CN1919194A - Liquid composition of sirolimus - Google Patents
Liquid composition of sirolimus Download PDFInfo
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- CN1919194A CN1919194A CNA2006101096882A CN200610109688A CN1919194A CN 1919194 A CN1919194 A CN 1919194A CN A2006101096882 A CNA2006101096882 A CN A2006101096882A CN 200610109688 A CN200610109688 A CN 200610109688A CN 1919194 A CN1919194 A CN 1919194A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
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- 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
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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Abstract
The invention discloses a liquid composition of immune inhibiting agent ciromos, which consists of soluble solution system with ciromos and pre-emulsifying condensed liquid system, wherein the ciromos can dissolve in the methyl glycol, PEG, surface activator and plant oil.
Description
Technical field
The present invention relates to drug preparation technique, particularly a kind of pharmaceutical composition for the treatment of the liquid form of immunosuppressant sirolimus.
Background technology
Sirolimus (Sirolimus) is the anti-immune antibiotic of a kind of Macrolide that is produced by Streptococcus, promptly reported its immunosuppressive activity in rat assist agent arthritis and experimental allergic cerebrospinal meningitis model in 1977, research to sirolimus has in recent years proved that it is a kind of potent immunosuppressive agent, it not only has significant curative effect to the various autoimmune sexual abnormality, and demonstrates the anti-rejection activity of significance on different types of organ transplantation animal model.Its effect mainly shows as suppressor T cell and T cell dependency B cell to the antigenic reaction of graft.It has unique mechanism of action, in recent years, the research of its mechanism of action has been had great progress.
Sirolimus by with the distinct mechanism of action of other immunosuppressant, suppress lymphocytic activation of T and propagation that antigen and cytokine (interleukin I L-2, IL-4 and IL-15) excite.Sirolimus also suppresses production of antibodies.In cell, sirolimus and immunophilin, i.e. FK conjugated protein-12 (FKBP-12) combination generates an immunosuppressive compound.This sirolimus FKBP-12 complex does not have influence to the activity of calcineurin.This complex and mammiferous sirolimus target molecule (mTOR, a kind of adjusting kinases of key) combination, and suppress its activity.The propagation of the T cell that cytokine drives has been checked in this kind inhibition, promptly suppresses in the cell cycle G1 phase to the development of S phase.
Experimental model studies show that sirolimus can prolong the survival period of allograft's (kidney, the heart, skin, islets of langerhans, small intestinal, pancreas-duodenum and bone marrow) of mice, rat, pig and/or primate.Sirolimus can reverse the heart of rat and the acute rejection of kidney allograft, and prolongs the transplant organ survival period of pre-sensitization rat.In some researchs, the immunosuppressive action of sirolimus may persist to and stops to treat back 6 months.The effect of this kind immunologic tolerance is at alloantigenic.
In the model of the rodent of autoimmune disease, sirolimus suppresses the immune-mediated reaction relevant with following disease: arthritis, autoimmune type i diabetes, autoimmune myocarditis, experimental allergic encephalomyelitis, graft versus host disease and the autoimmune uvea retinitis of systemic lupus erythematosus (sle), collagen protein initiation.
In JIUYUE, 1999 U.S. FDA official approval sirolimus listing, sirolimus gets the Green Light or registers in more than 20 countries so far, and preparation is oral liquid and tablet, is used for prevention of organ transplant patient's acute rejection.
There are some important deficiencies in existing oral liquid formulations agent.The one, stability is not very good, is to keep in Dark Place in the refrigerator of 2-8 ℃ (36-46 ) to the requirement of storing.In a single day medicine bottle is opened, and medicine should use up in January.Oral administration solution may produce slight muddiness when cold preservation.Secondly, the bioavailability of existing oral liquid is lower, is about 14%, and as a kind of expensive crude drug, low bioavailability may cause bigger loss; In addition, need when oral liquid (little packaged with plastic container) uses quantitatively to shift, use inconvenient.
According to these problems, the present invention has developed the fluid composition that is different from existing sirolimus oral liquid, is intended to improve its stability and bioavailability, improves storage requirement, and favourable patient takes and carries.
Summary of the invention
The invention provides a kind of fluid composition of sirolimus, be particularly related to solution system that contains sirolimus that a kind of and water can dissolve each other and a kind of pre-emulsifying concentrated solution system, this system can be made into content for liquid pharmaceutical preparation, as soft capsule, hard capsule and oral liquid etc. through processing.
The present invention's process is to choice of Solvent, the unexpected discovery, the sirolimus that is insoluble in water is particularly suitable for being dissolved in some solvents that dissolve each other with water, in the propylene glycol of liquid, the Polyethylene Glycol of liquid (PEG), further, the present invention finds that sirolimus also dissolves in some surfactants, as polyoxyethylene castor oil and some vegetable oil, in soybean oil, Semen Maydis oil, and the test of process stability experiment and some other technical parameter, find that these can reach the requirement of pharmacy.
The invention provides a kind of fluid composition of sirolimus.Said composition contains the solvent of sirolimus and solubilized sirolimus, the solvent of described solubilized sirolimus is selected from solution, surfactant, vegetable oil or their mixture that can dissolve each other with water, the solvent that described and water can dissolve each other is selected from propylene glycol, liquid macrogol, ethanol, glycerol or their mixture, preferably propylene glycol and contain the mixed with propylene glycol solvent.Wherein liquid macrogol be molecular weight between 200-600,300-400 preferably.
Wherein said surfactant is selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, poloxamer 188 (F68), sodium lauryl sulphate, cholate, deoxycholate.Polyoxyethylene castor oil preferably, consumption is 1%-60%, preferable amount is 45%.
Described vegetable oil can be soybean oil, Semen Maydis oil, Oleum sesami, safflower oil or their mixture.
Needs according to prescription also can add suitable pharmaceutic adjuvant such as stabilizing agent, sweeting agent and antibacterial etc.
Wherein said antibacterial is selected from benzoic acid, sodium benzoate, sorbic acid, p-Hydroxybenzoate, benzyl alcohol, chlorobutanol and thimerosal.Consumption is 0.01-2%, and preferable amount is 0.05-0.25%
Described stability is selected from BHA, BHT, propyl gallate, nor-couple of hydrogen guaiac acid, tocopherol and VE.Consumption is 0.005-0.1%.
Described correctives is selected from sweeting agent, essence.
Sweeting agent and essence can be chosen wantonly, as long as be fit to make all can selecting for use of oral liquid medicine preparation, as sucrose, protein sugar, sweetener, Aspartame, glucide, essence can select any odor type as Fructus Mali pumilae, Fructus Citri tangerinae, Fructus Musae, Fructus Vitis viniferae, Fructus Ananadis comosi, peach, Fructus Litchi or the like.Addition needs to decide on preparation, can operate according to prior art.
Preparation of the present invention, it is as follows that its prescription is formed (weight %):
Sirolimus 0.02-10%
Solubilized sirolimus and the solvent 80-99.98% that dissolves each other with water
Pharmaceutic adjuvant 0-10%
Wherein solubilized sirolimus and be preferably propylene glycol with solvent that water dissolves each other, or the mixture of polyoxyethylene castor oil and propylene glycol, for mixture, the ratio of polyoxyethylene castor oil and propylene glycol is 1-99%: 99-1%.
The most preferred prescription composition of the present invention is listed in the embodiment of the invention.
The composition of liquid medicine that has prepared a series of sirolimuss with solution system of the present invention, and carried out the research of stability and dissolution, found that the stability of the composition of liquid medicine of the sirolimus in incapsulating and dissolution in vitro obviously are better than corresponding oral liquid.
One of characteristics of the present invention are to have adopted the nonaqueous solvent that can dissolve each other with water as the disperse medium that dissolves the insoluble drug sirolimus.Help improving the stability and the bioavailability of this product like this.
Another characteristics of the present invention are to have adopted surfactant and the vegetable oil disperse medium as dissolving insoluble drug sirolimus.When preserving like this is nonaqueous system, helps the stable of this product; Meeting water can emulsifying, helps improving the bioavailability of this product.
Compositions of the present invention further can be made into pharmaceutical preparation.Compositions of the present invention directly can be packed in soft capsule or the hard capsule according to the galenic pharmacy routine techniques.Also oral liquid can be prepared into,, and an amount of correctives can be added as required as the oral liquid of single dose or the oral liquid of multiple dose, as sucrose, Aspartame, essence etc.
The method preparation of pharmaceutical preparation of the present invention is referring to embodiment.
One of advantage of the present invention shows, preparation of the present invention adopts is the nonaqueous solvent that can dissolve each other with the water medium as dissolving insoluble drug sirolimus, and the stability of system improves (existing oral liquid contains a large amount of phospholipid, and is very unstable).As solution system, the insoluble drug sirolimus is to be dispersed in the medium with molecularity, is ideal dispersity, mainly is the diffusion process of molecule before the absorption, therefore helps the absorption of medicine.
Another advantage of the present invention is, the present invention adopts surfactant and vegetable oil as the disperse medium that dissolves the insoluble drug sirolimus, in fact this formed so-called pre-microemulsion, this system is a non-aqueous solution when preserving, volume is little, system is stable, can be automatic emulsified but meet water after taking in vivo, help improving the bioavailability of this product.
Soft capsule that adopts among the present invention or hard capsule can provide a kind of physical barriers, can further strengthen stability of drug.Along with capsular quick disintegrate, drug molecule can diffuse out smoothly, helps the absorption of medicine.
Fluid composition of the present invention is taken 1 at every turn and just can be reached dosage after incapsulating.Pharmaceutical liquid composition of the present invention can be prepared into capsule etc., has more modern sense, and the outward appearance and the sense of taste etc. are easier to be accepted by the patient, and taking convenience does not have former preparation to need the deficiency that quantitatively shifts.Therefore the present invention can make the medication compliance of sirolimus preparation obviously improve, and this liver disease drug to prolonged application is very important.
Preferred compositions of the present invention obtains through screening, and said composition has promptly solved the stability problem of sirolimus oral formulations, and the medication compliance is obviously improved, and bioavailability is expected to be improved, and has obtained beyond thought effect.
The present invention is dissolved in the insoluble drug sirolimus in the suitable liquid system by selecting suitable prescription, makes the sirolimus solution system, and refabrication becomes suitable oral formulations.Preparation of the present invention can improve the stability of sirolimus, makes it can be 20-25 ℃ of preservation; Dissolution in vitro is compared with existing oral liquid and is increased, and therefore may improve the intravital absorption of sirolimus; Adopt appropriate dosage forms (as soft capsule, hard capsule etc.) can improve the compliance of medication simultaneously.
Conclusion: the described sirolimus fluid composition of this patent can improve the dissolubility of poorly water soluble drugs sirolimus, improves its stability and intestinal transmitance, tool exploitativeness and excellent application value.
Description of drawings
Fig. 1 sirolimus compositions is to the external transmittance curve of rat small intestine
The specific embodiment
By the following examples, further specify the present invention, but not as limitation of the present invention.
Embodiment 1:
The preparation of sirolimus fluid composition
Take by weighing sirolimus material medicine 0.5g, join in the container that fills the 500ml propylene glycol solution, stir up to whole dissolvings.Can heat in case of necessity and promote dissolving.Measure content with the HPLC method, promptly.
Embodiment 2:
The preparation of sirolimus fluid composition
Take by weighing sirolimus material medicine 0.5g, add the 150g polyoxyethylene castor oil, mix homogeneously adds propylene glycol to 500ml, stirs up to whole dissolvings; Also can earlier polyoxyethylene castor oil be dissolved in the propylene glycol solution, add the sirolimus material medicine again, stir up to whole dissolvings.Can heat in case of necessity and promote dissolving.Measure content with the HPLC method, promptly.
Embodiment 3:
The preparation of sirolimus fluid composition
Get polyoxyethylene castor oil 200g, add propylene glycol, stir, add sirolimus material medicine 0.5g again, stir up to whole dissolvings up to whole dissolvings to 500ml.Can heat in case of necessity and promote dissolving.Measure content with the HPLC method, promptly.
Embodiment 4:
Preparation contains the hard capsule of sirolimus compositions
Adopt constant volume method, the sirolimus fluid composition among embodiment 1 or the embodiment 3 is packed in the hard gelatin capsule, seal.Carry out the quality examination of capsule, promptly.
Embodiment 5:
Preparation contains the soft capsule of sirolimus compositions
Adopt pressing or dropping preparation method, the sirolimus fluid composition among embodiment 1 or the embodiment 3 is packed in the Perle.Carry out the quality examination of capsule, promptly.
Embodiment 6:
Preparation contains the oral liquid of sirolimus compositions
In the sirolimus fluid composition in embodiment 1 or embodiment 3, add and contain an amount of Aspartame and essence, fully dissolve mixing, divide in the bottle that installs to band scale and suction pipe, jump a queue, add a cover, promptly.
Embodiment 7:
The comparison of the sirolimus stability of Oral of sirolimus fluid composition of the present invention and prior art
The HPLC chromatographic condition: chromatographic column is C
8Post (250mm * 4.6mm I.D., 5 μ m) mobile phase be methanol-water-acetonitrile (30: 30: 40, V/V), column temperature is 40 ℃, flow velocity 1.5ml/min, the detection wavelength is 277nm.
Control formulation: sirolimus oral liquid
Test preparation: with sirolimus fluid composition in embodiment 1 and 3 is the hard capsule of content preparation
Assay method: get test preparation or control formulation, press the test method of accelerated stability, accelerated test is 10 days under 40 ℃ and 75%RH, carrying out HPLC sampling in 0,5,10 day analyzes, sirolimus reference substance solution with 100 μ g/ml is contrast, goes out the content of test preparation and control formulation with calculated by peak area by external standard method.
Result: see Table 1.
The accelerated tests study on the stability result of table 1 sirolimus compositions (in the hard capsule)
| Test specimen | 0 day | 5 days | 10 days |
| Sirolimus compositions embodiment 1 (ug/g) sirolimus compositions embodiment 3 (ug/g) sirolimus oral liquid (ug/g) | 906.16 909.09 943.38 | 906.04 909.01 849.52 | 906.18 909.04 789.21 |
Embodiment 8:
The sirolimus oral liquid of sirolimus fluid composition of the present invention and prior art is to the comparison of the external transmission rates of rat small intestine
The HPLC chromatographic condition: chromatographic column is C
8Post (250mm * 4.6mm I.D., 5 μ m) mobile phase be methanol-water-acetonitrile (30: 30: 40, V/V), column temperature is 40 ℃, flow velocity 1.5ml/min, the detection wavelength is 277nm.
Control formulation: sirolimus oral liquid
Sirolimus fluid composition among test preparation: the embodiment 1 and 3
Assay method: adopt the diffusion cell method to carry out the external test that sees through
Setting up the model of diffusion cell method by literature method, is biomembrane with the rat small intestine.Test preparation or control formulation dilution being caused 50 μ g/ml, put into the administration pond, is acceptable solution with 0.9%NaCl solution, takes a sample in accepting the pond at different time, injects chromatograph of liquid after the sample treatment, the record chromatogram; Sirolimus reference substance solution with 10 μ g/ml is contrast, goes out test preparation and the control formulation transport velocity to small intestinal by external standard method with calculated by peak area.
Result: see Fig. 1 and table 2.
Table 2 sirolimus compositions is to the external transmitance (%) of rat small intestine
| Test specimen | 1 hour | 2 hours | 3 hours |
| Sirolimus compositions embodiment 1 sirolimus compositions embodiment 3 sirolimus oral liquids | 22.3 39.3 11.9 | 46.4 62.4 24.5 | 51.1 82.1 34.6 |
The result as seen, the accelerated stability of sirolimus compositions and the transmitance of rat small intestine all is better than commercially available oral liquid.
Embodiment 9:
The preparation of sirolimus fluid composition
Take by weighing sirolimus material medicine 0.5g, join in the container that fills 500mlPEG300 solution, stir up to whole dissolvings.Can heat in case of necessity and promote dissolving.Measure content with the HPLC method, promptly.
Embodiment 10:
The preparation of sirolimus fluid composition
Take by weighing sirolimus material medicine 0.5g, join in the container that fills 500mlPEG400 solution, stir up to whole dissolvings.Can heat in case of necessity and promote dissolving.Measure content with the HPLC method, promptly.
Embodiment 11:
The preparation of sirolimus fluid composition
Take by weighing sirolimus material medicine 0.5g, add the 150g polyoxyethylene castor oil, mix homogeneously adds PEG300 to 500ml, stirs up to whole dissolvings.Also can polyoxyethylene castor oil be dissolved in the PEG300 solution earlier, add the sirolimus material medicine again, stir up to whole dissolvings.Can heat in case of necessity and promote dissolving.Measure content with the HPLC method, promptly.
Embodiment 12:
The preparation of sirolimus fluid composition
Take by weighing sirolimus material medicine 0.5g, add the 150g polyoxyethylene castor oil, mix homogeneously adds PEG400 to 500ml, stirs up to whole dissolvings.Also can polyoxyethylene castor oil be dissolved in the PEG400 solution earlier, add the sirolimus material medicine again, stir up to whole dissolvings.Can heat in case of necessity and promote dissolving.Measure content with the HPLC method, promptly.
Embodiment 13:
The preparation of sirolimus fluid composition
Take by weighing sirolimus material medicine 0.5g, and the mixed solution 450ml of adding polyoxyethylene castor oil and PEG400 (70%: 30%, V/V), stir up to whole dissolvings, add soybean oil 50ml again, stir up to whole dissolvings.Can heat in case of necessity and promote dissolving.Measure content with the HPLC method, promptly.
Embodiment 14:
The preparation of sirolimus fluid composition
Take by weighing sirolimus material medicine 0.5g, and the mixed solution 450ml of adding polyoxyethylene castor oil and PEG300 (70%: 30%, V/V), stir up to whole dissolvings, add soybean oil 50ml again, stir up to whole dissolvings.Can heat in case of necessity and promote dissolving.Measure content with the HPLC method, promptly.
Embodiment 15:
The preparation of sirolimus fluid composition
Take by weighing sirolimus material medicine 0.5g, and the mixed solution 450ml of adding polyoxyethylene castor oil and propylene glycol (70%: 30%, V/V), stir up to whole dissolvings, add soybean oil 50ml again, stir up to whole dissolvings.Can heat in case of necessity and promote dissolving.Measure content with the HPLC method, promptly.
Embodiment 16:
The preparation of sirolimus fluid composition
Take by weighing sirolimus material medicine 0.5g, (98%: 2%, V/V), stirring added soybean oil 50ml again up to whole dissolvings, stirs up to whole dissolvings to add polyoxyethylene castor oil and alcoholic acid mixed solution 450ml.Can heat in case of necessity and promote dissolving.Measure content with the HPLC method, promptly.
Embodiment 17:
The preparation of sirolimus fluid composition
Take by weighing sirolimus material medicine 0.5g, add polyoxyethylene castor oil 450ml, stir, add soybean oil 50ml again, stir up to whole dissolvings up to whole dissolvings.Can heat in case of necessity and promote dissolving.Measure content with the HPLC method, promptly.
Embodiment 18:
The preparation of sirolimus fluid composition
Take by weighing sirolimus material medicine 0.5g, add polyoxyethylene castor oil 450ml, stir, add Semen Maydis oil 50ml again, stir up to whole dissolvings up to whole dissolvings.Can heat in case of necessity and promote dissolving.Measure content with the HPLC method, promptly.
All can add certain antibacterial and/or stabilizing agent in above-mentioned each prescription.
Claims (10)
1, a kind of sirolimus fluid composition, it is characterized in that, described compositions contains the solvent of sirolimus and solubilized sirolimus, the solvent of described solubilized sirolimus is selected from solution, surfactant, the vegetable oil that can dissolve each other with water, and the described solvent that can dissolve each other with water is selected from propylene glycol, liquid macrogol, ethanol, glycerol.
2, the fluid composition of claim 1 is characterized in that, described surfactant is selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, poloxamer 188, sodium lauryl sulphate, cholate, deoxycholate.
3, the fluid composition of claim 1 is characterized in that, described vegetable oil is selected from soybean oil, Semen Maydis oil, Oleum sesami, safflower oil.
4, the fluid composition of claim 1 is characterized in that, also contains the pharmaceutic adjuvant that is fit to make liquid pharmaceutical formulation, and described pharmaceutic adjuvant is selected from stabilizing agent, correctives and antibacterial.
5, the fluid composition of claim 4, it is characterized in that, described antibacterial is selected from benzoic acid, sodium benzoate, sorbic acid, p-Hydroxybenzoate, benzyl alcohol, chlorobutanol and thimerosal, described stability is selected from BHA, BHT, propyl gallate, nor-couple of hydrogen guaiac acid, tocopherol and VE, described correctives is selected from sweeting agent, essence.
6, the fluid composition of claim 1 is characterized in that, its weight percent consists of:
Sirolimus 0.02～10%,
The solvent 80～99.98% of solubilized sirolimus,
Pharmaceutic adjuvant 0～10%.
7, the fluid composition of claim 6 is characterized in that, the solvent of described solubilized sirolimus is selected from propylene glycol, or the mixture of polyoxyethylene castor oil and propylene glycol, and described pharmaceutic adjuvant is selected from stabilizing agent, correctives and antibacterial.
8, the fluid composition of claim 7, it is characterized in that, described antibacterial is selected from benzoic acid, sodium benzoate, sorbic acid, p-Hydroxybenzoate, benzyl alcohol, chlorobutanol and thimerosal, described stability is selected from BHA, BHT, propyl gallate, nor-couple of hydrogen guaiac acid, tocopherol and VE, described correctives is selected from sweeting agent, essence.
9, with claim 1 fluid composition be the pharmaceutical preparation of content.
10, the pharmaceutical preparation of claim 8 is soft capsules, hard capsule or oral liquid.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006101096882A CN1919194A (en) | 2006-08-17 | 2006-08-17 | Liquid composition of sirolimus |
| PCT/CN2007/002470 WO2008022557A1 (en) | 2006-08-17 | 2007-08-16 | Liquid composition of sirolimus |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006101096882A CN1919194A (en) | 2006-08-17 | 2006-08-17 | Liquid composition of sirolimus |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1919194A true CN1919194A (en) | 2007-02-28 |
Family
ID=37777135
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006101096882A Pending CN1919194A (en) | 2006-08-17 | 2006-08-17 | Liquid composition of sirolimus |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN1919194A (en) |
| WO (1) | WO2008022557A1 (en) |
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| CN102499919A (en) * | 2011-10-13 | 2012-06-20 | 嘉兴富特吉生物科技有限公司 | Medicine combination containing low sirolimus dose for treating or preventing fibrotic diseases |
| CN106236732A (en) * | 2016-08-31 | 2016-12-21 | 佛山市弘泰药物研发有限公司 | A kind of preparation method of everolimus soft capsule |
| CN108434146A (en) * | 2017-02-16 | 2018-08-24 | 天津国际生物医药联合研究院 | A kind of solution and its preparation method and application of HIV-1 integrase inhibitors |
| WO2020184131A1 (en) * | 2019-03-08 | 2020-09-17 | 国立大学法人大阪大学 | Systemically-acting external preparation containing sirolimus or derivative thereof |
| CN115887407A (en) * | 2022-12-29 | 2023-04-04 | 深圳市泰力生物医药有限公司 | Sirolimus soft capsule and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HUP1400075A2 (en) | 2014-02-14 | 2015-08-28 | Druggability Technologies Ip Holdco Jersey Ltd | Complexes of sirolimus and its derivatives, process for the preparation thereof and pharmaceutical composition containing them |
| CN115569123B (en) * | 2022-12-08 | 2023-03-14 | 则正(济南)生物科技有限公司 | Vorinosane fumarate tablet and preparation method thereof |
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| AU543727B2 (en) * | 1980-06-02 | 1985-05-02 | Ayerst Mckenna & Harrison Inc. | Injectable composition of rapamycin |
| DK1033128T4 (en) * | 1993-09-28 | 2012-03-19 | Scherer Gmbh R P | Soft gelatin capsule making |
| IL111008A (en) * | 1993-09-30 | 1999-10-28 | American Home Prod | Rapamycin formulations for intravenous injection and their preparation |
| US5536729A (en) * | 1993-09-30 | 1996-07-16 | American Home Products Corporation | Rapamycin formulations for oral administration |
| IL115742A (en) * | 1994-10-26 | 2000-06-01 | Novartis Ag | Pharmaceutical compositions comprising a difficultly soluble active agent a hydrophilic phase a lipophilic phase and a surfactant |
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2006
- 2006-08-17 CN CNA2006101096882A patent/CN1919194A/en active Pending
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2007
- 2007-08-16 WO PCT/CN2007/002470 patent/WO2008022557A1/en active Application Filing
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102499919A (en) * | 2011-10-13 | 2012-06-20 | 嘉兴富特吉生物科技有限公司 | Medicine combination containing low sirolimus dose for treating or preventing fibrotic diseases |
| CN106236732A (en) * | 2016-08-31 | 2016-12-21 | 佛山市弘泰药物研发有限公司 | A kind of preparation method of everolimus soft capsule |
| CN108434146A (en) * | 2017-02-16 | 2018-08-24 | 天津国际生物医药联合研究院 | A kind of solution and its preparation method and application of HIV-1 integrase inhibitors |
| WO2020184131A1 (en) * | 2019-03-08 | 2020-09-17 | 国立大学法人大阪大学 | Systemically-acting external preparation containing sirolimus or derivative thereof |
| CN115887407A (en) * | 2022-12-29 | 2023-04-04 | 深圳市泰力生物医药有限公司 | Sirolimus soft capsule and preparation method thereof |
| CN115887407B (en) * | 2022-12-29 | 2023-08-18 | 深圳市泰力生物医药有限公司 | Sirolimus soft capsule and preparation method thereof |
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| Publication number | Publication date |
|---|---|
| WO2008022557A1 (en) | 2008-02-28 |
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