CA2362769C - Microcapsules for sustained release of drugs - Google Patents
Microcapsules for sustained release of drugs Download PDFInfo
- Publication number
- CA2362769C CA2362769C CA002362769A CA2362769A CA2362769C CA 2362769 C CA2362769 C CA 2362769C CA 002362769 A CA002362769 A CA 002362769A CA 2362769 A CA2362769 A CA 2362769A CA 2362769 C CA2362769 C CA 2362769C
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- Prior art keywords
- pharmaceutical preparation
- pharmaceutical
- microcapsules
- analogue
- micro
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5015—Organic compounds, e.g. fats, sugars
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
- A61P5/22—Drugs for disorders of the endocrine system of the parathyroid hormones for decreasing, blocking or antagonising the activity of calcitonin
Abstract
Micro-capsules for the slow release of drugs, consisting of a lactic-co- glycolic copolymer to which a plasticiser has been incorporated and which contain a drug of pharmaceutical interested within them.
Description
ti MICRO-CAPSULES FOR THE SUSTAINED RELEASE OF DRUGS
The present invention relates to a new type of micro-capsule or micro-bead for the sustained administration of drugs and to a procedure for their preparation.
A large variety of administration systems have been proposed for drugs that require administration over a long time period. The strategy described in the literature as the most successful is that of micro-encapsulation of the drug to administer in a polymer material of the biodegradable and biocompatible polyester type, such as polylactic-co-glycolic (PLGA). There are a large number of bibliographic references to io this strategy, such as: USP 5,445,832; ES 2009346; CH 661 206; CH 665 558;
ES
2037621; USP 4,652,441; ES 2020890; USP 4,728,721; USP 5,330,767; USP 4,917, 893; USP 4,652,441; EP 0 145 240; EP 0 2020 065; EP 0 190 833, among others for example.
These polymers have the peculiarity that they are degraded slowly within the body releasing the drug contained inside, and the products of this degradation (lactic acid and glycolic acid) are naturally present within the organism.
In the micro-capsules described in the literature of the state of the art it is very hard to achieve a satisfactory modulation of the encapsulated drug release, and to avoid an initial large drug release, as this can only be achieved by changing the composition of the polymer (the ratio of lactic-glycolic acid or the molecular weight thereof), which usually implies making important changes in the procedure for the production of the micro-capsules every time a modification in the drug release profile is desired.
In the article published by Pitt el al. in the Journal of Biomedical Materials Research, Vol. 13, pg 497-507, 1979, it is described that tributyl citrate accelerates the release of drugs, for example, progesterone, in microcapsules of polylactic polymers.
As a fruit of our research, we have surprisingly discovered that the addition of small amounts of citric acid esters, to the polymer constituting the micro-capsules, allows a very effective modulation of the liberation characteristics of the micro-capsules obtained, without the need to modify the composition of the polymer.
In the present specification the term modulating release from microcapsules is understood to mean a reduction in the initial release of encapsulated drug and a release of said drug that is almost linear in time. It is both surprising and unexpected, in view of that described by Pitt et al. that the incorporation of small amounts of citric acid ester into the microcapsule preparation of lactic-co-glycolic polymer that encapsulate a peptide of pharmaceutical interest allows the release of the drug to be almost linear and without the presence of sudden initial releases of the drug.
The object of an aspect of this invention consists of providing pharmaceutical of prepartions micro-capsules of polymers of lactic and glycolic acid plastified with small quantities of citric acid esters and which contain peptides.
The present invention also comprises the preparation and use of the aforementioned microcapsules.
SUMMARY OF THE INVENTION
According to an aspect of the present invention, there is provided a pharmaceutical preparation of microcapsules of lactic-co-glycolic copolymer which incorporates a peptide of pharmaceutical interest, wherein the copolymer that forms the microcapsules incorporates a citric acid ester as an additive.
According to one embodiment of the present invention, a percentage ratio between the lactate and glycolate units in the lactic-co-glycolic copolymer is between 100% of lactate and 90% of glycolate, both inclusive.
The citric acid esters useful for the purposes of the present invention are those normally used as plasticizers for pharmaceutical polymers, such as triethyl citrate, tributyl citrate and acetyl tributyl citrate. Use of triethyl citrate is preferable.
By peptides of pharmaceutical interest it is understood:
- analogues of LHRH such as tryptoreline, leuprolide, gosereline, busereline or cetrorelix - analogues of somatostatin such as somatostatin or octreotide - analogues of human calcitonin such as salmon calcitonin or carbocalcitonin.
The preparation of the micro-capsules can be carried out following any of the methods described in the literature such as, for example, those described in the USP
The present invention relates to a new type of micro-capsule or micro-bead for the sustained administration of drugs and to a procedure for their preparation.
A large variety of administration systems have been proposed for drugs that require administration over a long time period. The strategy described in the literature as the most successful is that of micro-encapsulation of the drug to administer in a polymer material of the biodegradable and biocompatible polyester type, such as polylactic-co-glycolic (PLGA). There are a large number of bibliographic references to io this strategy, such as: USP 5,445,832; ES 2009346; CH 661 206; CH 665 558;
ES
2037621; USP 4,652,441; ES 2020890; USP 4,728,721; USP 5,330,767; USP 4,917, 893; USP 4,652,441; EP 0 145 240; EP 0 2020 065; EP 0 190 833, among others for example.
These polymers have the peculiarity that they are degraded slowly within the body releasing the drug contained inside, and the products of this degradation (lactic acid and glycolic acid) are naturally present within the organism.
In the micro-capsules described in the literature of the state of the art it is very hard to achieve a satisfactory modulation of the encapsulated drug release, and to avoid an initial large drug release, as this can only be achieved by changing the composition of the polymer (the ratio of lactic-glycolic acid or the molecular weight thereof), which usually implies making important changes in the procedure for the production of the micro-capsules every time a modification in the drug release profile is desired.
In the article published by Pitt el al. in the Journal of Biomedical Materials Research, Vol. 13, pg 497-507, 1979, it is described that tributyl citrate accelerates the release of drugs, for example, progesterone, in microcapsules of polylactic polymers.
As a fruit of our research, we have surprisingly discovered that the addition of small amounts of citric acid esters, to the polymer constituting the micro-capsules, allows a very effective modulation of the liberation characteristics of the micro-capsules obtained, without the need to modify the composition of the polymer.
In the present specification the term modulating release from microcapsules is understood to mean a reduction in the initial release of encapsulated drug and a release of said drug that is almost linear in time. It is both surprising and unexpected, in view of that described by Pitt et al. that the incorporation of small amounts of citric acid ester into the microcapsule preparation of lactic-co-glycolic polymer that encapsulate a peptide of pharmaceutical interest allows the release of the drug to be almost linear and without the presence of sudden initial releases of the drug.
The object of an aspect of this invention consists of providing pharmaceutical of prepartions micro-capsules of polymers of lactic and glycolic acid plastified with small quantities of citric acid esters and which contain peptides.
The present invention also comprises the preparation and use of the aforementioned microcapsules.
SUMMARY OF THE INVENTION
According to an aspect of the present invention, there is provided a pharmaceutical preparation of microcapsules of lactic-co-glycolic copolymer which incorporates a peptide of pharmaceutical interest, wherein the copolymer that forms the microcapsules incorporates a citric acid ester as an additive.
According to one embodiment of the present invention, a percentage ratio between the lactate and glycolate units in the lactic-co-glycolic copolymer is between 100% of lactate and 90% of glycolate, both inclusive.
The citric acid esters useful for the purposes of the present invention are those normally used as plasticizers for pharmaceutical polymers, such as triethyl citrate, tributyl citrate and acetyl tributyl citrate. Use of triethyl citrate is preferable.
By peptides of pharmaceutical interest it is understood:
- analogues of LHRH such as tryptoreline, leuprolide, gosereline, busereline or cetrorelix - analogues of somatostatin such as somatostatin or octreotide - analogues of human calcitonin such as salmon calcitonin or carbocalcitonin.
The preparation of the micro-capsules can be carried out following any of the methods described in the literature such as, for example, those described in the USP
3,773,919. By way of description and without limitation thereto, the different procedures for 2a producing micro-capsules of the invention would be grouped into the following sections:
a) Method of coacervation:
A solution of polymer is prepared along with tri-ethyl citrate in a suitable solvent.
The drug to be encapsulated is suspended in the polymer and plasticiser solution and a non-solvent of the polymer is added to force deposition of the polymer on the drug crystals.
Examples of these procedures without using plasticiser can also be found in documents such as ES 2009346 or EP 052 510.
b) Double Emulsion Methods:
The drug to be encapsulated is dissolved in water or in a solution of some other co-adjuvant in is emulsified in a solution of the polymer and the plasticiser in a suitable solvent such as dichloromethane for example. The resulting emulsion is in turn emulsified in water or in an aqueous solution of an emulsifier such as polyvinylic alcohol. Once this second emulsion has been carried out the solvent in which the polymer was dissolved is eliminated through evaporation or extraction. The resulting micro-capsules are obtained directly by filtration. Examples of these procedures that do not use the plasticiser can also be found in documents such as USP 4,652,441.
c) Simple Emulsion Method:
The drug to be encapsulated, the polymer and the plasticiser are dissolved together in a suitable solvent. This solution is emulsified in water or a solution of an emulsifier such as polyvinyl acid and the organic solvent eliminated by evaporation or extraction. The resulting micro-capsules are recovered by filtration. Examples of these procedures that do not sue the plasticiser can also be found in documents such as USP
5,445,832.
d) Methods of solvent evaporation:
The drug to be encapsulated, the polymer and the plasticiser are dissolved together in a suitable solvent. This solution is evaporated to dryness and the resulting residue reduced down to a suitable size. Examples of this procedure, although not using the plasticiser, can be also be found in documents such as GB 2,209,937.
In the present invention, in all cases, the citric acid ester is deposited along with the polymer, plastifying it and advantageously modifying the hydrophobicity, flexibility and coating capacity characteristics of the polymer and the release profile of the micro-capsules obtained.
This is reducing the initial release of the encapsulated drug and making this 3o release almost linear in time.
The present invention is now described by means of following, non-limiting examples:
EXAMPLE 1: Production of micro-capsules, containing leuprolide acetate, which presents a drug release profile suitable for one month.
3 g of tri-ethyl citrate and 1.45 g of lactic-co-glycolic polymer (mw = 50000 with monomer ratio of 1/1) are dissolved in 50 ml of dichloromethane. When the polymer is fully dissolved 67 mg of leuprolide acetate are added and then suspended by sonication.
63 g of silicone of 350 cts is added slowly with intensive stirring. And when all the silicone has been added the content of the reactor is poured onto 2.5 1 of n-heptane and stirred for 1 hour.
The micro-capsules are recovered by filtration and dried under vacuum for 48 hours.
EXAMPLE 2: Production of micro-capsules with one-month release containing octreotide acetate.
2 g of tri-ethyl citrate and 1.45 g of lactic-co-glycolic polymer (mw = 50000 with monomer ratio of 1/1) are dissolved in 50 ml of dichloromethane. When the polymer is fully dissolved 67 mg of octreotide acetate are added and then suspended by sonication.
70 g of silicone of 350 cts is added slowly with intensive stirring. And when all the silicone has been added the content of the reactor is poured onto 2.5 1 of n-heptane and stirred for 1 hour.
The micro-capsules are recovered by filtration and dried under vacuum for 48 hours.
EXAMPLE 3: Production of micro-capsules with a three-month release profile containing Triptoreline acetate.
2 g of tri-ethyl citrate and 1.45 g of lactic-co-glycolic polymer (mw = 50000 with ' monomer ratio of 1/1) are dissolved in 50 ml of dichloromethane. When the polymer is fully dissolved 45 mg of triptoreline acetate are added and then suspended by sonication.
70 g of silicone of 350 cts is added slowly with intensive stirring. And when all the silicone has been added the content of the reactor is poured onto 2.5 1 of heptane and stirred for 1 hoiur.
The micro-capsules are recovered by filtration and dried under vacuum for 48 hours.
EXAMPLE 4: In vitro determination of the drug release by the micro-capsules obtained.
MATERIAL NEEDED:
12 plastic 10-m1 tubes with lid.
1 rack for tubes.
a) Method of coacervation:
A solution of polymer is prepared along with tri-ethyl citrate in a suitable solvent.
The drug to be encapsulated is suspended in the polymer and plasticiser solution and a non-solvent of the polymer is added to force deposition of the polymer on the drug crystals.
Examples of these procedures without using plasticiser can also be found in documents such as ES 2009346 or EP 052 510.
b) Double Emulsion Methods:
The drug to be encapsulated is dissolved in water or in a solution of some other co-adjuvant in is emulsified in a solution of the polymer and the plasticiser in a suitable solvent such as dichloromethane for example. The resulting emulsion is in turn emulsified in water or in an aqueous solution of an emulsifier such as polyvinylic alcohol. Once this second emulsion has been carried out the solvent in which the polymer was dissolved is eliminated through evaporation or extraction. The resulting micro-capsules are obtained directly by filtration. Examples of these procedures that do not use the plasticiser can also be found in documents such as USP 4,652,441.
c) Simple Emulsion Method:
The drug to be encapsulated, the polymer and the plasticiser are dissolved together in a suitable solvent. This solution is emulsified in water or a solution of an emulsifier such as polyvinyl acid and the organic solvent eliminated by evaporation or extraction. The resulting micro-capsules are recovered by filtration. Examples of these procedures that do not sue the plasticiser can also be found in documents such as USP
5,445,832.
d) Methods of solvent evaporation:
The drug to be encapsulated, the polymer and the plasticiser are dissolved together in a suitable solvent. This solution is evaporated to dryness and the resulting residue reduced down to a suitable size. Examples of this procedure, although not using the plasticiser, can be also be found in documents such as GB 2,209,937.
In the present invention, in all cases, the citric acid ester is deposited along with the polymer, plastifying it and advantageously modifying the hydrophobicity, flexibility and coating capacity characteristics of the polymer and the release profile of the micro-capsules obtained.
This is reducing the initial release of the encapsulated drug and making this 3o release almost linear in time.
The present invention is now described by means of following, non-limiting examples:
EXAMPLE 1: Production of micro-capsules, containing leuprolide acetate, which presents a drug release profile suitable for one month.
3 g of tri-ethyl citrate and 1.45 g of lactic-co-glycolic polymer (mw = 50000 with monomer ratio of 1/1) are dissolved in 50 ml of dichloromethane. When the polymer is fully dissolved 67 mg of leuprolide acetate are added and then suspended by sonication.
63 g of silicone of 350 cts is added slowly with intensive stirring. And when all the silicone has been added the content of the reactor is poured onto 2.5 1 of n-heptane and stirred for 1 hour.
The micro-capsules are recovered by filtration and dried under vacuum for 48 hours.
EXAMPLE 2: Production of micro-capsules with one-month release containing octreotide acetate.
2 g of tri-ethyl citrate and 1.45 g of lactic-co-glycolic polymer (mw = 50000 with monomer ratio of 1/1) are dissolved in 50 ml of dichloromethane. When the polymer is fully dissolved 67 mg of octreotide acetate are added and then suspended by sonication.
70 g of silicone of 350 cts is added slowly with intensive stirring. And when all the silicone has been added the content of the reactor is poured onto 2.5 1 of n-heptane and stirred for 1 hour.
The micro-capsules are recovered by filtration and dried under vacuum for 48 hours.
EXAMPLE 3: Production of micro-capsules with a three-month release profile containing Triptoreline acetate.
2 g of tri-ethyl citrate and 1.45 g of lactic-co-glycolic polymer (mw = 50000 with ' monomer ratio of 1/1) are dissolved in 50 ml of dichloromethane. When the polymer is fully dissolved 45 mg of triptoreline acetate are added and then suspended by sonication.
70 g of silicone of 350 cts is added slowly with intensive stirring. And when all the silicone has been added the content of the reactor is poured onto 2.5 1 of heptane and stirred for 1 hoiur.
The micro-capsules are recovered by filtration and dried under vacuum for 48 hours.
EXAMPLE 4: In vitro determination of the drug release by the micro-capsules obtained.
MATERIAL NEEDED:
12 plastic 10-m1 tubes with lid.
1 rack for tubes.
PROCEDURE:
Approximately 10 mg of micro-capsules containing leuprolide obtained according to example I are weighed into 12 10-m1 tubes.
To each tube 2 ml of phosphate buffer 1/30 M and pH = 7.0 are added.
Each tube is gently shaken to suspend the micro-capsules in the buffer, the tubes are sealed and placed in an oven at 37 C.
Taking samples for the control of the hydrolysis is carried out in accordance with the following table:
Table 1: Taking samples for analysis of leuprolide released.
ime u e no. ype of analysis , upernatant Supematant upernat.ant ane et e et e et Point u e no. ype o analysis Pellet Ild an Pellet Pellet and e et e et an Pellet The analysis of leuprolide released is carried out by HPLC in the following conditions:
Approximately 10 mg of micro-capsules containing leuprolide obtained according to example I are weighed into 12 10-m1 tubes.
To each tube 2 ml of phosphate buffer 1/30 M and pH = 7.0 are added.
Each tube is gently shaken to suspend the micro-capsules in the buffer, the tubes are sealed and placed in an oven at 37 C.
Taking samples for the control of the hydrolysis is carried out in accordance with the following table:
Table 1: Taking samples for analysis of leuprolide released.
ime u e no. ype of analysis , upernatant Supematant upernat.ant ane et e et e et Point u e no. ype o analysis Pellet Ild an Pellet Pellet and e et e et an Pellet The analysis of leuprolide released is carried out by HPLC in the following conditions:
COLUMN: Kromasil C-8; 25x0.45 cm ELUENT: Acetonitrile/water 30/70 + 0.05% trifluoracetic acid FLOW RATE:I ml/min DETECTION: UV 280 nm.
The samples are taken at the times indicated in table 1 and the analysis carried out by quantifying the peptide released in the supernatant (supematant analysis) or the residual peptide inside the micro-capsule (pellet analysis) depending on the hydrolysis time, as indicated in table 1.
The result of this analysis is indicated in Figure 1. In this figure, the results obtained are compared with a control assay performed with leuprolide microcapsules in which diethyl citrate has not been incorporated, in accordance with the method of example 1 .
The samples are taken at the times indicated in table 1 and the analysis carried out by quantifying the peptide released in the supernatant (supematant analysis) or the residual peptide inside the micro-capsule (pellet analysis) depending on the hydrolysis time, as indicated in table 1.
The result of this analysis is indicated in Figure 1. In this figure, the results obtained are compared with a control assay performed with leuprolide microcapsules in which diethyl citrate has not been incorporated, in accordance with the method of example 1 .
Claims (11)
1. A pharmaceutical preparation of microcapsules of lactic-co-glycolic copolymer which incorporates a peptide of pharmaceutical interest, wherein the copolymer that forms the microcapsules incorporates a citric acid ester as an additive.
2. A pharmaceutical preparation of microcapsules according to claim 1 wherein the citric acid ester is one of triethyl citrate, tributyl citrate or acetyl tributyl citrate.
3. A pharmaceutical preparation of microcapsules according to claim 2 wherein the citric acid ester is triethyl citrate.
4. A pharmaceutical preparation according to claim 3 wherein the amount of triethyl citrate contained in the preparation is in the range of 0.1% to 60% by weight of the copolymer.
5. A pharmaceutical preparation according to any one of claims 1 to 4 wherein the percentage ratio between the lactate and glycolate units in the lactic-co-glycolic copolymer is between 100% of lactate and 90% of glycolate, both inclusive.
6. A pharmaceutical preparation according to any one of claims 1 to 5 wherein the encapsulated peptide of pharmaceutical interest is an analogue of LHRH.
7. A pharmaceutical preparation according to claim 6 wherein the analogue of LHRH is one of tryptoreline, leuprolide, gosereline, busereline or cetrorelix.
8. A pharmaceutical preparation according to any one of claims 1 to 5 wherein the encapsulated peptide of pharmaceutical interest is somatostatin or an analogue thereof.
9. A pharmaceutical preparation according to claim 8 wherein the analogue of somatostatin is octreotide.
10. A pharmaceutical preparation according to any one of claims 1 to 5 wherein the encapsulated peptide of pharmaceutical interest is an analogue of human calcitonin.
11. A pharmaceutical preparation according to claim 10 wherein the analogue of human calcitonin is salmon calcitonin or carbocalcitonin.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ESP9902768 | 1999-12-17 | ||
| ES009902768A ES2169980B1 (en) | 1999-12-17 | 1999-12-17 | MICROCAPSULES FOR THE PROLONGED RELEASE OF PHARMACOS. |
| PCT/ES2000/000475 WO2001043724A1 (en) | 1999-12-17 | 2000-12-15 | Microcapsules for sustained release of drugs |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2362769A1 CA2362769A1 (en) | 2001-06-21 |
| CA2362769C true CA2362769C (en) | 2008-09-09 |
Family
ID=8310957
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002362769A Expired - Lifetime CA2362769C (en) | 1999-12-17 | 2000-12-15 | Microcapsules for sustained release of drugs |
Country Status (13)
| Country | Link |
|---|---|
| US (3) | US20020187196A1 (en) |
| EP (1) | EP1151746B1 (en) |
| JP (1) | JP5021880B2 (en) |
| AT (1) | ATE234608T1 (en) |
| AU (1) | AU774680B2 (en) |
| BR (1) | BRPI0008197B8 (en) |
| CA (1) | CA2362769C (en) |
| DE (1) | DE60001717T2 (en) |
| DK (1) | DK1151746T3 (en) |
| ES (2) | ES2169980B1 (en) |
| MX (1) | MXPA01008348A (en) |
| PT (1) | PT1151746E (en) |
| WO (1) | WO2001043724A1 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040097419A1 (en) * | 2002-11-19 | 2004-05-20 | Holger Petersen | Organic compounds |
| WO2006123360A2 (en) * | 2005-03-01 | 2006-11-23 | Sun Pharmaceutical Industries Limited | Microspheres containing octreotide acetate |
| KR101245919B1 (en) * | 2005-12-22 | 2013-03-20 | 노파르티스 아게 | Sustained release formulation comprising octreotide and two or more polylactide-co-glycolide polymers |
| ES2324009B1 (en) * | 2007-11-23 | 2010-05-21 | Gp Pharm S.A. | PHARMACEUTICAL COMPOSITION OF SUSTAINED RELEASE OF SOMATOSTATINE OR AN ANALOG OF HIS. |
| CN105267153B (en) * | 2015-11-27 | 2018-05-11 | 上海苏豪逸明制药有限公司 | A kind of Triptorelin sustained-release microparticle and preparation method thereof |
| CN110954491B (en) * | 2019-12-09 | 2022-11-15 | 北京博恩特药业有限公司 | Method for measuring in-vitro dissolution rate of goserelin acetate sustained-release implant |
| JP7371519B2 (en) | 2020-02-14 | 2023-10-31 | 村田機械株式会社 | Automatic warehouse |
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| US3773919A (en) | 1969-10-23 | 1973-11-20 | Du Pont | Polylactide-drug mixtures |
| EP0052610A1 (en) | 1980-05-29 | 1982-06-02 | NICKLAUS, Helen Carol | Stringed musical instrument teaching device and process |
| GB2132887A (en) * | 1982-11-15 | 1984-07-18 | Procter & Gamble | Enteric-coated anti-inflammatory compositions |
| CH661206A5 (en) | 1983-09-23 | 1987-07-15 | Debiopharm Sa | PROCESS FOR THE PREPARATION OF A MEDICINAL PRODUCT FOR THE TREATMENT OF HORMONDEPENDENT DISEASES. |
| JPS60100516A (en) | 1983-11-04 | 1985-06-04 | Takeda Chem Ind Ltd | Preparation of sustained release microcapsule |
| ATE61935T1 (en) * | 1985-02-07 | 1991-04-15 | Takeda Chemical Industries Ltd | PROCESS FOR PRODUCTION OF MICROCAPSULES. |
| JP2551756B2 (en) | 1985-05-07 | 1996-11-06 | 武田薬品工業株式会社 | Polyoxycarboxylic acid ester and method for producing the same |
| CH665558A5 (en) | 1985-10-09 | 1988-05-31 | Debiopharm Sa | Phase sepn. prodn. of microcapsules for water soluble pharmaceuticals - using fluoro-substd. aliphatic hydrocarbon as non-solvent in the hardening stage |
| GB2209937B (en) | 1987-09-21 | 1991-07-03 | Depiopharm S A | Water insoluble polypeptides |
| US5538739A (en) * | 1989-07-07 | 1996-07-23 | Sandoz Ltd. | Sustained release formulations of water soluble peptides |
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| EP0858772B1 (en) | 1995-10-05 | 2008-10-29 | Kabushiki Kaisha Toshiba | X-ray imaging apparatus |
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| GB9718986D0 (en) * | 1997-09-09 | 1997-11-12 | Danbiosyst Uk | Controlled release microsphere delivery system |
| US6818018B1 (en) * | 1998-08-14 | 2004-11-16 | Incept Llc | In situ polymerizable hydrogels |
-
1999
- 1999-12-17 ES ES009902768A patent/ES2169980B1/en not_active Expired - Fee Related
-
2000
- 2000-12-15 PT PT00985267T patent/PT1151746E/en unknown
- 2000-12-15 DE DE60001717T patent/DE60001717T2/en not_active Expired - Lifetime
- 2000-12-15 BR BRPI0008197A patent/BRPI0008197B8/en not_active IP Right Cessation
- 2000-12-15 EP EP00985267A patent/EP1151746B1/en not_active Expired - Lifetime
- 2000-12-15 JP JP2001544663A patent/JP5021880B2/en not_active Expired - Lifetime
- 2000-12-15 AT AT00985267T patent/ATE234608T1/en active
- 2000-12-15 DK DK00985267T patent/DK1151746T3/en active
- 2000-12-15 MX MXPA01008348A patent/MXPA01008348A/en active IP Right Grant
- 2000-12-15 US US09/913,671 patent/US20020187196A1/en not_active Abandoned
- 2000-12-15 CA CA002362769A patent/CA2362769C/en not_active Expired - Lifetime
- 2000-12-15 WO PCT/ES2000/000475 patent/WO2001043724A1/en active IP Right Grant
- 2000-12-15 ES ES00985267T patent/ES2194793T3/en not_active Expired - Lifetime
- 2000-12-15 AU AU21735/01A patent/AU774680B2/en not_active Expired
-
2005
- 2005-01-25 US US11/042,682 patent/US20050123618A1/en not_active Abandoned
-
2008
- 2008-04-23 US US12/148,893 patent/US9789064B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| AU774680B2 (en) | 2004-07-01 |
| AU2173501A (en) | 2001-06-25 |
| DK1151746T3 (en) | 2003-07-21 |
| DE60001717T2 (en) | 2004-03-18 |
| EP1151746B1 (en) | 2003-03-19 |
| MXPA01008348A (en) | 2004-03-19 |
| BRPI0008197B8 (en) | 2021-05-25 |
| ES2194793T3 (en) | 2003-12-01 |
| PT1151746E (en) | 2003-07-31 |
| CA2362769A1 (en) | 2001-06-21 |
| DE60001717D1 (en) | 2003-04-24 |
| BR0008197A (en) | 2002-01-22 |
| EP1151746A1 (en) | 2001-11-07 |
| US20020187196A1 (en) | 2002-12-12 |
| WO2001043724A1 (en) | 2001-06-21 |
| ES2169980B1 (en) | 2003-11-01 |
| US9789064B2 (en) | 2017-10-17 |
| ATE234608T1 (en) | 2003-04-15 |
| ES2169980A1 (en) | 2002-07-16 |
| BRPI0008197B1 (en) | 2017-05-09 |
| US20080233198A1 (en) | 2008-09-25 |
| US20050123618A1 (en) | 2005-06-09 |
| JP2003516960A (en) | 2003-05-20 |
| JP5021880B2 (en) | 2012-09-12 |
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