusion matrix of the present invention.
~n a first method, the matrix is formed at atmospheric pressure. Water and glycerol are first mixed together.
A polar plasticizer such a glycerol is a necessary compo-nent in the matrix. A matrix formed without a polar plastici-zer is not flexible and has poor diffusional contact with the skin causing unreliable diffusion release.
The polyvinylalcohol and polyvinylpyrrolidone are then added to the polar plasticizer-water mixture at room tempera-ture, with agitation. The mixture is heated to a temperature within the range of from about ~0 to about 95C at atmospheric pressure to extend the polymers. If desired, the mixture may be maintained at an elevated temperature for a period of time, based on polymer stability, prior to addition of the drug.
Thus, the mixture is stable for a period of time and may be kept for such a period before being mixed with the drug to be delivered to the patien-t. Thereafter, the mixture is tempera-ture-adjusted and the drug to be applied to the pa-tient is then added to the mixtuxe, with thorough agitation. Once a homogeneous mixture of the polymer solution and drug is ob-tained, the mixture is ready to be cast to form in a drug-containing diffusion matrix. After cas-ting the mixture is cooled to a temperature such that gelation occurs. In a ~ 1 ~355~
preferred embodiment, the drug may be dissolved by agitation in a suitable solvent such as gl~cerin and water. The thus-obtained solution can be maintained at room temperature for prolonged period without deterioration.
It has been found that curing is facilitated by subjec-ting the matrix to a temperature down -to about -20C immedi-ately after casting. The setting period is quickened considerably.
Sodium dodecyl sulfate or sorbitan (Tween-20) or other detergents may be added in an amount of 0.1 to 10~ by weight, based on the matrix, as a dispersing agent, if desired.
An absorption facilitator to insure skin penetration such as dimethylsulfoxide, decylmethylsulfoxide, or other penetra-tion enhancers may be added.
The present drug delivery device comprises the drug-containing diffusion matrix and means for fastening the matrix to the skin of a patient. Such means can take various forms, such as an occlusive backing layer forming a kind of "bandage"
with the diffusion ma-trix being held against the skin of a pa-tient being treated. A polyethylene or Mylar tape is contem-plated as one form of occlusive layer in accordance with thepresent invention. It can also take the form of an elastic band, such as a cloth band, a rubbery band or other material.
Here, the diffusion matrix is placed directly on -the skin and held in place by such elastic band which typically will be placed over the arm or wrist of the patient. An intermediate adhesive layer between the diffusion matrix and the skin capa-ble of permitting the transdermal application of the drug can also be used.
3~ The amount of the drug to be delivered per day to the pa-tient is in each case generally lower that the oral dosage.
This is accounted for by the fact that in oral applications much of the drug can be expected to be lost by the first pass through the liver. To assure that the desired quantity of the drug i.s delivered, an excess of the drug should be . . .
`~ ~ 63559 , -- S
incorporated in the ma-trix. Where ter~utali~e i5 used to pro-vide a bronchodilator effect, the daily amount to be delivered is generally about 1 to about 20 mg., preferably abou-t l-m~.
With ephedrine a decongestant effect is provided by delivering a daily amount of generally about 5 to about 30 mg., prefer-ably about 20 mg. With clonidone an antihypertensive effect is provided by delivering a daily amount of generally about 0.2 to about 0.6 mg., preferably about 0.4 mg. With phenyl-ephrine a decongestant effect is provided by delivering a daily amount of generally about ~ to about 50 mg., perferably about 2.5 mg. With phenylpropanolamine bronchodilator and nasal decongestant effects are provided by delivering a daily amount of generally about 2 to about 50 mg., preferably abou-t 10 mg. With chlorphenixamine maleate an antihistaminic effect is provided by delivering a daily amount of generally about 1 to about 30 mg., preferably about 3 mg. The estradiol esters used with this invention provide a uterine wall maintenance effect.
It will be appreciated that the above drugs may be added to the above mixture not only in the form of the pure chemical compound, but also in admixture with other drugs that may be transdermally applied or with other ingredients which are not incompatible with the desired objective of transdermally ad-ministering the drug to a patient. Thus, simple pharmacologi-cally acceptable derivatives of the drugs such as ethers,esters, amides, acetals, salts, and the like may be used.
With some drugs derivatives may actually be preferred.
The estradiol ester derivatives suitable for use accord-ing to this invention are pharmacologically acceptable esters particularly the 3-benzoate and 3-valerate es-ters of estra-diol. Estradiol diacetate and other esters of a pharmocologi-cally active type small enough to pass through the skin may ~lso be used. The esters suitable for this invention provide a source of pharmacologically active estradiol in the ~ 3 ~3559 bloodstream. It must also be understood that the estradiol esters contemplated herein may be administered in admixture with other drugs which are not incompatible with the clesired therapeutic objective.
The invention is illustrated by the following non-limiting Examples:
EXAMPLE I
Together there are mixed 30 gm. glycerol and 45 ml.
water. This mixture is heated to 90C; after reaching at least 70C there are slowly added 15 gm. polyvinylalcohol (P~A 100% hydrolyzed, molecular weight 115,000) and 8 gm.
polyvinylpyrrolidone (mw. 40,000). The mixture is stirred at 90C until solution is eEfected, whi~h may -take about 10 minutes; it will be appreciated that with larger quantities, a considerably longer period of time may be needed. 9~ ml. of this solution is then mixed with 2 gm. terbutaline, this mix-ture then being mechanically stirred until homogeneous. The homogeneous mixture is then poured into forms made o-f glass or stainless steel which serve as templates to produce a diffu-sion matrix having a thickness oE about 2 to ahout 3 mm. This diffusion matrix is then cut into pieces with a total surface area suitable for the administration of a pharmaceutically effective amount of terbutaline.
The diffusion matrix is applied to the skin of a patient in need of a bronchodilator effect, the terbutaline being transdermally delivered to the skin of the patient. The dif-fusion matrix is ideally applied to the skin of the patient by means of a single-piece bandage having the diffusion matrix in the center under the occlusive layer, the bandage being pro-vided to the patient with a peel-of cover much like a "band-aid".
E AMPLE II
In place of the glycerol of Example I, there is substi-tuted 5 gm~ polyethylene glycol having a molecular weight of 1000 and 25 ml. water. The resultant diffusion matrix is more ., :
1 ~ ~3S5~ 3 rigid than that of Example I.
EXAMPLE III
In place of the glycerol of Example I, there is substi-t~lted 5 gm. polyethylene glycol (mw. lrO00), 4 gm. glycerol and 21 ml. water. The resultant dif~usion matrix shares the improved rigidity of the dif~usion matrix of Example II, while providing contact with the skin characteristic of the glyc~rol in this type of diffusion matrix.
EXAMPLE IV
In place of the polyvinylalcohol and polyvinylpyrrilidone of E~ample I, there is substi-tuted 2~ by weigh-t agarose, yielding a diffusion matrix for the transdermal deli~ery of terbutaline.
EXAMPLES V-XXIV
E~amples V-XXIV correspond to Examples I-IV, but for the substitution for terbutaline of the same amounts of the fol-lowing drugs:
EXAMPLES DRUG
V-VIII ephedrine IX-XII clonidine XIII-XVI phenylephrine XVII-~X phenylpropanolamine XXI-XXIV chlorpheniramine maleate Each of these drugs exhibits its characteristic thera-peutic effect when administered via diffusion matrix.
E AMPLE XXV
Together there are mixed 20 gm. glycerol and 55 ml.
water. This mixture is heated 90C; after reaching at least 7QC. There are slowly added 15 gm. polyvinylalcohol (PVA
100% hydrolyzed, molecular weight 115,000) ana 8 gm. polyvi-nylpyrrolidone (mw. ~0,000). The mixture is stirred at 90C
unitl solution is effected, which may take about 10 minutes;
it will be appreciated that with larger guantities, a consi-derably longer period of time may be needed. 98 ml. of this solution is then mixed with 2 gm. estradiol diacetate, this . _~
--- 1 3 63~
-- & -- .
mixture then being mechanically stirred until homogeneous.
The homogeneous mlxture is then poured into forms made of glass or stainless steel which serve as templa-tes -to produce a dif-fusion matrix having a thickness of about 1 to 2 mm. This -diffusion matrix is then cut in-to square pieces of about 1 inch on each side, i.e., to provide a total surface area of about 6.5 cm2.
The diffusion matrix is applied to the skin of a patient in need of uterine wall maintenance, the estradiol ester deri-vative being transdermally delivered. The diffusion matrix isideally applied to the skin of the patient by means of a single-piece bandage having the diffusion ma-trix in the center under the occlusive layer, the bandage being provided to the patient with a peel-off cover much like a "band-aid".
EXAMPLE XXVI
Instead of casting the fluid homogeneous drug containing matrix with a 1 to 2 mm. thickness as disclosed in Example XXV, it is poured into oval forms 1 cm. thick. The cured dif-fusion matrix is applied in the form of a vaginal insert into a patient in need of uterine wall maintenancel the estradiol ester derivative being delivered in the vicinity of the cervix of the patient.
EXAMPLE XXVII
In place of the glycerol of Example XXV, there is substi-tuted 10 gm. polyethylene glycol having a molecular weight of 1000 and 10 ml. water. The resultant diffusion matrix is more rigid than that of Example XXV, thus improving its ease of application in the form of a vaginal insert.
EXAMPLE XXVIII
In place of the glycerol of Example XXV, there is substi-tuted 5 gm. polyethylene glycol (mw. 1000), 4 gm. glycerol, and 11 ml. water. The resultant diffusion ma-trix shares the improved rigidity of -the diffusion matrix of Example XXVII, while providing contact with the skin characteristic of the glycerol. This type of diffusion matrix is particularly ~ 1 ~355~ ~
9 ~
sultable for transdermal application EXAMPLE XXIX
In place of the polyvinylalcohol and polyvinylpyrro~idone of Example XXV, there is substituted 2 gm. agarose and 21 m~.
water, yielding a difusion matrix for the delivery of estra-diol ester derivative. .
i
FOR ADMINISTR~TION OF D~UGS
SUMMARY OF THE INVENTION
The present invention relates to a polymeric diffusion matrix containing one or more drugs suitable for transdermal administration to a patient. More particularly, the invention xelates to a polymeric diffusion matrix containing one or more of such drugs characterized by a sustained relase o-E such drugs. Among the drugs suitable for administration in the polymeric diffusion matrix of this invention are terbutaline, ephedrine, clonidine, phenylephrine, estradiol esters, phenyl-propanolamine, and chlorpheniramine maleate.
A self-supporting polymeric diffusion matrix is provided for the sus-tained release of a drug or drugs in order to transdermally deliver said drug to a patient, and provide said patient with a therapeutic effect, said matrix comprising from about 2 to about 60% by weight of a polar plasticizer; from about 6 to about 20% by weight polyvinylalcohol; from about 2 to about 10% by weight polyvinylpyrrolidone; and a pharmaceu-tically effective amount of drug to provide a sustained release of sa;d drug over a prolonged period.
In one embodiment the polar plasticizer is glycerol pre-sent in an amount of from about 2 to about 60~ by weight. In another embodiment -the polar plasticizer is polyethylene gly-col present in an amount of from about 2 to about 15% by weight. ~ still further embodiment contemplates a mixture of glycerol and polyethylene glycol wherein the la-tter is present in an amount by weight of from about 1 to about 5 parts per weight glycerol.
The self-suppor-ting polymeric diffusion matrix generally '~ .
355g contains a mixture of polyvinylalcohol and polyvinylpyrroli-done, although it will be understood that other polymeric mix-tures may be used provided they yield the desired sustained release effect. For example, both the polyvinylalcohol and the polyvinylpyrrolidone may be completely replaced with from about 1 to ahout 9% agar or agarose, and preferably from about 1.5 to 3% agar or agarose, 2% agar or agarose being particu-larly preferred.
As the polyvinylalcohol used in the present invention there is generally contemplated one having a molecular weight from about 50,000 to about 150,000, and more preferably about 100,000 to about 150,000, 115,000 having been used in related systems of the present inven-tors with success. The polyvinyl-alcohol should be hydrolyzed, generally at least to the extent of 90%, with a preferred embodiment being at least ~5% hydro-lyzed. Polyvinylpyrrolidone should have a molecular weigh-t of from about 15,000 to about ~5,000, and more preferably from about 20,000 to about 60,000. Polyvinylpyrrolidone with a molecular weight of 40,000 is a particularly preferred embodiment.
The amount by weight of the ingredients other than the polar plasticizer generally should be in the following ranges:
polyvinylalcohol is generally present in an amount of -from about 6 to about 20% by weight, with 10% being a preferred embodiment; polyvinylpyrrolidone is present generally in an amount of from about 2 to about 10% by weight.
~ he water-soluble polymer can be replaced with (in addi-tion to agar~ yum arabic, gum tragacanth t polyacrylic acid, polymethacrylic acid, polyvinyloxazolidone, polyvinylmorpho-linone, and polyvinylpiperidone.
Polyalkylene glycols such as polyethylene glycol andpolypropylene glycol may replace all or part of the glycerol.
It is possible to replace the polyvinylalcohol with poly-mers of hydroxyethylacrylate, polymers of hydroxyethylmetha-crylate, polymers of hydroxypropylacrylate, and polymers of ~ ~ ~;3~59 hydroxypropylmethacrylate.
In forming the matrix, excess water is not required. In accordance with a preferred aspect o.E the present invention, about 2~ by weigh-t of any of the drugs listed above are inclu-ded in the difEusion matrix. The resultant homogeneous mix-ture is poured into forms preferably made of glass or stain~
less steel, these forms or templates producing a diffusion matrix having a thickness of about 1 to about 3 mm. in accor-dance with a preferred aspect of the present invention~ This diffusion is either cast or cut into pieces of the desired size.
The following methods may be used for preparing the dif-fusion matrix of the present invention.
~n a first method, the matrix is formed at atmospheric pressure. Water and glycerol are first mixed together.
A polar plasticizer such a glycerol is a necessary compo-nent in the matrix. A matrix formed without a polar plastici-zer is not flexible and has poor diffusional contact with the skin causing unreliable diffusion release.
The polyvinylalcohol and polyvinylpyrrolidone are then added to the polar plasticizer-water mixture at room tempera-ture, with agitation. The mixture is heated to a temperature within the range of from about ~0 to about 95C at atmospheric pressure to extend the polymers. If desired, the mixture may be maintained at an elevated temperature for a period of time, based on polymer stability, prior to addition of the drug.
Thus, the mixture is stable for a period of time and may be kept for such a period before being mixed with the drug to be delivered to the patien-t. Thereafter, the mixture is tempera-ture-adjusted and the drug to be applied to the pa-tient is then added to the mixtuxe, with thorough agitation. Once a homogeneous mixture of the polymer solution and drug is ob-tained, the mixture is ready to be cast to form in a drug-containing diffusion matrix. After cas-ting the mixture is cooled to a temperature such that gelation occurs. In a ~ 1 ~355~
preferred embodiment, the drug may be dissolved by agitation in a suitable solvent such as gl~cerin and water. The thus-obtained solution can be maintained at room temperature for prolonged period without deterioration.
It has been found that curing is facilitated by subjec-ting the matrix to a temperature down -to about -20C immedi-ately after casting. The setting period is quickened considerably.
Sodium dodecyl sulfate or sorbitan (Tween-20) or other detergents may be added in an amount of 0.1 to 10~ by weight, based on the matrix, as a dispersing agent, if desired.
An absorption facilitator to insure skin penetration such as dimethylsulfoxide, decylmethylsulfoxide, or other penetra-tion enhancers may be added.
The present drug delivery device comprises the drug-containing diffusion matrix and means for fastening the matrix to the skin of a patient. Such means can take various forms, such as an occlusive backing layer forming a kind of "bandage"
with the diffusion ma-trix being held against the skin of a pa-tient being treated. A polyethylene or Mylar tape is contem-plated as one form of occlusive layer in accordance with thepresent invention. It can also take the form of an elastic band, such as a cloth band, a rubbery band or other material.
Here, the diffusion matrix is placed directly on -the skin and held in place by such elastic band which typically will be placed over the arm or wrist of the patient. An intermediate adhesive layer between the diffusion matrix and the skin capa-ble of permitting the transdermal application of the drug can also be used.
3~ The amount of the drug to be delivered per day to the pa-tient is in each case generally lower that the oral dosage.
This is accounted for by the fact that in oral applications much of the drug can be expected to be lost by the first pass through the liver. To assure that the desired quantity of the drug i.s delivered, an excess of the drug should be . . .
`~ ~ 63559 , -- S
incorporated in the ma-trix. Where ter~utali~e i5 used to pro-vide a bronchodilator effect, the daily amount to be delivered is generally about 1 to about 20 mg., preferably abou-t l-m~.
With ephedrine a decongestant effect is provided by delivering a daily amount of generally about 5 to about 30 mg., prefer-ably about 20 mg. With clonidone an antihypertensive effect is provided by delivering a daily amount of generally about 0.2 to about 0.6 mg., preferably about 0.4 mg. With phenyl-ephrine a decongestant effect is provided by delivering a daily amount of generally about ~ to about 50 mg., perferably about 2.5 mg. With phenylpropanolamine bronchodilator and nasal decongestant effects are provided by delivering a daily amount of generally about 2 to about 50 mg., preferably abou-t 10 mg. With chlorphenixamine maleate an antihistaminic effect is provided by delivering a daily amount of generally about 1 to about 30 mg., preferably about 3 mg. The estradiol esters used with this invention provide a uterine wall maintenance effect.
It will be appreciated that the above drugs may be added to the above mixture not only in the form of the pure chemical compound, but also in admixture with other drugs that may be transdermally applied or with other ingredients which are not incompatible with the desired objective of transdermally ad-ministering the drug to a patient. Thus, simple pharmacologi-cally acceptable derivatives of the drugs such as ethers,esters, amides, acetals, salts, and the like may be used.
With some drugs derivatives may actually be preferred.
The estradiol ester derivatives suitable for use accord-ing to this invention are pharmacologically acceptable esters particularly the 3-benzoate and 3-valerate es-ters of estra-diol. Estradiol diacetate and other esters of a pharmocologi-cally active type small enough to pass through the skin may ~lso be used. The esters suitable for this invention provide a source of pharmacologically active estradiol in the ~ 3 ~3559 bloodstream. It must also be understood that the estradiol esters contemplated herein may be administered in admixture with other drugs which are not incompatible with the clesired therapeutic objective.
The invention is illustrated by the following non-limiting Examples:
EXAMPLE I
Together there are mixed 30 gm. glycerol and 45 ml.
water. This mixture is heated to 90C; after reaching at least 70C there are slowly added 15 gm. polyvinylalcohol (P~A 100% hydrolyzed, molecular weight 115,000) and 8 gm.
polyvinylpyrrolidone (mw. 40,000). The mixture is stirred at 90C until solution is eEfected, whi~h may -take about 10 minutes; it will be appreciated that with larger quantities, a considerably longer period of time may be needed. 9~ ml. of this solution is then mixed with 2 gm. terbutaline, this mix-ture then being mechanically stirred until homogeneous. The homogeneous mixture is then poured into forms made o-f glass or stainless steel which serve as templates to produce a diffu-sion matrix having a thickness oE about 2 to ahout 3 mm. This diffusion matrix is then cut into pieces with a total surface area suitable for the administration of a pharmaceutically effective amount of terbutaline.
The diffusion matrix is applied to the skin of a patient in need of a bronchodilator effect, the terbutaline being transdermally delivered to the skin of the patient. The dif-fusion matrix is ideally applied to the skin of the patient by means of a single-piece bandage having the diffusion matrix in the center under the occlusive layer, the bandage being pro-vided to the patient with a peel-of cover much like a "band-aid".
E AMPLE II
In place of the glycerol of Example I, there is substi-tuted 5 gm~ polyethylene glycol having a molecular weight of 1000 and 25 ml. water. The resultant diffusion matrix is more ., :
1 ~ ~3S5~ 3 rigid than that of Example I.
EXAMPLE III
In place of the glycerol of Example I, there is substi-t~lted 5 gm. polyethylene glycol (mw. lrO00), 4 gm. glycerol and 21 ml. water. The resultant dif~usion matrix shares the improved rigidity of the dif~usion matrix of Example II, while providing contact with the skin characteristic of the glyc~rol in this type of diffusion matrix.
EXAMPLE IV
In place of the polyvinylalcohol and polyvinylpyrrilidone of E~ample I, there is substi-tuted 2~ by weigh-t agarose, yielding a diffusion matrix for the transdermal deli~ery of terbutaline.
EXAMPLES V-XXIV
E~amples V-XXIV correspond to Examples I-IV, but for the substitution for terbutaline of the same amounts of the fol-lowing drugs:
EXAMPLES DRUG
V-VIII ephedrine IX-XII clonidine XIII-XVI phenylephrine XVII-~X phenylpropanolamine XXI-XXIV chlorpheniramine maleate Each of these drugs exhibits its characteristic thera-peutic effect when administered via diffusion matrix.
E AMPLE XXV
Together there are mixed 20 gm. glycerol and 55 ml.
water. This mixture is heated 90C; after reaching at least 7QC. There are slowly added 15 gm. polyvinylalcohol (PVA
100% hydrolyzed, molecular weight 115,000) ana 8 gm. polyvi-nylpyrrolidone (mw. ~0,000). The mixture is stirred at 90C
unitl solution is effected, which may take about 10 minutes;
it will be appreciated that with larger guantities, a consi-derably longer period of time may be needed. 98 ml. of this solution is then mixed with 2 gm. estradiol diacetate, this . _~
--- 1 3 63~
-- & -- .
mixture then being mechanically stirred until homogeneous.
The homogeneous mlxture is then poured into forms made of glass or stainless steel which serve as templa-tes -to produce a dif-fusion matrix having a thickness of about 1 to 2 mm. This -diffusion matrix is then cut in-to square pieces of about 1 inch on each side, i.e., to provide a total surface area of about 6.5 cm2.
The diffusion matrix is applied to the skin of a patient in need of uterine wall maintenance, the estradiol ester deri-vative being transdermally delivered. The diffusion matrix isideally applied to the skin of the patient by means of a single-piece bandage having the diffusion ma-trix in the center under the occlusive layer, the bandage being provided to the patient with a peel-off cover much like a "band-aid".
EXAMPLE XXVI
Instead of casting the fluid homogeneous drug containing matrix with a 1 to 2 mm. thickness as disclosed in Example XXV, it is poured into oval forms 1 cm. thick. The cured dif-fusion matrix is applied in the form of a vaginal insert into a patient in need of uterine wall maintenancel the estradiol ester derivative being delivered in the vicinity of the cervix of the patient.
EXAMPLE XXVII
In place of the glycerol of Example XXV, there is substi-tuted 10 gm. polyethylene glycol having a molecular weight of 1000 and 10 ml. water. The resultant diffusion matrix is more rigid than that of Example XXV, thus improving its ease of application in the form of a vaginal insert.
EXAMPLE XXVIII
In place of the glycerol of Example XXV, there is substi-tuted 5 gm. polyethylene glycol (mw. 1000), 4 gm. glycerol, and 11 ml. water. The resultant diffusion ma-trix shares the improved rigidity of -the diffusion matrix of Example XXVII, while providing contact with the skin characteristic of the glycerol. This type of diffusion matrix is particularly ~ 1 ~355~ ~
9 ~
sultable for transdermal application EXAMPLE XXIX
In place of the polyvinylalcohol and polyvinylpyrro~idone of Example XXV, there is substituted 2 gm. agarose and 21 m~.
water, yielding a difusion matrix for the delivery of estra-diol ester derivative. .
i
Claims (22)
1. A self-supporting polymeric diffusion matrix for the sustained release of a drug selected from the group consisting of estradiol esters suitable for transdermal delivery phenylpropanolamine, chlorpheniramine maleate, clonidine, phenylephrine, terbutaline, and ephedrine in order to trans-dermally deliver said drug to a patient and provide said patient with a therapeutic effect, said matrix comprising from about 2 to about 60% of a polar plasticizer, from about 6 to about 20% by weight polyvinylalcohol, from about 2 to about 10% by weight polyvinylpyrrolidone, and a pharmaceutically effective amount of said drug to provide a sustained release of said drug over a prolonged period.
2. The polymeric diffusion matrix of claim 1 wherein said polar plasticizer is glycerol.
3. The polymeric diffusion matrix of claim 1 wherein said polyvinylalcohol has a molecular weight of about 50,000 to about 150,000.
4. The polymeric diffusion matrix of claim 1 wherein said polyvinylalcohol has a molecular weight of about 100,000 to about 150,000.
5. The polymeric diffusion matrix of claim 1 wherein said polyvinylpyrrolidone has a molecular weight of from about 15,000 to about 85,000.
6. The polymeric diffusion matrix of claim 1 wherein said polyvinylpyrrolidone has a molecular weight of about 20,000 to about 60,000.
7. The polymeric diffusion matrix of claim 1 wherein said polyvinylpyrrolidone has a molecular weight of 40,000 and said polyvinylalcohol has a molecular weight of 115,000.
8. The polymeric diffusion matrix of claim 1 wherein said polar plasticizer is polyethylene glycol present in an amount of about 2 to about 15% by weight.
9. The polymeric diffusion matrix of claim 1 wherein said polar plasticizer is a mixture of glycerol and polyethylene glycol wherein said polyethylene glycol is present in an amount by weight of from about 1 to about 5 parts per weight glycerol.
10. A method for the transdermal delivery of terbu-taline to a patient to provide said patient with a bronchodilator effect, comprising applying to said patient a self-supporting diffusion matrix comprising from about 2 to about 60% by weight of a polar plasticizer, from about 6 to about 20% by weight polyvinylalcohol, from about 2 to about 10% by weight polyvinylpyrrolidone, and a pharmaceutically effective amount of terbutaline to provide a sustained release of said terbutaline over a prolonged period.
11. The method of claim 10 wherein said terbutaline is present in an amount to provide sustained release of about 1 to about 20 mg. per day.
12. A method for the transdermal delivery of ephedrine to a patient to provide said patient with a decongestant effect, comprising applying to said patient a self-supporting diffusion matrix comprising from about 2 to about 60% by weight of a polar plasticizer, from about 6 to about 20% by weight polyvinylalcohol, from about 2 to about 10% by weight polyvinylpyrrolidone, and a pharmaceutically effective amount of ephedrine to provide a sustained release of said ephedrine over a prolonged period.
13. The method of claim 12 wherein said ephedrine is present in an amount to provide sustained release of about 5 to about 20 mg. per day.
14. A method for the transdermal delivery of clonidine to a patient to provide said patient with a antihypertensive effect, comprising applying to said patient a self-supporting diffusion matrix comprising from about 2 to about 60% by weight of a polar plasticizer, from about 6 to about 20% by weight polyvinylalcohol, from about 2 to about 10% by weight polyvinylpyrrolidone, and a pharmaceutically effective amount of clonidine to provide a sustained release of said clonidine over a prolonged period.
15. The method of claim 14 wherein said clonidine is present in an amount to provide sustained release of about 0.2 to about 0.4 mg. per day.
16. A method for the transdermal delivery of phenylephrine to a patient to provide said patient with a decongestant effect, comprising applying to said patient a self-supporting diffusion matrix comprising from about 2 to about 60% by weight of a polar plasticizer, from about 6 to about 20% by weight polyvinylalcohol, from about 2 to about 10% by weight polyvinylpyrrolidone, and a pharmaceutically effective amount of phenylephrine to provide a sustained release of said phenylephrine over a prolonged period.
17. The method of claim 16 wherein said phenylephrine is present in an amount to provide sustained release of about 2 to about 50 mg. per day.
18. A method for the transdermal delivery of phenylpropanolamine to a patient to provide said patient with a bronchodilator effect, comprising applying to said patient a self-supporting diffusion matrix comprising from about 2 to about 60% by weight of a polar plasticizer, from about 6 to about 20% by weight polyvinylalcohol, from about 2 to about 10% by weight polyvinylpyrrolidone, and a pharmaceutically effective amount of phenylephrine to provide a sustained release of said phenylpropanolamine over a prolonged period.
19. The method of claim 18 wherein said phenylpropanolamine is present in an amount to provide sustained release of about 2 to about 50 mg. per day.
20. A method for the transdermal delivery of chlorpheniramine maleate to a patient to provide said patient with a antihistaminic effect, comprising applying to said patient a self-supporting diffusion matrix comprising from about 2 to about 60% by weight of a polar plasticizer, from about 6 to about 20% by weight polyvinylalcohol, from about 2 to about 10% by weight polyvinylpyrrolidone, and a pharmaceutically effective amount of chlorpheniramine maleate to provide a sustained release of said chlorpheniramine maleate over a prolonged period.
21. The method of claim 20 wherein said chlorpheniramine maleate is present in an amount to provide sustained release of about 1 to about 30 mg. per day.
22. A method for the transdermal delivery of estradiol esters suitable for transdermal delivery to a patient to provide said patient with a uterine wall maintenance effect, comprising applying to said patient a self-supporting diffusion matrix comprising from about 2 to about 60% by weight of a polar plasticizer, from about 6 to about 20% by weight polyvinylalcohol, from about 2 to about 10% by weight polyvinylpyrrolidone, and a physiologically effective amount of an estradiol ester suitable for transdermal delivery to provide a sustained release of said estradiol ester suitable for transdermal delivery over a prolonged period.
Applications Claiming Priority (16)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US16700880A | 1980-07-09 | 1980-07-09 | |
US167,010 | 1980-07-09 | ||
US06/167,106 US4292303A (en) | 1979-08-14 | 1980-07-09 | Polymeric diffusion matrix containing clonidine |
US167,009 | 1980-07-09 | ||
US167,008 | 1980-07-09 | ||
US06/167,101 US4294820A (en) | 1979-08-14 | 1980-07-09 | Polymeric diffusion matrix containing phenylephrine |
US06/167,009 US4289749A (en) | 1979-08-14 | 1980-07-09 | Polymeric diffusion matrix containing phenylpropanolamine |
US167,104 | 1980-07-09 | ||
US167,101 | 1980-07-09 | ||
US167,106 | 1980-07-09 | ||
US06/167,010 US4292301A (en) | 1979-08-14 | 1980-07-09 | Polymeric diffusion matrix containing ephedrine |
US06/167,104 US4292302A (en) | 1979-08-14 | 1980-07-09 | Polymeric diffusion matrix containing terbutaline |
US06/167,729 US4291014A (en) | 1979-01-11 | 1980-07-11 | Polymeric diffusion matrix containing estradiol diacetate |
US167,729 | 1980-07-11 | ||
US217,400 | 1980-12-17 | ||
US06/217,400 US4321252A (en) | 1979-08-14 | 1980-12-17 | Polymeric diffusion matrix containing ester derivatives of estradiol |
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CA1163559A true CA1163559A (en) | 1984-03-13 |
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JPS58206751A (en) * | 1982-05-26 | 1983-12-02 | 日石三菱株式会社 | Wound covering material |
FR2532546B1 (en) * | 1982-09-07 | 1985-12-27 | Biotrol Sa Lab | SKIN PROTECTION PASTE |
FR2548021B1 (en) * | 1983-06-29 | 1986-02-28 | Dick P R | PROLONGED AND CONTINUOUS DERMAL PHARMACEUTICAL COMPOSITIONS BASED ON ESSENTIAL FATTY ACIDS |
DE3409079A1 (en) * | 1984-03-13 | 1985-09-19 | Bayer Ag, 5090 Leverkusen | MEDICAL PLASTER |
SE457326B (en) * | 1986-02-14 | 1988-12-19 | Lejus Medical Ab | PROCEDURES FOR PREPARING A QUICK SUBSTANTIAL CANDLES CONTAINING BLA MICROCRISTALLIN CELLULOSA |
US4860543A (en) * | 1986-08-08 | 1989-08-29 | Helix Technology Corporation | Vibration isolation system for a linear reciprocating machine |
SU1705319A1 (en) * | 1987-10-23 | 1992-01-15 | Всесоюзный Научно-Исследовательский Институт Биотехнологии | Polymer diffuse matrix composition for transdermal drug introduction |
IT1261305B (en) * | 1993-06-22 | 1996-05-14 | Gevipi Ag | VIBRATION AND NOISE DAMPING DEVICE, FOR HYDRAULIC SYSTEMS |
DE4429667C2 (en) * | 1994-08-20 | 1996-07-11 | Lohmann Therapie Syst Lts | Estradiol TTS with water-binding additives and process for its preparation |
US6719997B2 (en) | 2000-06-30 | 2004-04-13 | Dermatrends, Inc. | Transdermal administration of pharmacologically active amines using hydroxide-releasing agents as permeation enhancers |
US6602912B2 (en) | 2000-06-30 | 2003-08-05 | Dermatrends, Inc. | Transdermal administration of phenylpropanolamine |
US6673363B2 (en) | 1999-12-16 | 2004-01-06 | Dermatrends, Inc. | Transdermal and topical administration of local anesthetic agents using basic enhancers |
WO2001043734A2 (en) * | 1999-12-16 | 2001-06-21 | Dermatrends, Inc. | Transdermal administration of phenylpropanolamine |
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US2693438A (en) * | 1951-02-21 | 1954-11-02 | Norwich Pharma Co | Preformed, nonadherent films for application to open lesions |
US2804073A (en) * | 1953-01-26 | 1957-08-27 | Protective Teatments Inc | Fluid surgical dressing |
BE638231A (en) * | 1962-03-16 | |||
US3214338A (en) * | 1964-07-31 | 1965-10-26 | Ehrlich Joseph Ronald | Medicament releasing film-forming ointments and process of making |
SU219116A1 (en) * | 1965-11-26 | 1973-03-20 | А. А. Вишневский, Т. Т. Даурова, М. И. Долгина, И. А. Паников, Ф. П. Сидельковска , М. И. Шрайбер | FILM FOR PRIMARY PROCESSING OF THE BURN SURFACE |
DE1617282A1 (en) * | 1965-11-30 | 1975-02-06 | Astra Pharma Prod | DEVICE FOR LOCAL ANESTHETIZATION BY LOCAL APPLICATION AND METHOD FOR MANUFACTURING THIS DEVICE |
GB1213295A (en) * | 1967-04-27 | 1970-11-25 | Boots Pure Drug Co Ltd | Improvements in therapeutic compositions for topical application |
FR2047874A6 (en) * | 1969-06-10 | 1971-03-19 | Nouvel Lucien | |
US3577516A (en) * | 1969-12-02 | 1971-05-04 | Nat Patent Dev Corp | Preparation of spray on bandage |
DE2012775C3 (en) * | 1970-03-18 | 1973-10-04 | V.P. Variopharm Gmbh Herstellung Und Vertrieb Pharmazeutischer, Kosmetischer Und Chemischer Erzeugnisse, 6656 Einoed | Ointment foils and process for their manufacture |
US3892905A (en) * | 1970-08-12 | 1975-07-01 | Du Pont | Cold water soluble plastic films |
US4210633A (en) * | 1978-10-20 | 1980-07-01 | Eli Lilly And Company | Flurandrenolide film formulation |
IL59063A (en) * | 1979-01-11 | 1983-12-30 | Key Pharma | Polymeric diffusion matrix for release of pharmaceutical dosage |
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WO1982000099A1 (en) | 1982-01-21 |
NO153638B (en) | 1986-01-20 |
NO153638C (en) | 1986-05-07 |
AU7415181A (en) | 1982-02-02 |
FR2486397A1 (en) | 1982-01-15 |
SE447448B (en) | 1986-11-17 |
NL8120270A (en) | 1982-06-01 |
DE3152182A1 (en) | 1983-02-10 |
CH658597A5 (en) | 1986-11-28 |
GB2089210A (en) | 1982-06-23 |
NO820722L (en) | 1982-03-08 |
BE889549A (en) | 1981-11-03 |
IT1237327B (en) | 1993-05-31 |
IT8219833A0 (en) | 1982-02-24 |
SE8201337L (en) | 1982-03-04 |
JPS57500980A (en) | 1982-06-03 |
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