CN1883474A - A composition containing macrolide compound and porous water insoluble hydrophilic carrier - Google Patents
A composition containing macrolide compound and porous water insoluble hydrophilic carrier Download PDFInfo
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- CN1883474A CN1883474A CN 200510012615 CN200510012615A CN1883474A CN 1883474 A CN1883474 A CN 1883474A CN 200510012615 CN200510012615 CN 200510012615 CN 200510012615 A CN200510012615 A CN 200510012615A CN 1883474 A CN1883474 A CN 1883474A
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Abstract
The invention discloses a composition comprising macrolide compounds and porous water-insoluble hydrophilic carrier. By using one or more porous water-insoluble hydrophilic carriers to replace water-soluble carriers, the objective of increasing dissolving rate and improving biological availability can be achieved.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, more properly, the invention discloses a kind of pharmaceutical composition that contains macrolides compound.
Background technology
Macrolides compound is an active ingredient in pharmaceutical of the present invention, it is macrolides compound by the tricyclic lactam structure of streptomyces hygroscopicus microorganism belonging to genus generation, comprise rapamycin, FK506, ascosin and analog thereof or derivant, these tricyclic compoundses have stronger immunocompetence, antibacterial activity and other pharmacological activities, being mainly used in the treatment of aspects such as the immunologic rejection reaction of organ transplantation or tissue transplantation and autoimmune disease and inflammation, asthma, tumor, antifungal, xerophthalmia clinically, more and more is that people pay attention to now.
Such macrolides compound belongs to high lipophilic hydrophobic compound, almost insoluble in water, and be dissolved in organic solvents such as methanol, ethanol, acetone, chloroform, therefore drug dissolution is very low, seldom be absorbed by the body after oral, crossing low absorption can cause drug bioavailability can be subjected to food effect, (he can not take charge of (FK506) capsule description can to cause effect of drugs that bigger individual variation is arranged yet, Chinese invention patent application number 99806415.7), make drug safety and effectiveness be adversely affected.Simultaneously, also can increase drug use amount and price.Thereby improve the insoluble drug dissolution and improve the hot issue that its bioavailability is current technical field solution.
Specializing rapamycin (Rapamycin also claims sirolimus) and its derivant (being referred to as rapamycin), is a kind of thricyclic macrolide para-immunity inhibitor of 31 membered lactams structures.It is by different cytokine receptor disabling signal conduction, blocking-up T lymphocyte and other cells are by the process of G1 phase to the S phase, thereby performance immunosuppressive effect, it is the most promising in the world at present novel potent immunosuppressant, strong 100 times and toxicity of the third generation immunosuppressant ciclosporin that specific activity is used clinically is low, can be used for anti-repulsive interaction of organ transplantation and autoimmune diseasees such as treatment rheumatoid arthritis, lupus erythematosus.From present clinical practice, it has good anti-repulsive interaction, and with immunosuppressant such as Ciclosporin A (CsA) and FK506 good synergism is arranged, and is a kind of good effect, low toxicity, and no nephrotoxicity also has the neotype immunosuppressant of antitumor action.Rapamycin is by the trade name exploitation listing of U.S. Wyeth-Ayerst company with RAPAMUNE, drugs approved by FDA thunder pareira element share with ciclosporin clinically and was applicable to that kidney moves and grows patient that every day, dosage was 2 to 5 milligrams (the English description FDA of rapamycin oral liquid website http://www.fda.gov) in August, 1999.
Thereby mainly contain following patent with the oral formulations research that improves the special rapamycin drug dissolution of such macrolides compound and improve its bioavailability recent years: Chinese patent 94116780.1 has been announced a kind of oral liquid of rapamycin, be to add an amount of soil temperature-80 with soybean phospholipid as cosolvent to be mixed with into a kind of oily oral administration solution, soybean phosphatide itself is just water insoluble, after the water dilution, need vigorous stirring could form a kind of emulsion with the plain oral liquid of the thunder pareira of its hydrotropy, this emulsion particle diameter is very big, the solution instability, the average bioavailability in oral back has only 14%.Thereby for improve macrolides compound particularly the dissolution of rapamycin improve its bioavailability, reduce the greatly different difference between the individuality, the pharmaceutical composition of exploitation new class is necessary.
Summary of the invention
The invention discloses the combination of oral medication of the solid-state discrete form that water insoluble carriers that a kind of macrolides compound and one or more have porous hydrophilic form, obviously improved the dissolution of rapamycin.Present solid dispersion technology often adopts water-solubility carrier to increase the stripping of insoluble drug, improves its bioavailability.The present invention has porous water insoluble hydrophilic carrier with one or more and replaces water-solubility carrier to reach the increase dissolution equally, improves the purpose of bioavailability, has further enlarged the use of solid dispersion technology.
Porous water insoluble hydrophilic carrier described in the present invention is meant colloidality silicon dioxide, aluminium silicate, magnesium silicate, aluminium-magnesium silicate, activated alumina, magnesium oxide, kieselguhr, kaolin.
The weight ratio 1: 0.1 to 1: 10 of macrolides compound and porous water insoluble hydrophilic carrier in the compositions disclosed by the invention, preferred 1: 0.5～1: 3.
The preparation of unit dose contains macrolides compound 0.1mg-10mg among the present invention, preferred 0.5-5mg.
Compositions disclosed by the invention can also contain one or more surfactants, and suitable has: polyoxyethylene-polyoxypropylene copolymer and block copolymer, as poloxamer 188; Sodium lauryl sulphate or sodium laurylsulfate; Lecithin; Polyoxyethylene fatty acid ester class such as Myrj 53; Polyoxyethylene aliphatic alcohol ether class such as Brij30; The cholesterol of sterols such as ethoxylation, Solulan C24, Cholesteryl hexadecanoate; Cholic acid or cholate; Fatty acid cane sugar ester; Tocopherol polyethyleneglycol succinate Vitamin E TPGS; Saturated polyglycolyzed glyceride Gelucira such as Gelucira 44/14 etc.The weight ratio of macrolides compound and surfactant 1: 0.1 to 1: 5, preferred 1: 0.2～1: 1.
Pharmaceutical composition of the present invention can contain one or more antioxidant, comprises malonic acid, citric acid, L-1-cystine mono hydrochloride, L-sodium L-ascorbate-2-phosphate, VE, propyl gallate, BHT, BHA, TBHQ, tea polyphenols.Preferred malonic acid, citric acid, L-1-cystine mono hydrochloride, L-sodium L-ascorbate-2-phosphate.The part by weight of antioxidant is 0.01 to 5%, preferred 0.05%～2% of a composition total weight.
Can contain one or more disintegrating agents in the compositions of the present invention, disintegrating agent is an adjuvant commonly used in the pharmaceutical preparation, can be cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, carboxymethyl starch sodium, sodium starch glycol, modified starch etc., but above-mentioned disintegrating agent can use also use in conjunction separately.
If add disintegrating agent in the present invention, the weight ratio of macrolides compound and disintegrating agent is 1: 0.5 to 1: 4, preferred 1: 1.
Can contain one or more excipient in the compositions of the present invention, add the loss of solid dispersion minimizing in pulverizing ground and mixed adjuvant process that excipient forms, excipient comprises lactose, microcrystalline Cellulose, sucrose etc.The weight ratio of macrolides compound and excipient is 1: 0.5～1: 8, preferred 1: 2～1: 4.
Known that by existing technology colloidality silicon dioxide has special structure, generally Chang Zuowei lubricant or fluidizer, disintegrating agent use in pharmaceutical preparation.Itself has very large specific surface area 200-600m
2/ g, it is the nanoporous hydrophilic material, have hole of uniform size, hole average diameter＜50nm is about general 10nm, has stronger adsorptivity, drug solution is adsorbed and enters loose structure, and after co-precipitation, medicine is by enclose or be adsorbed in its hole, make insoluble drug be evenly distributed on the good dispersity of maintenance in the nanometer hole, form the nano-solid preparation.Because its special structure, colloidality silicon dioxide is that the agent of solid hydrophilic powder emulsifying (is seen " pharmaceutics " (third edition, the Xi Nianzhu chief editor, the People's Health Publisher, P107), be dispersed in and form colloid solution in the water, insoluble drug is contained by micelle or adsorbs and afterwards makes dissolubility increase the stripping that has obviously improved insoluble drug.We find many porous water insoluble hydrophilic materials simultaneously, has similarity as aluminium silicate, magnesium silicate, aluminium-magnesium silicate, activated alumina, magnesium oxide, kieselguhr, kaolin etc., one or more mixing wherein can be used as the water-insoluble dispersible carrier of solid dispersion, for medicine provides good disperse medium.From the preparation uniformity of dosage units of preparation and stripping result as can be seen preparation the higher uniformity and dissolution are arranged.Because their special structural property and solid dispersion technologies can obviously increase the dissolubility of insoluble medicine, and then improve the bioavailability of insoluble medicine.
Adopt above technology, we are prepared into the obviously solid dispersion compositions of solubilising with above-mentioned slightly solubility Macrocyclolactone lactone kind medicine.
The preparation process of solid dispersion compositions of the present invention is:
(1) macrolides compound is dissolved in single solvent or solvent mixture.Solvent can be a kind of alcohol, as ethanol, methanol or isopropyl alcohol; A kind of ester is as ethyl acetate, butyl acetate; A kind of ether is as diethyl ether; A kind of ketone is as acetone, butanone; Or a kind of halogenated hydrocarbon, as dichloroethanes, 1.2-dichloroethanes.
(2) again with one or more porous water insoluble hydrophilic carrier full and uniform dispersion in (1).
(3) one or more antioxidant are added in (2), fully dissolving stirs.
(4) one or more surfactants are added in (3), fully dissolving stirs.
(5) one or more disintegrating agents are added in (4), stir.
(6) one or more excipient are added in above-mentioned (5), stir.
(7) by drying under reduced pressure or spray drying solvent is removed, pulverized and ground 80 mesh sieves, obtain uniform solid-state dispersive composition.
(8) with solid-state dispersive composition (7) and adjuvant mix homogeneously such as filler, lubricant, disintegrating agent, correctives or sweeting agent, can be prepared into powder agent, granule, ordinary tablet, oral cavity disintegration tablet, dispersible tablet, capsule.With rapamycin and FK506 is example, and unit dose contains rapamycin or the FK506 of 0.1mg-10mg, more preferably 0.5-5mg.
The above-mentioned composition that process drying under reduced pressure or spray drying obtain can add adjuvants such as one or more filleies, lubricant, disintegrating agent, correctives and sweeting agent and be prepared into powder agent, granule, ordinary tablet, oral cavity disintegration tablet, dispersible tablet, capsule, and filler commonly used is lactose, microcrystalline Cellulose, starch, sucrose etc.Lubricant commonly used such as magnesium stearate, Pulvis Talci, micropowder silica gel etc.Correctives and sweeting agent commonly used can be Fructus Citri Limoniae essence, Herba Menthae essence, aspartame etc.
By stripping experiment, all increase significantly with the dissolution of the macrolides compound preparation of method for preparing than former powder and the simple mixture of adjuvant, see stripping for details and test.
Macrolides compound disclosed by the invention and porous water insoluble hydrophilic support or carrier mixture are prepared into solid pharmaceutical composition, being equally applicable to the applicant is that 200510012558.2 denominations of invention are a kind of patent of invention that contains the pharmaceutical composition of macrolides compound in the application number of application on May 31st, 2005, be specially the microemulsified pre-concentration liquid of disclosed macrolides compound in the invention and porous water insoluble hydrophilic support or carrier mixture and be prepared into solid pharmaceutical composition, can improve the dissolubility of macrolides compound equally.Further, microemulsified pre-concentration liquid adding porous water insoluble hydrophilic support or carrier mixture can fully absorb microemulsified pre-concentration liquid and reach capacity, and form the pressed powder that has certain flowability and compressibility uniformly.Microemulsified pre-concentration liquid and porous water insoluble hydrophilic support or carrier mixture weight ratio are 1: 20～20: 1, preferred 1: 2～2: 1.Also can fully absorb microemulsified pre-concentration liquid with water-solubility carrier, as maltodextrin, starch etc.On the basis of above-mentioned composition, add adjuvants such as filler, disintegrating agent, lubricant, correctives, sweeting agent and be prepared into powder agent, granule, ordinary tablet, oral cavity disintegration tablet, dispersible tablet, capsule.
Its preparation process is:
(1) the microemulsified pre-concentration liquid of preparation macrolides compound.
(2) add porous water insoluble hydrophilic carrier or carrier mixture and fully absorb microemulsified pre-concentration liquid and reach capacity, abundant mix homogeneously forms and has certain flowability and compressibility pressed powder.
(3) cross 80 mesh sieves, obtain uniform pressed powder.
(4) add adjuvants such as filler, disintegrating agent, lubricant, correctives, sweeting agent and be prepared into powder agent, granule, ordinary tablet, oral cavity disintegration tablet, dispersible tablet, capsule.With rapamycin and FK506 is example, and unit dose contains rapamycin or the FK506 of 0.1mg-10mg, more preferably 0.5-5mg.
By experiment, all increase significantly, see the stripping experiment for details than the simple mixtures of former powder and adjuvant with the dissolution of the macrolides compound preparation of method for preparing.
The specific embodiment
Following examples, experimental example only are further detailed the present invention, should not be construed as limitation of the present invention.
Unless explain especially, all adjuvants are commercially available, pharmaceutic adjuvant rank among the present invention.
Rapamycin is North China Pharmacuetical Group New Drug Research ﹠ Development Co., Ltd's product
Embodiment contains the preparation of compositions of macrolides compound and porous water insoluble hydrophilic carrier
Embodiment 1
With the rapamycin is that example is made the solid composite that contains following component:
Rapamycin 1mg
Colloidality silica 1 mg
After rapamycin is dissolved in dehydrated alcohol, colloidality silicon dioxide is disperseed wherein, stir 30min, drying under reduced pressure 24 hours obtains solid and pulverizes and ground 80 mesh sieves, mixes 80 mesh sieves three times with an amount of microcrystalline Cellulose again, mixing fill capsule or tabletting.
Embodiment 2
With the rapamycin is that example is made the solid composite that contains following component:
Rapamycin 1mg
Colloidality silicon dioxide 2mg
After rapamycin is dissolved in dehydrated alcohol, colloidality silicon dioxide is disperseed wherein, stir 30min, drying under reduced pressure 24 hours obtains solid and pulverizes and ground 80 mesh sieves, mixes 80 mesh sieves three times with an amount of microcrystalline Cellulose again, mixing fill capsule or tabletting.
Embodiment 3
Rapamycin 1mg
Colloidality silicon dioxide 5mg
After rapamycin is dissolved in dehydrated alcohol, colloidality silicon dioxide is disperseed wherein, stir 30min, drying under reduced pressure 24 hours obtains solid and pulverizes and ground 80 mesh sieves, mixes 80 mesh sieves three times with an amount of microcrystalline Cellulose again, mixing fill capsule or tabletting.
Embodiment 4
Rapamycin 1mg
Lactose 4mg
After rapamycin is dissolved in dehydrated alcohol, lactose is disperseed wherein, stir 30min, drying under reduced pressure 24 hours obtains solid and pulverizes and ground 80 mesh sieves, mixes 80 mesh sieves three times with an amount of microcrystalline Cellulose again, mixing fill capsule or tabletting.
Embodiment 5
Rapamycin 1mg
Lactose 30mg
After rapamycin is dissolved in dehydrated alcohol, lactose is disperseed wherein, stir 30min, drying under reduced pressure 24 hours obtains solid and pulverizes and ground 80 mesh sieves, mixes 80 mesh sieves three times with an amount of microcrystalline Cellulose again, mixing fill capsule or tabletting.
Embodiment 6
Make the solid composite that contains following component:
Rapamycin 1mg
Colloidality silicon dioxide 2mg
Cross-linking sodium carboxymethyl cellulose 1mg
Lactose 4mg
After rapamycin is dissolved in dehydrated alcohol, the colloidality silica supports is disperseed wherein, stir 30min, add cross-linking sodium carboxymethyl cellulose and lactose, stir, drying under reduced pressure 24 hours obtains the solid pulverizing and ground 80 mesh sieves, mixed 80 mesh sieves three times, mixing fill capsule or tabletting with an amount of microcrystalline Cellulose again
Embodiment 7
Make the solid composite that contains following component:
Rapamycin 1mg
Colloidality silicon dioxide 2mg
Poloxamer188 0.25mg
Cross-linking sodium carboxymethyl cellulose 1mg
Lactose 4mg
Preparation method of composition: after rapamycin is dissolved in an amount of dehydrated alcohol, the colloidality silica supports is disperseed wherein, stir 30min, add Poloxamer188, cross-linking sodium carboxymethyl cellulose and lactose successively, stir, drying under reduced pressure 24 hours obtains the solid pulverizing and ground 80 mesh sieves, mixed 80 mesh sieves three times, mixing fill capsule or tabletting with an amount of microcrystalline Cellulose again.
Embodiment 8
Make the solid composite that contains following component:
Rapamycin 1mg
Malonic acid 0.05%
Colloidality silicon dioxide 2mg
Poloxamer188 0.25mg
Cross-linking sodium carboxymethyl cellulose 1mg
Lactose 4mg
Preparation method of composition: after rapamycin is dissolved in an amount of ethanol, add malonic acid to dissolving, the colloidality silica supports is disperseed wherein, stir 30min, add Poloxamer188, cross-linking sodium carboxymethyl cellulose and lactose successively, drying under reduced pressure 24 hours obtains the solid pulverizing and ground 80 mesh sieves, mixed 80 mesh sieves three times with an amount of microcrystalline Cellulose again, mixing fill capsule or tabletting.
Embodiment 9
Make the solid composite (Comparative formulation) that contains following component:
Microemulsified pre-concentration liquid (the containing principal agent 80mg) 1.5g of rapamycin
Colloidality silica 1 g
Microcrystalline Cellulose 9g
Lactose 3.5g
Cross-linking sodium carboxymethyl cellulose 0.8g
Magnesium stearate 0.2g
Total amount 16g
Preparation method of composition:
The microemulsified pre-concentration liquid of preparation rapamycin adds colloidality silicon dioxide and fully absorbs to saturated, and fully mix homogeneously is crossed 80 mesh sieves.Add other adjuvant and mix, cross 80 mesh sieves three times, mixing fill capsule or tabletting.
Embodiment 10
Make the solid composite (Comparative formulation) that contains following component:
Rapamycin 1mg
Cross-linking sodium carboxymethyl cellulose 4mg
Lactose 10mg
Microcrystalline Cellulose 65mg
Preparation method of composition: rapamycin and above-mentioned adjuvant are crossed 80 mesh sieves respectively, and mixing is sieved, mixing fill capsule or tabletting.
Experimental example stripping experiment
(1) test specimen
Press the sample-A of embodiment 1 preparation
Press the sample-B of embodiment 2 preparations
Press the sample-C of embodiment 3 preparations
Press the sample-D of embodiment 4 preparations
Press the sample-E of embodiment 5 preparations
Press the sample-F of embodiment 6 preparations
Press the sample-G of embodiment 7 preparations
Press the sample-H of embodiment 8 preparations
Press the sample-I of embodiment 9 preparations
Press sample (the control sample)-J of embodiment 10 preparations
(2) experimental technique
The test employing " 2000 editions appendix XC of Chinese pharmacopoeia " dissolution method " three therapeutic methods of traditional Chinese medicine (cuvette slurry method), medium is 0.2% sodium lauryl sulphate, and rotating speed is 100r/min, experimentizes, and above-mentioned sample 30min dissolution the results are shown in Table 1
(3) experimental result
Table 1
| Sample | A | B | C | D | E | F | G | H | I | J |
| Dissolution % | 60.31 | 85.49 | 84.38 | 43.22 | 78.95 | 87.37 | 94.06 | 94.32 | 88.16 | 28.28 |
With Comparative formulation J (embodiment 10) ratio, as can be seen, colloidality silicon dioxide has obvious solubilization as the insoluble hydrophilic support of porous in the solid dispersion, as embodiment 1, embodiment 2 and embodiment 3.Lactose also has solubilization, as embodiment 4, but needs to add the obvious solubilising of relatively large ability, as embodiment 5.Because lactose adds as excipient in the preparation of our exploitation, the amount of lactose is less relatively, therefore plays the still porous water insoluble hydrophilic carrier colloidality silicon dioxide of decisive solubilization, as embodiment 6.Add surfactant, further increased the stripping of rapamycin, as embodiment.After microemulsified pre-concentration liquid was prepared into solid preparation, obviously solubilising for the microemulsion formulation with greater advantage (bioavailability height, individual variation is little), provided a kind of solid preparation form, as embodiment 9.
Claims (10)
1. compositions that contains macrolides compound and porous water insoluble hydrophilic carrier, wherein macrolides compound is rapamycin, FK506, ascosin and analog thereof or derivant, preferred rapamycin; Porous water insoluble hydrophilic carrier is one of colloidality silicon dioxide, aluminium silicate, magnesium silicate, aluminium-magnesium silicate, activated alumina, magnesium oxide, kieselguhr, kaolin or its mixture.
2. the described compositions of claim 1, wherein the weight ratio of macrolides compound and porous water insoluble hydrophilic carrier is 1: 0.1 to 1: 10, preferred 1: 0.5～1: 3.
3. claim 1 or 2 arbitrary described compositionss also contain surfactant, and surfactant can be for polyoxyethylene-polyoxypropylene copolymer and block copolymer, as poloxamer 188; Sodium lauryl sulphate or sodium laurylsulfate; Lecithin; Polyoxyethylene fatty acid ester class such as Myrj53; Polyoxyethylene aliphatic alcohol ether class such as Brij30; The cholesterol of sterols such as ethoxylation, SolulanC24, Cholesteryl hexadecanoate; Cholic acid or cholate; Fatty acid cane sugar ester; Tocopherol polyethyleneglycol succinate Vitamin E TPGS; One of saturated polyglycolyzed glyceride Gelucira such as Gelucira 44/14 or its mixture.
4. the described compositions of claim 3, wherein the weight ratio of macrolides compound and surfactant is 1: 0.1 to 1: 5, preferred 1: 0.2～1: 1.
5. claim 1 or 2 arbitrary described compositionss also contain antioxidant, and antioxidant can be malonic acid, citric acid, L-1-cystine mono hydrochloride, L-sodium L-ascorbate-2-phosphate, VE, propyl gallate, BHT, BHA, TBHQ, tea polyphenols.One of preferred malonic acid, citric acid, L-1-cystine mono hydrochloride, L-sodium L-ascorbate-2-phosphate or its mixture.
6. the described compositions of claim 5, wherein the part by weight of antioxidant is 0.01% to 5%, preferred 0.05%～2% of a composition total weight.
7. claim 1 or 2 arbitrary described compositionss, also contain disintegrating agent, disintegrating agent is one of cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, carboxymethyl starch sodium, sodium starch glycol, modified starch or its mixture.
The described mixture of 8 claim 7, the weight ratio of macrolides compound and disintegrating agent are 1: 0.5 to 1: 4, preferred 1: 1.
9 claim 1 or 2 arbitrary described compositionss can contain excipient, and excipient can be one of lactose, microcrystalline Cellulose, sucrose or its mixture.
10. the described compositions of claim 9, wherein the weight ratio of macrolides compound and excipient is 1: 0.5～1: 8, preferred 1: 2～1: 4.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101554376B (en) * | 2009-05-06 | 2011-11-30 | 北京大学 | High-bioavailability rapamycin composition and preparation method thereof |
| EP3104891A1 (en) * | 2014-02-11 | 2016-12-21 | Lam Therapeutics, Inc. | Rapamycin for the treatment of lymphangioleiomyomatosis |
| CN106309395A (en) * | 2016-09-22 | 2017-01-11 | 沈阳药科大学 | Tacrolimus sustained-release tablets and preparation method thereof |
| CN109431997A (en) * | 2018-12-20 | 2019-03-08 | 武汉科福新药有限责任公司 | A kind of rapamycin locally injecting preparation and preparation method thereof |
| US11103449B2 (en) | 2014-04-04 | 2021-08-31 | AI Therapeutics, Inc. | Inhalable rapamycin formulation for treating age-related conditions |
| US11123289B2 (en) | 2013-10-08 | 2021-09-21 | AI Therapeutics, Inc. | Rapamycin for the treatment of lymphangioleiomyomatosis |
| US11491143B2 (en) | 2014-10-07 | 2022-11-08 | AI Therapeutics, Inc. | Inhalable rapamycin formulation for the treatment of pulmonary hypertension |
-
2005
- 2005-06-22 CN CN 200510012615 patent/CN1883474A/en active Pending
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101554376B (en) * | 2009-05-06 | 2011-11-30 | 北京大学 | High-bioavailability rapamycin composition and preparation method thereof |
| US11123289B2 (en) | 2013-10-08 | 2021-09-21 | AI Therapeutics, Inc. | Rapamycin for the treatment of lymphangioleiomyomatosis |
| US11744797B2 (en) | 2013-10-08 | 2023-09-05 | AI Therapeutics, Inc. | Rapamycin for the treatment of lymphangioleiomyomatosis |
| EP3104891A1 (en) * | 2014-02-11 | 2016-12-21 | Lam Therapeutics, Inc. | Rapamycin for the treatment of lymphangioleiomyomatosis |
| US11103449B2 (en) | 2014-04-04 | 2021-08-31 | AI Therapeutics, Inc. | Inhalable rapamycin formulation for treating age-related conditions |
| US11648199B2 (en) | 2014-04-04 | 2023-05-16 | Al Therapeutics, Inc. | Inhalable rapamycin formulation for treating age-related conditions |
| US11491143B2 (en) | 2014-10-07 | 2022-11-08 | AI Therapeutics, Inc. | Inhalable rapamycin formulation for the treatment of pulmonary hypertension |
| CN106309395A (en) * | 2016-09-22 | 2017-01-11 | 沈阳药科大学 | Tacrolimus sustained-release tablets and preparation method thereof |
| CN106309395B (en) * | 2016-09-22 | 2019-09-20 | 沈阳药科大学 | A kind of tacrolimus sustained release piece and preparation method thereof |
| CN109431997A (en) * | 2018-12-20 | 2019-03-08 | 武汉科福新药有限责任公司 | A kind of rapamycin locally injecting preparation and preparation method thereof |
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Open date: 20061227 |