CA1312547C - Fatty acids and their small chain esters as penetration enhancers in aqueous systems - Google Patents
Fatty acids and their small chain esters as penetration enhancers in aqueous systemsInfo
- Publication number
- CA1312547C CA1312547C CA000566547A CA566547A CA1312547C CA 1312547 C CA1312547 C CA 1312547C CA 000566547 A CA000566547 A CA 000566547A CA 566547 A CA566547 A CA 566547A CA 1312547 C CA1312547 C CA 1312547C
- Authority
- CA
- Canada
- Prior art keywords
- composition according
- opioid
- weight
- pharmaceutically acceptable
- drug
- 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 - Fee Related
Links
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT
Saturated or unsaturated fatty acids of 8-18 carbon atoms or a C1-C4 alkyl ester thereof in an aqueous system are described as skin absorption enhancers resulting in effective and non-irritating transdermal compositions comprising the above in combination with a therapeutically active ingredient.
Saturated or unsaturated fatty acids of 8-18 carbon atoms or a C1-C4 alkyl ester thereof in an aqueous system are described as skin absorption enhancers resulting in effective and non-irritating transdermal compositions comprising the above in combination with a therapeutically active ingredient.
Description
1 3 ~ 2 5 ~ b FATTY ACIDS AND THEIR SMALL CHAIN
ESTERS AS PENETRATION ENHANCERS
IN AQUEOUS SYST~MS
BACKGROUND OF THE INVENTION
This invention relates to pharmaceutical compositions which are useful in effecting transdermal delivery of a therapeutic dose of a therapeutically active ingredient to the systemic circulation of a mammal.
As a specific and preferred application, k~lerapeutically active ingredien-t~ or drugs 5UC~I a5 opioid~ may be ~lngled out a~ pre~rred activ~
lngred.~eIIt~ ln ~uch trall~deLmal sy~tem~.
Many opioid~ are know~ to have poor bioavaila-bility in the mammalian systemic circulation due to extensive initial metabolism of the drug by the liver and intestines. Furthermore, the bioavailability of orally administered opioids may be unpredictable since various factors such as changes in acidity and food content can cause changes in the amount of drug absorbed from the gastrointestinal tract. Also, oral administration does not necessarily ensure good patient compliance.
Parenteral`administration of opioids provides better bioavailability than oral administration.
However, the various routes of parenteral administra-tion such as intravenous, intramuscular, and subcutaneous delivery are not convenient for chronic therapy. This is particularly true for -those opioids which exhibit short biological activity half-lives.
Topical formulations of opioids do not necessarily provide delivery of a therapeutic dose of the drug to the systemic circulation and thus provide ~dY~
.
~3~2~
poor or unpredictable bioavailability. Natural oils containing sa-turated or unsaturated fatty acids have been described in such topical formulations with drugs used for local anesthetic purposes.
Transdermal delivery of opioid drugs to the mammalian systemic circulation have been described as an alternative mode of administration which can provide the following advantages:
1. Improved and predictable bioavailability of the opioid as compared to oral administration since transdermal delivery avoids initial metabolism by the liver and intestines, and unpredictable absorption from the gastrointestinal tract.
ESTERS AS PENETRATION ENHANCERS
IN AQUEOUS SYST~MS
BACKGROUND OF THE INVENTION
This invention relates to pharmaceutical compositions which are useful in effecting transdermal delivery of a therapeutic dose of a therapeutically active ingredient to the systemic circulation of a mammal.
As a specific and preferred application, k~lerapeutically active ingredien-t~ or drugs 5UC~I a5 opioid~ may be ~lngled out a~ pre~rred activ~
lngred.~eIIt~ ln ~uch trall~deLmal sy~tem~.
Many opioid~ are know~ to have poor bioavaila-bility in the mammalian systemic circulation due to extensive initial metabolism of the drug by the liver and intestines. Furthermore, the bioavailability of orally administered opioids may be unpredictable since various factors such as changes in acidity and food content can cause changes in the amount of drug absorbed from the gastrointestinal tract. Also, oral administration does not necessarily ensure good patient compliance.
Parenteral`administration of opioids provides better bioavailability than oral administration.
However, the various routes of parenteral administra-tion such as intravenous, intramuscular, and subcutaneous delivery are not convenient for chronic therapy. This is particularly true for -those opioids which exhibit short biological activity half-lives.
Topical formulations of opioids do not necessarily provide delivery of a therapeutic dose of the drug to the systemic circulation and thus provide ~dY~
.
~3~2~
poor or unpredictable bioavailability. Natural oils containing sa-turated or unsaturated fatty acids have been described in such topical formulations with drugs used for local anesthetic purposes.
Transdermal delivery of opioid drugs to the mammalian systemic circulation have been described as an alternative mode of administration which can provide the following advantages:
1. Improved and predictable bioavailability of the opioid as compared to oral administration since transdermal delivery avoids initial metabolism by the liver and intestines, and unpredictable absorption from the gastrointestinal tract.
2. A stable blood serum level of ~he d~rug re~ulting in a pro].onged phaxmacological eEEect similar to lntravenou~ ln~u~:lQrl.
3. Easily ~djustable dosing rate whlch prov.ides maximization o efEicacy and minimization of side effects.
4. Easily removable drug source which provides rapid cessation of dosing and elimination of the drug from the body fluids.
5. Convenience of dosing which provides improved patient comfort as compared to parenteral adminis-tration and the possibility of greater patient compliance as compared to oral adminis-tration.
Transdermal drug delivery is dis-tinguished from topical drug delivery by the fact that while a transdermal formulation is specifically designed to provide a predictable and therapeutically significant rate of delivery of the drug to the systemic circulation, a topical formulation is specifically designed to provide a therapeutic effect only to the local area to which the drug is applied. Furthermore, topical formulations are often designed to prevent any systemic delivery of the drug in order to minimize ~3~ 2~
side-effects. However, even if the topical delivery of a drug does result in systemic absorption, the amount of drug delivery to the circulation is variable and uncontrolled.
European Patent Publication 0 171 742 describes such a sy~tem for the transdermal delivery of opioids using saturated or unsaturated fatty alcohols as acids or esters thereof with a carrier or vehicle such as propylene glycol resulting in an organic system, i.e.
suspension or gel. The disadvantage of this system is that the use of propylene glycol or other known organic solvents causes irritation to the skin.
It has now been found that saturated or unsaturated E~t-t~ acid~ or ~-ter~ thereof, uch as linolelc acid, 1~ eE~ecti~e as a skin absorpt.lon enhancer ln pur~ly a~ueou~ ~ys~k~ms thus leading ~o new and effective tran~dermal compositions without skin irritation~
SUMMARY OF THE INVENTION
~ccordingly the present invention relates to a pharmaceutical composition adapted for transdermal delivery of a therapeutically effective amount of a drug to the systemic circulation of a mammal comprising an aqueous suspension containing:
a therapeutically effective amount of a drug or a pharmaceutically acceptable salt thereof;
an effective amount of a saturated or unsaturated fatty acid of 8-18 carbon atoms or a Cl-C4 alkyl ester thereof, and a pharmaceutically acceptable excipient.
Another aspect of the present invention is a method or the transdermal delivery of a therapeuti-cally effective amount of a drug to the systemic circulation of a mammal which comprises administering to said mammal in an aqueous suspension:
~2~ 7 a therapeutically effective amount of a drug or a pharmaceutically acceptable salt thereof;
an effective amount of a saturated or unsaturated fatty acid of C8 -Cl 8 carbon atoms or a C1-C4 alkyl ester thereof, and a pharmaceutically acceptable excipient.
DESCRIPTION OF PREFERRED EMBODIMENTS
Although the present aqueous transdermal composition encompasses the combination with any drug, the preferred utility of such a composition is wi-th opioid~.
~ y th~ -term "oploid" ;L~ mean~ any ~atural or synthetic opio~d aIl~lgcsic ~uch as morphlne, oxymorphone, Eentanyl, meper.idine, propoxyphene, or oxycodone; any natural or synthetic narcotic antagonist such as nalmefene, naloxone or naltrexone;
any natural or synthetic mixed opioid agonist/antagonist such as nalbuphine, butorphanol, buprenorphine or pentazocine; or any pharmaceutically acceptable salt thereof.
By the term "pharmaceutically accep-table salt" is meant any non-toxic pharmaceutically suitable sal-t of an opioid which has therapeutic properties in mammals.
Preparation of such salts is well-known to those skilled in pharmaceuticals. Pharmaceutically acceptable salts of opioids include acetates, naphthylates, tosylates, succinates, hydrochlorides, palmitates, stearates, oleates, pamoates, laurates, valerates, hydrobromides, sulfates, methane sulfonates, tartrates, citrates, and maleates.
The term "saturated or unsaturated fatty acid of 8-18 carbon atoms" means any such acid or ester thereof effective in enhanciny the penetration of a drug through the mammalian skin. Preferred are . ..... .. ... , ~
11 312~ ~
linoleic and oleic acids and their C1-C4 alkyl esters.
Most preferred is linoleic acid.
Pharmaceutically acceptable excipients are additional materials used in the compositions to bind the effective ingredients into a cream or lotion form suitable for administration on the skin per se or through known devices such as bandaids, tapes, patches, and the like. These excipients are, for example, carbopol 934, carbopol*940, carbopol 941, (B. F. Goodrich and Co. they are acrylic acid, water soluble resin polymers, with molecular weights of 3,000,000; 4,000,000; and 1,250,000 respectively);
tween*20, (ICI Americas) polysorbate 20 polyoxy-ethylene 20 sorbita~ monolaurate, ox other tweerls*such AS tween*40, tween*60, and tween~80, and other pharmaceutically acceptable emulsifiexs such as polyethyleneglycol esters, e.g. polyethyleneglycol monolaurates, can also be used.
The effectiveness of the present invention is illustrated by the following examples and results illustrated in table form which compares the permeation of oxymorphone through hairless mouse skin from organic and aqueous enhancer systems containing linoleic acid.
* trade mark 1 3 ~ PI
* - ~ ~ ~ ~`~
~I~ N ~ ~ I_t ~ t O ~ . O I at rt ~t ~t ~ U
,~-rl ~ l~ t~ O ~-rt '~ ~t ~ ~t t~ ~D I h ~
X ~ l O ~ O I ~ Ul a~
~t _ r~ 8 o ,~
U
r ~ rt tlt U~ ~t ~ p P~ .~ ~ 0 O X ~ ;t IttJ) 14 U d~ ~o o. I ~
¢ O ~ t ~Z; ~ -~t Ul rl _ X rt ~ ~ ~11~ 0 ~4 0 rt U ~ l O ~ ~ t ~ ~ ~ O X
_ ~Lt ~ 1~
R X
o~ ra 3 r1 1¢ o ¢ o Id E~ ~ E~ U~ t~l rt ~ -r~ ~D
. ~ Q U O ~ - ~¢ - U-rt ~
~i Fl~ 0 ~t 11~) r I x r I
t ~j O l¢ O ~ t`V ~;~
~LI ~~J r~
u~ o ~n ~ ~1 - ` ~.3125~
-7~
Aqueous Systems Formulations Flux Lag Time (containing 5% w~w oxymorphone (~ q/cm7 /h) (h) LA 30% *
(0.3% Carbopol*+ 2.5% Tween 20) 70% 667.45 6.8 LA ~0% ,.
~0.3% Carbopol* + 2.5% Tween*20) 80% 636.11 9.3 LA 10% * *
0.3% Carbopol + 2.S% Tween 20) 90% 672.76 4.3 LA 5% * *
(0.3% Carbopol + 2.5% Tween 20) 95% 543.82 9.5 L~ 20% *
(2.5% Tween 20) 80% ~8~.46 4.4 0.3% Carbopol* 38.31 17 0.3% Carbopol*~ 2.5% Tween*20 19.73 15.61 Leqend LA = Linoleic Acid PG = Propylene Glycol TA = Triacetin Note: Since the aqueous systems are suspensions, they are constantly providing maximum availability of oxymorphone or pe~neation (i.e. maximum flux);
therefore, to compare permeability data with the organic systems, maximum flux values had to be calculated. Using the premeability coefficients for O.5% oxymorphone solutions in the linoleic acid:propylene glycol:triacetin mixtures, maximum fluxes were calculated by multiplying the saturation solubility of oxymorphone in the respective system by its corresponding permeability coefficient. However, it should bç noted that the aqueous dispersions (5%
w/w drug) became depleted of drug causing a plateau in cumulative average concentration versus time graphs, * trade mark 13t2~7 therefore, higher flux values may be anticipated with the aqueous systems.
As shown in the table, aqueous systems containing the model fatty acid, linoleic acid, effectively enhanced the permea-tion of a model drug through the skin. The usual dose of oxymorphone is 6-10 mg per day which would be adequately provided by any of the aqueous systems containing linoleic acid from a 10 cm2 patch.
Transdermal drug delivery is dis-tinguished from topical drug delivery by the fact that while a transdermal formulation is specifically designed to provide a predictable and therapeutically significant rate of delivery of the drug to the systemic circulation, a topical formulation is specifically designed to provide a therapeutic effect only to the local area to which the drug is applied. Furthermore, topical formulations are often designed to prevent any systemic delivery of the drug in order to minimize ~3~ 2~
side-effects. However, even if the topical delivery of a drug does result in systemic absorption, the amount of drug delivery to the circulation is variable and uncontrolled.
European Patent Publication 0 171 742 describes such a sy~tem for the transdermal delivery of opioids using saturated or unsaturated fatty alcohols as acids or esters thereof with a carrier or vehicle such as propylene glycol resulting in an organic system, i.e.
suspension or gel. The disadvantage of this system is that the use of propylene glycol or other known organic solvents causes irritation to the skin.
It has now been found that saturated or unsaturated E~t-t~ acid~ or ~-ter~ thereof, uch as linolelc acid, 1~ eE~ecti~e as a skin absorpt.lon enhancer ln pur~ly a~ueou~ ~ys~k~ms thus leading ~o new and effective tran~dermal compositions without skin irritation~
SUMMARY OF THE INVENTION
~ccordingly the present invention relates to a pharmaceutical composition adapted for transdermal delivery of a therapeutically effective amount of a drug to the systemic circulation of a mammal comprising an aqueous suspension containing:
a therapeutically effective amount of a drug or a pharmaceutically acceptable salt thereof;
an effective amount of a saturated or unsaturated fatty acid of 8-18 carbon atoms or a Cl-C4 alkyl ester thereof, and a pharmaceutically acceptable excipient.
Another aspect of the present invention is a method or the transdermal delivery of a therapeuti-cally effective amount of a drug to the systemic circulation of a mammal which comprises administering to said mammal in an aqueous suspension:
~2~ 7 a therapeutically effective amount of a drug or a pharmaceutically acceptable salt thereof;
an effective amount of a saturated or unsaturated fatty acid of C8 -Cl 8 carbon atoms or a C1-C4 alkyl ester thereof, and a pharmaceutically acceptable excipient.
DESCRIPTION OF PREFERRED EMBODIMENTS
Although the present aqueous transdermal composition encompasses the combination with any drug, the preferred utility of such a composition is wi-th opioid~.
~ y th~ -term "oploid" ;L~ mean~ any ~atural or synthetic opio~d aIl~lgcsic ~uch as morphlne, oxymorphone, Eentanyl, meper.idine, propoxyphene, or oxycodone; any natural or synthetic narcotic antagonist such as nalmefene, naloxone or naltrexone;
any natural or synthetic mixed opioid agonist/antagonist such as nalbuphine, butorphanol, buprenorphine or pentazocine; or any pharmaceutically acceptable salt thereof.
By the term "pharmaceutically accep-table salt" is meant any non-toxic pharmaceutically suitable sal-t of an opioid which has therapeutic properties in mammals.
Preparation of such salts is well-known to those skilled in pharmaceuticals. Pharmaceutically acceptable salts of opioids include acetates, naphthylates, tosylates, succinates, hydrochlorides, palmitates, stearates, oleates, pamoates, laurates, valerates, hydrobromides, sulfates, methane sulfonates, tartrates, citrates, and maleates.
The term "saturated or unsaturated fatty acid of 8-18 carbon atoms" means any such acid or ester thereof effective in enhanciny the penetration of a drug through the mammalian skin. Preferred are . ..... .. ... , ~
11 312~ ~
linoleic and oleic acids and their C1-C4 alkyl esters.
Most preferred is linoleic acid.
Pharmaceutically acceptable excipients are additional materials used in the compositions to bind the effective ingredients into a cream or lotion form suitable for administration on the skin per se or through known devices such as bandaids, tapes, patches, and the like. These excipients are, for example, carbopol 934, carbopol*940, carbopol 941, (B. F. Goodrich and Co. they are acrylic acid, water soluble resin polymers, with molecular weights of 3,000,000; 4,000,000; and 1,250,000 respectively);
tween*20, (ICI Americas) polysorbate 20 polyoxy-ethylene 20 sorbita~ monolaurate, ox other tweerls*such AS tween*40, tween*60, and tween~80, and other pharmaceutically acceptable emulsifiexs such as polyethyleneglycol esters, e.g. polyethyleneglycol monolaurates, can also be used.
The effectiveness of the present invention is illustrated by the following examples and results illustrated in table form which compares the permeation of oxymorphone through hairless mouse skin from organic and aqueous enhancer systems containing linoleic acid.
* trade mark 1 3 ~ PI
* - ~ ~ ~ ~`~
~I~ N ~ ~ I_t ~ t O ~ . O I at rt ~t ~t ~ U
,~-rl ~ l~ t~ O ~-rt '~ ~t ~ ~t t~ ~D I h ~
X ~ l O ~ O I ~ Ul a~
~t _ r~ 8 o ,~
U
r ~ rt tlt U~ ~t ~ p P~ .~ ~ 0 O X ~ ;t IttJ) 14 U d~ ~o o. I ~
¢ O ~ t ~Z; ~ -~t Ul rl _ X rt ~ ~ ~11~ 0 ~4 0 rt U ~ l O ~ ~ t ~ ~ ~ O X
_ ~Lt ~ 1~
R X
o~ ra 3 r1 1¢ o ¢ o Id E~ ~ E~ U~ t~l rt ~ -r~ ~D
. ~ Q U O ~ - ~¢ - U-rt ~
~i Fl~ 0 ~t 11~) r I x r I
t ~j O l¢ O ~ t`V ~;~
~LI ~~J r~
u~ o ~n ~ ~1 - ` ~.3125~
-7~
Aqueous Systems Formulations Flux Lag Time (containing 5% w~w oxymorphone (~ q/cm7 /h) (h) LA 30% *
(0.3% Carbopol*+ 2.5% Tween 20) 70% 667.45 6.8 LA ~0% ,.
~0.3% Carbopol* + 2.5% Tween*20) 80% 636.11 9.3 LA 10% * *
0.3% Carbopol + 2.S% Tween 20) 90% 672.76 4.3 LA 5% * *
(0.3% Carbopol + 2.5% Tween 20) 95% 543.82 9.5 L~ 20% *
(2.5% Tween 20) 80% ~8~.46 4.4 0.3% Carbopol* 38.31 17 0.3% Carbopol*~ 2.5% Tween*20 19.73 15.61 Leqend LA = Linoleic Acid PG = Propylene Glycol TA = Triacetin Note: Since the aqueous systems are suspensions, they are constantly providing maximum availability of oxymorphone or pe~neation (i.e. maximum flux);
therefore, to compare permeability data with the organic systems, maximum flux values had to be calculated. Using the premeability coefficients for O.5% oxymorphone solutions in the linoleic acid:propylene glycol:triacetin mixtures, maximum fluxes were calculated by multiplying the saturation solubility of oxymorphone in the respective system by its corresponding permeability coefficient. However, it should bç noted that the aqueous dispersions (5%
w/w drug) became depleted of drug causing a plateau in cumulative average concentration versus time graphs, * trade mark 13t2~7 therefore, higher flux values may be anticipated with the aqueous systems.
As shown in the table, aqueous systems containing the model fatty acid, linoleic acid, effectively enhanced the permea-tion of a model drug through the skin. The usual dose of oxymorphone is 6-10 mg per day which would be adequately provided by any of the aqueous systems containing linoleic acid from a 10 cm2 patch.
Claims (9)
1. A pharmaceutical composition adapted for trans-dermal delivery of a therapeutically effective amount of a natural or synthetic opioid to the systemic circulation of a mammal consisting essentially of an aqueous suspension containing:
a therapeutically effective amount of a natural or synthetic opioid or a pharmaceutically acceptable salt thereof;
an effective amount of a saturated or unsaturated fatty acid of 8-18 carbon atoms or a C1-C4 alkyl ester thereof, and a pharmaceutically acceptable excipient.
a therapeutically effective amount of a natural or synthetic opioid or a pharmaceutically acceptable salt thereof;
an effective amount of a saturated or unsaturated fatty acid of 8-18 carbon atoms or a C1-C4 alkyl ester thereof, and a pharmaceutically acceptable excipient.
2. A composition according to claim 1, wherein opioid is morphine, oxymorphone, fentanyl, meperidine, propoxyphen, or oxycodone; a natural or synthetic narcotic antagonist: nalmefene, naloxone, naltrexone, nalbuphine, butorphanol, buprenorphine or pentazocine; or a pharmaceutically acceptable salt thereof.
3. A composition according to claim 2, wherein the opioid is oxymorphone.
4. A composition according to claim 1, wherein the fatty acid is linoleic or oleic.
5. A composition according to claim 1, wherein the aqueous suspension contains up to 0.1-10% by weight of opioid.
6. A composition according to claim 1, wherein the aqueous suspension contains from about 1 to about 30% by weight of a saturated or unsaturated fatty acid of 8-18 carbon atoms or a C1-C4 alkyl ester thereof.
7. A composition according to claim 6, wherein the aqueous suspension contains from about 1 to about 20% by weight of linoleic or oleic acid or a C1-C4 alkyl ester thereof.
8. A composition according to claim 6, wherein the aqueous system contains about 1 to about 30% by weight of linoleic acid.
9. A composition according to claim 6, wherein the aqueous system contains about 10 to about 20% by weight of linoleic acid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US5652087A | 1987-06-01 | 1987-06-01 | |
| US056,520 | 1987-06-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1312547C true CA1312547C (en) | 1993-01-12 |
Family
ID=22004948
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000566547A Expired - Fee Related CA1312547C (en) | 1987-06-01 | 1988-05-12 | Fatty acids and their small chain esters as penetration enhancers in aqueous systems |
Country Status (3)
| Country | Link |
|---|---|
| AT (1) | ATE79277T1 (en) |
| CA (1) | CA1312547C (en) |
| DE (1) | DE3873770T2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10237057A1 (en) * | 2002-08-09 | 2004-03-25 | Grünenthal GmbH | Transdermal therapeutic systems containing buprenorphine, useful in treating pain or urinary incontinence, also containing mu-, kappa- or delta-opioid receptor antagonist to reduce abuse potential |
| DE10237056A1 (en) * | 2002-08-09 | 2004-03-04 | Grünenthal GmbH | Transdermal therapeutic systems containing buprenorphine, useful in treating pain or urinary incontinence, also containing mu-, kappa- or delta-opioid receptor antagonist to reduce abuse potential |
-
1988
- 1988-05-12 CA CA000566547A patent/CA1312547C/en not_active Expired - Fee Related
- 1988-05-16 AT AT88905280T patent/ATE79277T1/en not_active IP Right Cessation
- 1988-05-16 DE DE8888905280T patent/DE3873770T2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| DE3873770T2 (en) | 1992-12-24 |
| ATE79277T1 (en) | 1992-08-15 |
| DE3873770D1 (en) | 1992-09-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4879297A (en) | Fatty acids and their small chain esters as penetration enhancers in aqueous systems | |
| EP0375689B1 (en) | A pharmaceutical composition adapted for transdermal delivery of an opoid drug. | |
| US4626539A (en) | Trandermal delivery of opioids | |
| AU2013305563B2 (en) | Chemical compositions and methods for enhancing transdermal delivery of therapeutic agents | |
| KR100445449B1 (en) | Skin Permeation Enhancer Compositions Using Acyl Lactylates | |
| EP0261429B1 (en) | Penetration enhancement systems and the preparation thereof | |
| EP1962817B1 (en) | Transdermal delivery of a salt form of meptazinol | |
| ES2784756T3 (en) | Abuse deterrent opioid / opioid antagonist transdermal patch | |
| US10786574B2 (en) | Transdermal formulations | |
| US9687528B2 (en) | Transdermal formulations | |
| US20090169605A1 (en) | Novel Tape Preparation | |
| JP2003501467A (en) | Pharmaceutical formulations and methods containing intranasal morphine | |
| CN101621999A (en) | The transdermal formulation that percutaneous absorbs medical composition, medical composition storage element and utilized this storage element | |
| KR20080071185A (en) | Pharmaceutical compositions comprising buprenorphine | |
| US4931283A (en) | Menthol enhancement of transdermal drug delivery | |
| EP0742011A1 (en) | Percutaneously absorbable preparation | |
| EP0147146A2 (en) | Enhancement of transdermal drug delivery | |
| JPS6183116A (en) | Percutaneous transfer of opioid | |
| JPH04128231A (en) | Method of treating addiction to cocaine or heroin comprising percutaneously delivering buprenorphine | |
| CA1312547C (en) | Fatty acids and their small chain esters as penetration enhancers in aqueous systems | |
| JP2001064205A (en) | Medication composition | |
| JPH0640947A (en) | Composition for percutaneous absorption preparation and percutaneous absorption preparation | |
| JP2001089359A (en) | Gel or gel preparation for nasal drip of analgesic component | |
| EP0416804A1 (en) | External preparation containing amusulosin | |
| WO1992019271A1 (en) | Percutaneous administration and absorption promoter composition and external preparation for percutaneous administration |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed |