Title of Invention	"A PROCESS FOR THE PREPARATION OF AN IMPROVED TRANSDERMAL TAPE/PATCH FOR THE ADMINISTRATION OF ENKEPHALINE PEPTIDES USEFUL AS ANALGESIC"
Abstract	A process for the preparation of an improved transdermal Tape/patch for the administration of enkephaline peptides useful as analgesic which comprises of (i) dissolving peptide compound such as herein described and the cyclodextrin or cyclodextrin derivative in a ratio 1:1 to 1:5 in polar solvent, (ii) shaking the solution at 10-50°C for 1-6 hours to make a clear solution (iii) removing the solvent by conventional methods to obtain peptide cyclodextrin complex (iv) preparing a drug matrix by dissolving resultant complex in an enhancer molecule such as herein described at a temperature in the range of 40-80° C, adding alcohol into the resulting solution obtained in step (iv) to get a milky white latex, (v) dissolving peptide compound or its cyclodextrin complex in alcohol or glycol, containing any of the known penetration enhancers as herein described (vi) adding the milky white latex of the polymers formed earlier in step(iv) to the above said mixture as prepared in step (v) and the hydrogel so formed was uniformly poured into the container of desired size and shape and allowed to dry to get a smooth patch/tape.

Title of Invention

"A PROCESS FOR THE PREPARATION OF AN IMPROVED TRANSDERMAL TAPE/PATCH FOR THE ADMINISTRATION OF ENKEPHALINE PEPTIDES USEFUL AS ANALGESIC"

Abstract

A process for the preparation of an improved transdermal Tape/patch for the administration of enkephaline peptides useful as analgesic which comprises of (i) dissolving peptide compound such as herein described and the cyclodextrin or cyclodextrin derivative in a ratio 1:1 to 1:5 in polar solvent, (ii) shaking the solution at 10-50°C for 1-6 hours to make a clear solution (iii) removing the solvent by conventional methods to obtain peptide cyclodextrin complex (iv) preparing a drug matrix by dissolving resultant complex in an enhancer molecule such as herein described at a temperature in the range of 40-80° C, adding alcohol into the resulting solution obtained in step (iv) to get a milky white latex, (v) dissolving peptide compound or its cyclodextrin complex in alcohol or glycol, containing any of the known penetration enhancers as herein described (vi) adding the milky white latex of the polymers formed earlier in step(iv) to the above said mixture as prepared in step (v) and the hydrogel so formed was uniformly poured into the container of desired size and shape and allowed to dry to get a smooth patch/tape.

Full Text	The present invention relates to a process for the preparation of an improved insdermal Tape/patch for the administration of enkephaline peptides useful as algesic. More particularly the present invention relates to a process for the eparation of a device containing a complex of beta-cyclodextrin with met kephalin analogue which is useful as an analgesic in the form of transdermal itch. Cyclodextrins are reported in the literature that they increase water lubility, dissolution, bioavailability and stability of compound by forming elusion complexes. [Z. Shao, R. Krishnamoorthy and A. K. Mitra, Pharma. ;s., 9: 1157-1163 (1992)]. Recently it was reported in the literature that beta- clodextrins increased the half life of leucine enkephaline from 44 min to 75 min in ise of enzymatic hydrolysis with leucine amino - peptidase (W. J. Irwin, A. K. wivedi, P.A. Holbrook and M.J. Dey., Pharma. Res. 11, 1698-1703, 1994). N- bstituted amides of L-tyrosyl-D-Alanyl-glycyl-L-N-Methylphenyl alanyl glycine ssess high analgesic activity [K.B. Mathur, S. D. Sharma, W. Waq, B. indo, R . Raghubir, G.K. Patnaik and B. N. Dhawan. (Indian Patent No. 173568 . 19.10.89)]. These compounds were found to be more active by intra-muscular iub-cutaneous route rather than by oral route. The reason may be enzymatic gradation of these enkephalin analogs, due to the action of saliva and/or gastric ice etc. One of these peptide, L-tyrosyl-D-alanyl-glycyl-L-N-methyl lenyl alanyl glycinyl-N-isopropylamide was found to be safe in the eclinical studies and it is now ready for the clinical trails. The intra-uscular / sub-cutaneous route is an invasive route of administration and help of a paramedical person is required. On the other way transdermal route is very simple and easy to use as it can be applied by the patient himself. No transdermal drug delivery system employing these peptide is known till date. In the present dosage forms the drug is administered transdemally in the form of its cyclodextrin complexes (Indian patent application No. 2641/DEL/96 dt. 29. 11. 97). L-tyrosyl-D-alanyl-glycyl-L-N-methyl phenyl alanyl glycinyl-N-isopropylamide is an analgesic compound affecting at the opioid receptors like morphine, codeine etc. but is more useful as it is devoide of addiction forming nature. Therefore the object of the present invention is to provide a process for the preparation of a transdermal device useful as a new analgesic. More particularly, the objective of the present invention is to provide a process for the preparation of transdermal device containing peptide compounds. The process of the present invention involves the formation of 1:1 or 1:2 enclusion complexes of the appropriate met. enkephalins derivatives with cyclodextrins by any of the methods like kneading, freeze drying, spray drying, coprecipitation or by solvent evaporation, washing the resultant complex with methanol : chloroform (1:4) to remove the uncomplexed enkephaline derivative, drying to get free flowing powder . With the in vivo efficacy data of the above formulation we observed that in the transdermal patch of cyclodextrin complexes of enkephaline derivatives the dose was reduced to about 33% of the original dose of the enkephaline derivative m transdermal patch. Accordingly, the present invention provides a process for the preparation of an improved transdermal Tape/patch for the administration of enkephaline peptides useful as analgesic which comprises of (i) dissolving peptide compound such as herein described and the cyclodextrin or cyclodextrin derivative in a ratio of 1:1 to 1:5 in polar solvent, (ii) shaking the solution at 10-50°C for 1-6 hours to make a clear solution (iii) removing the solvent by conventional methods to obtain peptide-cyclodextrin complex (iv) preparing a drug matrix by dissolving resultant complex in an enhancer molecule such as herein described at a temperature in the range of 40-80°C, adding alcohol into the resulting solution obtained in step (iv) to get a milky white latex, (v) dissolving peptide compound or its cyclodextrin complex in alcohol or glycol, containing any of the known penetration enhancers as herein described (vi) adding the milky white latex of the polymers formed earlier in step (iv) to the above said mixture as prepared in step (v) and the hydrogel so formed was uniformly poured into the container of desired size and shape and allowed to dry to get a smooth patch/tape. The peptide compound used for preparation of device may be such as analgesic Leu-enkephaline/Met-enkaphaline or their derivatives. The cyclodextrins used may be such as the naturally occurring beta-cyclodextrin, and the like or from their derivatives like dimethyl beta-cyclodextrin or hydroxy propvl beta-cyclodextrin. Polar solvent used for making solution in step (i) may be such as alcohols having 1 -carbon atoms, water or mixture thereof. The amount of peptide compound used may range from 5 to 3 5% by weight of the inclusion complex. The mixture of PEG 400, polypropylene glycol, dialkyl sulfoxides, azone or tritan X-100 used may range from 25 to 40% w/v solution. The formulation may be made in the form of patches/ tapes. Penetration enhancer used in step (v) may be such as polyethylene glycol, polypropylene glycol, dialkyl sulfoxides, azone or tritan X-100 or their combinations. Alcohol used in step (iv) may contain 1-4 carbon atoms. Accordingly the present invention provides a transdermal device prepared by the process as described above. The following examples broadly illustrate the nature of the invention and the manner in which it is to be performed without limiting the nature, scope and application of the invention. Example - I L-tyrosyl-D-alanyl-glycyl-L-N-methyl phenyl alanyl glycinyl N-isopropylamide (0.5 g) and beta-cyclodextrin (1 g) was added to 50 ml of water in a flask. The solution was left shaking at 40 C for 5 hrs to make a clear solution. This solution was frozen and then freeze dried. The free flowing L-tyrosyl-D-alanyl-glycyl- L-N-methyl phenyl alanyl glycinyl N-isopropyl amide :beta-cyclodextrin complex (1:1) so obtained was washed with 10 ml methanol : chloroform (1:4) and dried. Polyvinyl alcohol (4 g) and polyvinylpyrrolidone (2 g) were taken in a 250 ml beaker and stirred at 75 C, 120 ml ethyl alcohol (50% v/v) was slowly added into this to get a fine latex. L-tyrosyl-D-alanyl-glycyl- L-N-methyl phenyl alanyl glycinyl N-isopropyl amide: beta-CD (1:1) complex (1.8 g) was taken & sus- pended in propylene glycol (2 ml) PEG 400 (0.5 ml), poly propylene glycol (2 ml) and tritan X-100 (1.5 ml) by using sonicater. Polymer latex prepared in earlier step was transferred to it by continuous sterring and further stirred for _15 minutes. The hydrogel so formed was uniformly poured into a petri dish and allowed to dry for approximately 8 hrs. The next day a yellow colored patch was obtained. This was covered with the plastic film and cut into the desired size. The patches so obtained were properly packed in a polythene lined blister type packing to avoid coming into contact with moisture before use. Example - 2 Polyvinyl alcohol (2 g) and polyvinylpyrrolidone (1 g) were taken in a 250 ml beaker and stirred at 75 C, 60 ml ethyl alcohol (50% v/v) was slowly added into this to get a fine latex. L-tyrosyl-D-alanyl-glycyl- L-N-methyl phenyl alanyl glycinyl N-isopropyl amide (0.9 g) was taken & dissolved in propylene glycol (1 ml) PEG 4 00 (0.25 ml), poly propylene glycol (1 ml) and tritan X-100 (0.75 ml) by using sonicater. Polymer latex prepared in earlier step was transferred to it by continuous sterring and further stirred for 15 minutes. The hydrogel so formed was uniformly poured into a petri dish and allowed to dry for approximately 8 hrs. The next day a yellow colored patch was obtained. This was covered with the plastic film and cut into the desired size. The patches so obtained were properly packed in a polythene lined blister type packing to avoid coming into contact with moisture before use. Example - 3 L-tyrosyl-D-Alanyl-glycyl-L-N-methyl phenyl alanyl glycinyl )N-isopropyl amide (0.5 g) and hydroxy propyl beta-cyclodextrin (1.2 g) was added to 50 ml of water in a flask. The solution was left sh.ak-.ng at 40 C for 5 hrs to make a clear solution. This solution was frozen and then freeze dried. The free flowing L-tyrosyl D-alanyl- glycyl-L-N-methyl phenyl alanyl glycinyl N-isopropyl amide: hydroxy propyl beta cyclodextrin complex (1:1) so obtained was washed with 10 ml methanol : chloroform (1:4) and dried. Polyvinyl alcohol (4 g) and polyvinylpyrrolidone (2 g) were taken in a 250 ml beaker and stirred at 75 C, 12 0 ml ethyl alcohol (50% v/v) was slowly added into this to get a fine latex. L-tyrosyl-D-alanyl-glycyl- L-N-methyl phenyl alanyl glycinyl N-isopropyl amiderhydroxy propyl beta-CD(1:1) complex (1.8 g) was taken & suspended in propylene glycol (2 ml) PEG 400 (0.5 ml), poly propylene glycol (2 ml) and n-decyl methyl sulfoxides (0.15 g) by using sonicater. Polymer latex prepared in earlier step was transferred to it by continuous sterring and further stirred for 15 minutes. The hydrogel so formed was uniformly poured into a petri dish and allowed to dry for approximately 8 hrs. The next day a yellow colored patch was obtained. This was covered with the plastic film and cut into the desired size. The patches so obtained were properly packed in a polythene lined blister type packing to avoid coming into contact with moisture before use. Example - 4 Polyvinyl alcohol (2 g) and polyvinylpyrrolidone (1 g) were taken in a 250 ml beaker and stirred at 75 C, 60 ml ethyl alcohol (50% v/v) was slowly added into this to get a fine latex. Leu-enkephaline (0.9 g) was taken & dissolved in propylene glycol (1 ml) PEG 400 (0.25 ml), poly propylene glycol (1 ml) and tritan X-100 (0.75 ml) by using sonicater. Polymer latex prepared in earlier step was transferred to it by continuous sterring and further stirred for 15 minutes. The hydrogel so formed was uniformly poured into a petri dish and allowed to dry for approximately 8 hrs. The next day a yellow colored patch was obtained. This was covered with the plastic film and cut into the desired size. The patches so obtained were properly packed in a polythene lined blister type packing to avoid coming into contact with moisture before use. The advantages of these new device, as prepared by the process of the present invention, are that they provide transdermal delivery of enkephaline peptides useful as analgesic. These preparation stablises the drugs and reduces the oral dose of the costly drugs. The analgesic effect obtained by the formulation, as prepared by the process described in example 1, in rats indicate that the analgesic activity of 82/205 : BCD complex (1:1) which contains 1/3 dose was significantly higher than the compound as such in transdermal patch. The duration of action is also doubled with with 82/205 : BCD complex (1:1) with profound analdesia. Packed in polythene covered blister type packing these formulations are stable over a long period of time under varying climatic conditions. We claim: 1. A process for the preparation of an improved transdermal Tape/patch for the administration of enkephaline peptides useful as analgesic which comprises of (i) dissolving peptide compound such as herein described and the cyclodextrin or cyclodextrin derivative in a ratio of 1:1 to 1:5 in polar solvent, (ii) shaking the solution at 10-50°C for 1-6 hours to make a clear solution (iii) removing the solvent by conventional methods to obtain peptide-oyclodextrin complex (iv) preparing a drug matrix by dissolving resultant complex in an enhancer molecule such as herein described at a temperature in the range of 40-80°C, adding alcohol into the resulting solution obtained in step (iv) to get a milky white latex, (v) iissolving peptide compound or its cyclodextrin complex in alcohol or glycol, containing tny of the known penetration enhancers as herein described (vi) adding the milky white atex of the polymers formed earlier in step (iv) to the above said mixture as prepared in tep (v) and the hydrogel so formed was uniformly poured into the container of desired size md shape and allowed to dry to get a smooth patch/tape. A process as claimed in claim 1 wherein the cyclodextrin used is such as alpha, beta r gama-cyclodextrin or their derivatives. A process as claimed in claims 1 & 2 wherein the peptide compound used is such as ; aalgesic Met-enkaphaline/Leu-enkephaline or their derivatives. A process as claimed in claims 1-3 wherein the amount of peptide compound used inges from 5 mg to 50 mg per square cm. 5. A process as claimed in claims 1-4 wherein the amount of cyclodextrins used ranges from 1-5 times of the we'ght of peptide compound. 6. A process as claimed in claims 1-5 wherein the enhancer molecule used are polyethylene glycol, polypropylene glycol, dialkyl sulphoxides, azone or tritan x-100 or their compitation. 7. A process for the preparation of an improved transdermal Tape/patch for the administration of enkephaline peptides useful as analgesic substantially as herein described with reference to the examples.

Full Text

The present invention relates to a process for the preparation of an improved insdermal Tape/patch for the administration of enkephaline peptides useful as algesic.
More particularly the present invention relates to a process for the
eparation of a device containing a complex of beta-cyclodextrin with met
kephalin analogue which is useful as an analgesic in the form of transdermal
itch. Cyclodextrins are reported in the literature that they increase water
lubility, dissolution, bioavailability and stability of compound by forming
elusion complexes. [Z. Shao, R. Krishnamoorthy and A. K. Mitra, Pharma.
;s., 9: 1157-1163 (1992)]. Recently it was reported in the literature that beta-
clodextrins increased the half life of leucine enkephaline from 44 min to 75 min in
ise of enzymatic hydrolysis with leucine amino - peptidase (W. J. Irwin, A. K.
wivedi, P.A. Holbrook and M.J. Dey., Pharma. Res. 11, 1698-1703, 1994). N-
bstituted amides of L-tyrosyl-D-Alanyl-glycyl-L-N-Methylphenyl alanyl glycine
ssess high analgesic activity [K.B. Mathur, S. D. Sharma, W. Waq, B.
indo, R . Raghubir, G.K. Patnaik and B. N. Dhawan. (Indian Patent No. 173568
. 19.10.89)]. These compounds were found to be more active by intra-muscular
iub-cutaneous route rather than by oral route. The reason may be enzymatic
gradation of these enkephalin analogs, due to the action of saliva and/or gastric
ice etc. One of these peptide, L-tyrosyl-D-alanyl-glycyl-L-N-methyl
lenyl alanyl glycinyl-N-isopropylamide was found to be safe in the eclinical studies and it is now ready for the clinical trails. The intra-uscular / sub-cutaneous route is an

invasive route of administration and help of a paramedical person is required. On the other way transdermal route is very simple and easy to use as it can be applied by the patient himself. No transdermal drug delivery system employing these peptide is known till date. In the present dosage forms the drug is administered transdemally in the form of its cyclodextrin complexes (Indian patent application No. 2641/DEL/96 dt. 29. 11. 97). L-tyrosyl-D-alanyl-glycyl-L-N-methyl phenyl alanyl glycinyl-N-isopropylamide is an analgesic compound affecting at the opioid receptors like morphine, codeine etc. but is more useful as it is devoide of addiction forming nature.
Therefore the object of the present invention is to provide a process for the preparation of a transdermal device useful as a new analgesic. More particularly, the objective of the present invention is to provide a process for the preparation of transdermal device containing peptide compounds. The process of the present invention involves the formation of 1:1 or 1:2 enclusion complexes of the appropriate met. enkephalins derivatives with cyclodextrins by any of the methods like kneading, freeze drying, spray drying, coprecipitation or by solvent evaporation, washing the resultant complex with methanol : chloroform (1:4) to remove the uncomplexed enkephaline derivative, drying to get free flowing powder . With the in vivo efficacy data of the above formulation we observed that in the transdermal patch of cyclodextrin complexes of enkephaline derivatives the dose was reduced to about 33% of the original dose of the enkephaline derivative m transdermal patch.

Accordingly, the present invention provides a process for the preparation of an improved transdermal Tape/patch for the administration of enkephaline peptides useful as analgesic which comprises of (i) dissolving peptide compound such as herein described and the cyclodextrin or cyclodextrin derivative in a ratio of 1:1 to 1:5 in polar solvent, (ii) shaking the solution at 10-50°C for 1-6 hours to make a clear solution (iii) removing the solvent by conventional methods to obtain peptide-cyclodextrin complex (iv) preparing a drug matrix by dissolving resultant complex in an enhancer molecule such as herein described at a temperature in the range of 40-80°C, adding alcohol into the resulting solution obtained in step (iv) to get a milky white latex, (v) dissolving peptide compound or its cyclodextrin complex in alcohol or glycol, containing any of the known penetration enhancers as herein described (vi) adding the milky white latex of the polymers formed earlier in step (iv) to the above said mixture as prepared in step (v) and the hydrogel so formed was uniformly poured into the container of desired size and shape and allowed to dry to get a smooth patch/tape.
The peptide compound used for preparation of device may be such as analgesic Leu-enkephaline/Met-enkaphaline or their derivatives.
The cyclodextrins used may be such as the naturally occurring beta-cyclodextrin, and the like or from their derivatives like dimethyl beta-cyclodextrin or hydroxy propvl beta-cyclodextrin.
Polar solvent used for making solution in step (i) may be such as alcohols having 1 -carbon atoms, water or mixture thereof.

The amount of peptide compound used may range from 5 to 3 5% by weight of the inclusion complex. The mixture of PEG 400, polypropylene glycol, dialkyl sulfoxides, azone or tritan X-100 used may range from 25 to 40% w/v solution. The formulation may be made in the form of patches/ tapes.
Penetration enhancer used in step (v) may be such as polyethylene glycol, polypropylene glycol, dialkyl sulfoxides, azone or tritan X-100 or their combinations.
Alcohol used in step (iv) may contain 1-4 carbon atoms.
Accordingly the present invention provides a transdermal device prepared by the process as described above.
The following examples broadly illustrate the nature of the invention and the manner in which it is to be performed without limiting the nature, scope and application of the invention.
Example - I
L-tyrosyl-D-alanyl-glycyl-L-N-methyl phenyl alanyl glycinyl N-isopropylamide (0.5 g) and beta-cyclodextrin (1 g) was added to 50 ml of water in a flask. The solution was left shaking at 40 C for 5 hrs to make a clear solution. This solution was frozen and then freeze dried. The free flowing L-tyrosyl-D-alanyl-glycyl- L-N-methyl phenyl alanyl glycinyl N-isopropyl amide :beta-cyclodextrin complex (1:1) so obtained was washed with 10 ml methanol : chloroform (1:4) and dried.
Polyvinyl alcohol (4 g) and polyvinylpyrrolidone (2 g) were taken in a 250 ml beaker and stirred at 75 C, 120 ml ethyl alcohol (50% v/v) was slowly added into this to get a fine latex. L-tyrosyl-D-alanyl-glycyl- L-N-methyl phenyl alanyl glycinyl N-isopropyl amide: beta-CD (1:1) complex (1.8 g) was taken & sus-

pended in propylene glycol (2 ml) PEG 400 (0.5 ml), poly propylene glycol (2 ml) and tritan X-100 (1.5 ml) by using sonicater. Polymer latex prepared in earlier step was transferred to it by continuous sterring and further stirred for _15 minutes. The hydrogel so formed was uniformly poured into a petri dish and allowed to dry for approximately 8 hrs. The next day a yellow colored patch was obtained. This was covered with the plastic film and cut into the desired size. The patches so obtained were properly packed in a polythene lined blister type packing to avoid coming into contact with moisture before use.
Example - 2 Polyvinyl alcohol (2 g) and polyvinylpyrrolidone (1 g) were taken in a 250 ml beaker and stirred at 75 C, 60 ml ethyl alcohol (50% v/v) was slowly added into this to get a fine latex. L-tyrosyl-D-alanyl-glycyl- L-N-methyl phenyl alanyl glycinyl N-isopropyl amide (0.9 g) was taken & dissolved in propylene glycol (1 ml) PEG 4 00 (0.25 ml), poly propylene glycol (1 ml) and tritan X-100 (0.75 ml) by using sonicater. Polymer latex prepared in earlier step was transferred to it by continuous sterring and further stirred for 15 minutes. The hydrogel so formed was uniformly poured into a petri dish and allowed to dry for approximately 8 hrs. The next day a yellow colored patch was obtained. This was covered with the plastic film and cut into the desired size. The patches so obtained were properly packed in a polythene lined blister type packing to avoid coming into contact with moisture before use.

Example - 3
L-tyrosyl-D-Alanyl-glycyl-L-N-methyl phenyl alanyl glycinyl )N-isopropyl amide (0.5 g) and hydroxy propyl beta-cyclodextrin (1.2 g) was added to 50 ml of water in a flask. The solution was left sh.ak-.ng at 40 C for 5 hrs to make a clear solution. This solution was frozen and then freeze dried. The free flowing L-tyrosyl D-alanyl- glycyl-L-N-methyl phenyl alanyl glycinyl N-isopropyl amide: hydroxy propyl beta cyclodextrin complex (1:1) so obtained was washed with 10 ml methanol : chloroform (1:4) and dried.
Polyvinyl alcohol (4 g) and polyvinylpyrrolidone (2 g) were taken in a 250 ml beaker and stirred at 75 C, 12 0 ml ethyl alcohol (50% v/v) was slowly added into this to get a fine latex. L-tyrosyl-D-alanyl-glycyl- L-N-methyl phenyl alanyl glycinyl N-isopropyl amiderhydroxy propyl beta-CD(1:1) complex (1.8 g) was taken & suspended in propylene glycol (2 ml) PEG 400 (0.5 ml), poly propylene glycol (2 ml) and n-decyl methyl sulfoxides (0.15 g) by using sonicater. Polymer latex prepared in earlier step was transferred to it by continuous sterring and further stirred for 15 minutes. The hydrogel so formed was uniformly poured into a petri dish and allowed to dry for approximately 8 hrs. The next day a yellow colored patch was obtained. This was covered with the plastic film and cut into the desired size. The patches so obtained were properly packed in a polythene lined blister type packing to avoid coming into contact with moisture before use.
Example - 4
Polyvinyl alcohol (2 g) and polyvinylpyrrolidone (1 g) were taken in a 250 ml beaker and stirred at 75 C, 60 ml ethyl alcohol

(50% v/v) was slowly added into this to get a fine latex. Leu-enkephaline (0.9 g) was taken & dissolved in propylene glycol (1 ml) PEG 400 (0.25 ml), poly propylene glycol (1 ml) and tritan X-100 (0.75 ml) by using sonicater. Polymer latex prepared in earlier step was transferred to it by continuous sterring and further stirred for 15 minutes. The hydrogel so formed was uniformly poured into a petri dish and allowed to dry for approximately 8 hrs. The next day a yellow colored patch was obtained. This was covered with the plastic film and cut into the desired size. The patches so obtained were properly packed in a polythene lined blister type packing to avoid coming into contact with moisture before use.
The advantages of these new device, as prepared by the process of the present invention, are that they provide transdermal delivery of enkephaline peptides useful as analgesic. These preparation stablises the drugs and reduces the oral dose of the costly drugs. The analgesic effect obtained by the formulation, as prepared by the process described in example 1, in rats indicate that the analgesic activity of 82/205 : BCD complex (1:1) which contains 1/3 dose was significantly higher than the compound as such in transdermal patch. The duration of action is also doubled with with 82/205 : BCD complex (1:1) with profound analdesia. Packed in polythene covered blister type packing these formulations are stable over a long period of time under varying climatic conditions.

We claim:
1. A process for the preparation of an improved transdermal Tape/patch for the
administration of enkephaline peptides useful as analgesic which comprises of (i) dissolving peptide compound such as herein described and the cyclodextrin or cyclodextrin derivative in a ratio of 1:1 to 1:5 in polar solvent, (ii) shaking the solution at 10-50°C for 1-6 hours to make a clear solution (iii) removing the solvent by conventional methods to obtain peptide-oyclodextrin complex (iv) preparing a drug matrix by dissolving resultant complex in an enhancer molecule such as herein described at a temperature in the range of 40-80°C, adding alcohol into the resulting solution obtained in step (iv) to get a milky white latex, (v) iissolving peptide compound or its cyclodextrin complex in alcohol or glycol, containing tny of the known penetration enhancers as herein described (vi) adding the milky white atex of the polymers formed earlier in step (iv) to the above said mixture as prepared in tep (v) and the hydrogel so formed was uniformly poured into the container of desired size md shape and allowed to dry to get a smooth patch/tape.
A process as claimed in claim 1 wherein the cyclodextrin used is such as alpha, beta r gama-cyclodextrin or their derivatives.
A process as claimed in claims 1 & 2 wherein the peptide compound used is such as ; aalgesic Met-enkaphaline/Leu-enkephaline or their derivatives.
A process as claimed in claims 1-3 wherein the amount of peptide compound used inges from 5 mg to 50 mg per square cm.

5. A process as claimed in claims 1-4 wherein the amount of cyclodextrins used ranges from 1-5 times of the we'ght of peptide compound.
6. A process as claimed in claims 1-5 wherein the enhancer molecule used are polyethylene glycol, polypropylene glycol, dialkyl sulphoxides, azone or tritan x-100 or their compitation.
7. A process for the preparation of an improved transdermal Tape/patch for the administration of enkephaline peptides useful as analgesic substantially as herein described with reference to the examples.

Documents:

502-DEL-1998-Abstract.pdf

502-del-1998-claims.pdf

502-del-1998-complete specification (granted).pdf

502-del-1998-correspondence-others.pdf

502-DEL-1998-Correspondence-PO.pdf

502-del-1998-description (complete).pdf

502-del-1998-form-1.pdf

502-DEL-1998-Form-2.pdf

502-del-1998-form-4.pdf

« Previous Patent

Next Patent »

Patent Number

187991

Indian Patent Application Number

502/DEL/1998

PG Journal Number

31/2002

Publication Date

03-Aug-2002

Grant Date

13-Mar-2003

Date of Filing

26-Feb-1998

Name of Patentee

COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH

Applicant Address

RAFI MARG,NEW DELHI-110001,INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	MADHU KHANNA	CENTRAL DRUG RESEARCH INSTITUTE,CHATTAR MANZIL,LUCKNOW,INDIA.
2	ANIL KUMAR DWIVEDI	CENTRAL DRUG RESEARCH INSTITUTE,CHATTAR MANZIL,LUCKNOW,INDIA.
3	SATYAWAN SINGH	CENTRAL DRUG RESEARCH INSTITUTE,CHATTAR MANZIL,LUCKNOW,INDIA.
4	RAM RAGHUBIR	CENTRAL DRUG RESEARCH INSTITUTE,CHATTAR MANZIL,LUCKNOW,INDIA.

PCT International Classification Number

A61K 31/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA