CN109431997B - Local rapamycin injection and preparation method thereof - Google Patents
Local rapamycin injection and preparation method thereof Download PDFInfo
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- CN109431997B CN109431997B CN201811563216.3A CN201811563216A CN109431997B CN 109431997 B CN109431997 B CN 109431997B CN 201811563216 A CN201811563216 A CN 201811563216A CN 109431997 B CN109431997 B CN 109431997B
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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
- A61K47/06—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
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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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
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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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
- A61K9/10—Dispersions; Emulsions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
Abstract
The invention discloses a local rapamycin injection and a preparation method thereof, which are used for treating vascular malformation with serious pathological changes and deep subcutaneous tissues, have the effects of long-acting and slow release, and have good compatibility in vivo and easy metabolism. The rapamycin local injection preparation comprises 0.02-0.05g of rapamycin, 1-3g of organic solvent, 6-10g of phospholipid, 8-12g of glyceride and 0.6-1.2g of stabilizer; dissolving rapamycin in an organic solvent, adding phospholipid, glyceride and a stabilizer, and uniformly mixing to obtain the local rapamycin injection.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a local rapamycin injection and a preparation method thereof.
Background
Vascular malformations (vascular tumors) are also called as ductal tumors, and are called as hemangiomas and lymphangiomas depending on the location and subtype of the disease. Vascular malformations are not true tumors arising from abnormal proliferation of blood or lymphatic vessels.
At present, common methods for treating vascular malformation comprise oral and external drug treatment, surgical excision, laser treatment, sclerosing agent injection and the like, and no method can treat all types of vascular malformations; it is determined by the type, location, depth of the lesion and the age of the patient. The operation treatment is generally suitable for patients with larger lesion parts and non-exposed positions and good effect on independent lesions. However, because the diseased region has abundant blood vessels and large blood volume, the risk is high during the operation, and local deformity and even dysfunction can be caused sometimes after the diseased tissue is removed. The laser treatment has obvious treatment effect on superficial vascular malformation and small side effect, but cannot treat deep vascular malformation. The sclerosing agent is injected to enable vascular tissues to be fibrotic and locked to generate scar contraction and reduce tumor bodies, but after the sclerosing agent is injected, the vascular tissues at pathological change positions are fibrotic, so that local functions of an organism can be influenced and even lost, and the sclerosing agent is not suitable for treating key parts and large-volume vascular malformations.
The treatment of vascular malformation with drugs is an important means. Propranolol, timolol, pingyangmycin and the like are commonly used for treating infantile hemangioma, such as patents CN107281094A and CN102836418A, and local injection sclerosing agent, oral rapamycin and the like are commonly used for treating adult vascular malformation. The medicine can be prepared into different dosage forms, and a more proper dosage form can be selected according to different pathological conditions. Such as malformation of blood vessels on the surface layer of skin, and can be made into cream or patch for external use; for small vascular malformations in vivo, oral preparations can be adopted; for the malformation of blood vessels with serious pathological changes and deep subcutaneous tissues, the external preparation can hardly achieve the treatment effect, the oral administration can hardly achieve the treatment effect because the concentration of local medicines is not high, and the local injection is usually needed to control the disease condition. The local injection is a clinical commonly used treatment method and has the advantages of high local drug concentration, good curative effect, convenient administration and the like. However, after the local injection of the common injection, the medicine in the lesion site is carried away due to the blood circulation, which reduces the medicine concentration in the lesion site, and the treatment effect is also affected because the medicine cannot be continuously released in the lesion site. Therefore, the long-acting preparation of local rapamycin injection is expected to bring better treatment effect. The existing long-acting preparation for local injection usually adopts the technologies of microspheres, temperature-sensitive gel and the like. The technical problems of the long-acting local injection preparation are as follows: firstly, the selection of a drug carrier needs to have good compatibility and degradability with a human body, so that serious side effects such as anaphylactic reaction and the like generated after the drug carrier is injected into the human body are avoided; secondly, the local injection preparation needs to have good slow release effect, otherwise, the medicine enters the blood circulation of the whole body too fast, causes over high blood concentration, causes adverse reactions such as fever, hypotension, bradycardia and the like, and is not beneficial to exerting the medicine effect on the lesion part for a long time.
Lyotropic liquid crystals, which are liquid crystals formed by two or more compounds including solvent compounds, exhibit a liquid crystal phase in an aqueous solution at a concentration within a certain range, are widely regarded as drug carriers, particularly as long-acting injection carriers. The components of phospholipid and glyceride in the lyotropic liquid crystal are materials with good human body compatibility, are easy to metabolize in a human body, and can quickly form liquid crystal after being injected into the human body, so that the sustained-release effect is achieved. For example, CN106924172A discloses a huperzine A lyotropic liquid crystal preparation which has good medium and long-acting slow release performance.
At present, in the field of vascular malformation treatment, a local sustained-release long-acting injection preparation for treating vascular malformation with serious pathological changes and deep subcutaneous parts is urgently needed.
Disclosure of Invention
The invention aims to solve the problems in the prior art, and provides a local rapamycin injection which is used for treating vascular malformation with serious pathological changes and deep subcutaneous tissues, has the effects of long-acting and slow release, and is good in compatibility in vivo and easy to metabolize.
In order to achieve the purpose, the invention adopts the technical scheme that:
a local rapamycin injection comprises rapamycin 0.02-0.05g, organic solvent 1-3g, phospholipid 6-10g, glyceride 8-12g and stabilizer 0.6-1.2 g.
Preferably, the rapamycin local injection preparation comprises 0.02-0.05g of rapamycin, 1-2g of organic solvent, 7-9g of phospholipid, 8-10g of glyceride and 0.8-1g of stabilizer.
Further, the phospholipid comprises one or two of soybean lecithin and egg yolk lecithin, and the egg yolk lecithin is preferred.
Further, the glyceride comprises one or more of glyceryl dioleate, glyceryl trioleate and glyceryl stearate, and is preferably glyceryl dioleate.
Further, the organic solvent is ethanol.
Further, the stabilizer is poloxamer 407 or low molecular polyethylene glycol.
The invention also provides a preparation method of the local rapamycin injection preparation, which comprises the following steps: dissolving rapamycin in an organic solvent, adding phospholipid, glyceride and a stabilizer, uniformly mixing to obtain a flowing liquid, and finally filtering and sterilizing to obtain the local rapamycin injection preparation.
Compared with the prior art, the invention has the beneficial effects that:
(1) the rapamycin local injection preparation is not available in the prior art, and the rapamycin is prepared into a local sustained-release injection preparation, so that the targeting of rapamycin for treating vascular malformation is improved, and the rapamycin local injection preparation is particularly suitable for treating vascular malformation with deep lesion.
(2) The phospholipid and the glyceride are selected as lyotropic liquid crystal materials, have good compatibility with human bodies and are easy to metabolize.
(3) The rapamycin local injection preparation has low viscosity and is convenient to inject; after being injected to a diseased site, the liquid crystal is converted into liquid crystal when meeting water, so that a good slow release effect is achieved, and the slow release time can exceed 20 days.
(4) The stabilizer is added into the preparation, which is beneficial to improving the stability of solute liquid crystal and prolonging the slow release time.
Drawings
FIG. 1 is a graph of the cumulative in vitro sustained release rate of a local rapamycin injectable formulation.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the accompanying drawings, and it is obvious that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The technical solution of the present invention will be further described in detail with reference to the following specific examples.
Example 1
Preparation of rapamycin local injection preparation
(1) A rapamycin topical injection comprises rapamycin 0.02g, ethanol 2g, soybean lecithin 7g, glycerol dioleate 10g, and poloxamer 407 0.6 g. The preparation method comprises the following steps: dissolving rapamycin 0.02g in ethanol 2g, stirring to dissolve completely, adding soybean lecithin 7g, glycerol dioleate 10g and poloxamer 407 0.6g, stirring for 1 hr to obtain fluid liquid, and processing60Co-irradiated gamma-ray radiation sterilization is carried out, and the rapamycin local injection preparation A1 is obtained.
(2) A rapamycin local injection comprises rapamycin 0.03g, ethanol 2g, egg yolk lecithin 8g, glycerol dioleate 8g, and polyethylene glycol 200 1 g. The preparation method comprises the following steps: dissolving rapamycin 0.03g in ethanol 2g, stirring, adding egg yolk lecithin 8g, glycerol dioleate 8g and polyethylene glycol 200 1g, stirring for 0.5 hr to obtain fluid, and processing60Co-irradiated gamma-ray radiation sterilization is carried out, and the rapamycin local injection preparation A2 is obtained.
(3) A rapamycin topical injection comprises rapamycin 0.04g, ethanol 3g, egg yolk lecithin 7g, triolein 8g, and poloxamer 407 1.2 g. The preparation method comprises the following steps: dissolving rapamycin 0.04g in ethanol 3g, stirring to dissolve completely, adding egg yolk lecithin 7g, triolein 8g and poloxamer 407 1.2g, stirring for 2 hr to obtain fluid liquid, and processing60Co-irradiated gamma-ray radiation sterilization is carried out, and the rapamycin local injection preparation A3 is obtained.
(4) A rapamycin topical injection comprises rapamycin 0.05g, ethanol 1g, egg yolk lecithin 6g, glyceryl stearate 12g, and polyethylene glycol 400 0.8 g. The preparation method comprises the following steps: dissolving rapamycin 0.05g in ethanol 5g, stirring, adding egg yolk lecithin 30g, glyceryl stearate 60g and polyethylene glycol 400 4g, stirring for 2 hr to obtain fluid, and processing60Co-irradiated gamma-ray radiation sterilization is carried out, and the rapamycin local injection preparation A4 is obtained.
(5) A local rapamycin injection comprises rapamycin 0.02g and rapamycin 2gAlcohol, 7g of soybean lecithin and 10g of glycerol dioleate. The preparation method comprises the following steps: dissolving rapamycin 0.02g in ethanol 2g, stirring to dissolve completely, adding soybean lecithin 7g and glycerol dioleate 10g, stirring for 1 hr to obtain fluid, and processing60And (3) performing gamma ray radiation sterilization by Co irradiation to obtain a rapamycin local injection preparation B1.
(6) A local rapamycin injection comprises 0.02g of rapamycin, 2g of ethanol, 4g of soybean lecithin, 13g of glycerol dioleate and 0.6g of poloxamer 407. The preparation method comprises the following steps: dissolving rapamycin 0.02g in ethanol 2g, stirring, adding egg yolk lecithin 4g and glycerol dioleate 13g, stirring for 0.5 hr to obtain fluid, and processing60And (3) performing gamma ray radiation sterilization by Co irradiation to obtain a rapamycin local injection preparation B2.
(7) A rapamycin topical injection comprises rapamycin 0.03g, ethanol 3g, egg yolk lecithin 11g, triolein 4g, and poloxamer 407 1.2 g. The preparation method comprises the following steps: dissolving rapamycin 0.03g in ethanol 3g, stirring to dissolve completely, adding egg yolk lecithin 11g, triolein 4g and poloxamer 407 1.2g, stirring for 2 hr to obtain fluid liquid, and processing60And (3) performing gamma ray radiation sterilization by Co irradiation to obtain a rapamycin local injection preparation B3.
Example 2
Anti-dilution property and needle penetration test of rapamycin local injection preparation
0.5ml of the rapamycin local injection preparation A1-A4 and B1-B3 prepared in example 1 are respectively put into a 5ml centrifuge tube, 4ml of water is added, and whether the diffusion phenomenon exists or not is observed, so that the diffusion phenomenon does not exist, and the preparation has good anti-scatter performance. The diffusions are denoted as "-", and the non-diffusions are denoted as "+". Then rapamycin local injection preparations A1-A4 and B1-B3 are respectively taken, a 1ml sterile syringe and a No. 5 needle head are adopted to carry out needle penetration experiments, and the preparation can be injected smoothly to show that the needle penetration is good. A smooth pass is recorded as "+", and a smooth pass is not recorded as "-". The test results are shown in table 1.
Table 1: anti-dilution property and needle penetration test
| Sample number | Resistance to scattering | Needle penetration property |
| A1 | + | + |
| A2 | + | + |
| A3 | + | + |
| A4 | + | + |
| B1 | - | + |
| B2 | - | + |
| B3 | - | - |
The rapamycin local injection preparation has good anti-sparseness and needle penetration, poor anti-sparseness can be caused when no stabilizer is added or the dosage of phospholipid is low, and the dosage of phospholipid is high, so that the anti-sparseness and the needle penetration can not meet the requirements of the preparation.
Example 3
In vitro sustained release experiment of rapamycin local injection preparation
In vitro release characteristics were experimentally examined by a dialysis bag method using rapamycin local injection preparations A1-A4 and B1-B3 prepared in example 1. The release medium was PBS buffer containing 5% tween 20, ph 7.4. The specific experimental steps are as follows: 5g of rapamycin local injection preparation is respectively added with water with the same amount, and the mixture is kept stand for 0.5h to form liquid crystal. Then, the mixture was added to a dialysis bag, both ends were clipped, the dialysis bag was placed in 300mL of PBS buffer containing 5% tween 20, ph7.4, and the temperature of the water bath was maintained at 37 ℃ and the rotation speed was 30r/min, the whole system was sealed to prevent evaporation, and 1mL was sampled at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, and 24 days, and 1mL of release medium was added every time. The removed sample was passed through a 0.22 μm microfiltration membrane and the rapamycin concentration was determined by HPLC. The cumulative release rate Q at each time point was calculated as shown in fig. 1.
As can be seen from FIG. 1, examples A1-A4 had excellent sustained release technical effects, and sustained release was terminated only after 20 days, thus demonstrating that the local injectable formulation made of rapamycin had a technical effect of sustained release over a long period. Comparative examples B1-B3, however, showed poor sustained release. Wherein B1 does not use stabilizer, but has a certain slow release effect due to better proportioning of phospholipid and glyceride, the slow release effect can be finished in about 10 days, but the slow release effect is inferior to that of the embodiment due to the lack of the stabilizer. The proportions of B2 and B3 phospholipid and glyceride fell outside the range of the ratio of the amount used in the present invention, and the sustained-release effect was inferior in spite of the addition of the stabilizer, and inferior to comparative example B1. It is thus demonstrated that the ratio of phospholipids to glycerides plays a decisive role in the sustained release effect, with a greater effect than that of the stabilizer. As can be seen from the final cumulative release rates, the cumulative release rates for all samples were close to 100%, indicating that the local rapamycin injectable formulations prepared using the formulations of the present invention were eventually able to be completely released.
Example 4
Stability test of rapamycin local injection preparation
Temperature influence: taking a proper amount of rapamycin local injection preparation A1 in the same batch, respectively filling the rapamycin local injection preparation in sealed clean brown penicillin bottles, respectively sampling on the 0 th day, the 5 th day and the 10 th day at the temperature of 4 ℃, 25 ℃, 37 ℃ and 60 ℃, comparing the change of the appearance shape and the drug content with the initial sample, measuring the content by adopting an HPLC method, and inspecting the temperature of the rapamycin local injection preparation, wherein the experimental result is shown in Table 2. The results show that a temperature higher than 25 ℃ has an influence on the stability of the rapamycin local injection preparation, and thus the rapamycin local injection preparation needs to be preserved in the shade.
Table 2: influence of Windomae on local injectable formulations of rapamycin
| Temperature (. degree.C.) | Time (sky) | Appearance character | Content (%) |
| 4 | 0 | Pale yellow oily liquid | 100.13 |
| 4 | 5 | Pale yellow oily liquid | 100.13 |
| 4 | 10 | Pale yellow oily liquid | 100.12 |
| 25 | 0 | Pale yellow oily liquid | 100.13 |
| 25 | 5 | Pale yellow oily liquid | 99.87 |
| 25 | 10 | Pale yellow oily liquid | 99.86 |
| 37 | 0 | Pale yellow oily liquid | 100.13 |
| 37 | 5 | Pale yellow oily liquid | 99.59 |
| 37 | 10 | Yellow deepening liquid | 99.42 |
| 60 | 0 | Pale yellow oily liquid | 100.13 |
| 60 | 5 | Deepening the yellow color and depositing | 87.42 |
| 60 | 10 | Deep yellow and coagulated | 76.21 |
Long-term stability: taking a proper amount of rapamycin local injection preparation A1-A4, respectively filling the rapamycin local injection preparation in a sealed clean brown penicillin bottle, respectively sampling at the temperature of 4 ℃, respectively on the 0 th day, the 5 th day and the 10 th day, comparing the change of the appearance shape and the drug content with the initial sample, measuring the content by using an HPLC method, and observing the temperature on the rapamycin local injection preparation, wherein the experimental results are shown in Table 3. The results show that the local rapamycin injection preparation has stable performance under the condition of sealed storage at 4 ℃.
Table 3: long term stability test results
| Temperature (. degree.C.) | Time (moon) | Appearance character | Content (%) |
| |
0 | Pale yellow oily liquid | 100.13 |
| A1 | 1 | Pale yellow oily liquid | 100.10 |
| |
2 | Pale yellow oily liquid | 100.02 |
| |
0 | Pale yellow oily liquid | 100.25 |
| A2 | 1 | Pale yellow oily liquid | 100.24 |
| |
2 | Pale yellow oily liquid | 100.24 |
| |
0 | Pale yellow oily liquid | 99.36 |
| A3 | 1 | Pale yellow oily liquid | 99.35 |
| |
2 | Pale yellow oily liquid | 99.30 |
| |
0 | Pale yellow oily liquid | 100.14 |
| A4 | 1 | Pale yellow oily liquid | 100.11 |
| |
2 | Pale yellow oily liquid | 100.09 |
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (4)
1. A local rapamycin injection for treating vascular malformation is characterized by comprising the following raw materials: 0.02-0.05g of rapamycin, 1-3g of an organic solvent, 6-10g of a phospholipid, 8-12g of a glyceride and 0.6-1.2g of a stabilizer; the phospholipid is one or two of soybean lecithin or egg yolk lecithin, and the organic solvent is ethanol;
the glyceride comprises one or more selected from diglycerol oleate, glyceryl trioleate or glyceryl stearate;
the stabilizer is poloxamer 407 or polyethylene glycol;
the preparation method of the local rapamycin injection preparation for treating vascular malformation comprises the steps of dissolving rapamycin in an organic solvent, adding phospholipid, glyceride and a stabilizer, uniformly mixing, and finally filtering and sterilizing to obtain the local rapamycin injection preparation.
2. The local rapamycin injection preparation for treating vascular malformation according to claim 1, which comprises the following raw materials: 0.02-0.05g of rapamycin, 1-2g of organic solvent, 7-9g of phospholipid, 8-10g of glyceride and 0.8-1g of stabilizing agent.
3. A topical injectable formulation of rapamycin for the treatment of vascular malformations according to claim 1, characterized in that said phospholipid is egg yolk lecithin.
4. A topical injectable formulation of rapamycin for the treatment of vascular malformations according to claim 1, characterized in that the glyceride is glycerol dioleate.
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| IL111008A (en) * | 1993-09-30 | 1999-10-28 | American Home Prod | Rapamycin formulations for intravenous injection and their preparation |
| US5516770A (en) * | 1993-09-30 | 1996-05-14 | American Home Products Corporation | Rapamycin formulation for IV injection |
| US20030054042A1 (en) * | 2001-09-14 | 2003-03-20 | Elaine Liversidge | Stabilization of chemical compounds using nanoparticulate formulations |
| CN1872058B (en) * | 2005-05-31 | 2011-03-30 | 华北制药集团新药研究开发有限责任公司 | Medication composition of containing macrolides |
| CN1883474A (en) * | 2005-06-22 | 2006-12-27 | 华北制药集团新药研究开发有限责任公司 | A composition containing macrolide compound and porous water insoluble hydrophilic carrier |
| CN101032463A (en) * | 2007-04-19 | 2007-09-12 | 山东华诺生物科技有限公司 | Sirolimus injection and preparing technique thereof |
| CN101366715A (en) * | 2007-08-15 | 2009-02-18 | 上海医药工业研究院 | Rapamycin composition and preparation thereof |
| CN101827523A (en) * | 2007-08-16 | 2010-09-08 | 马库赛特公司 | Formulations for treatment of ocular diseases or conditions |
| CN101926757B (en) * | 2010-09-01 | 2013-01-02 | 北京大学 | Liquid composition of indissolvable medicines and preparation method thereof |
| CN102008437B (en) * | 2010-11-23 | 2012-11-14 | 赵晨 | Rapamycin microemulsion injection for eyes and preparation method and application thereof |
| TW201503912A (en) * | 2013-03-19 | 2015-02-01 | Novartis Ag | Pharmaceutical compositions comprising everolimus |
| CN105193732A (en) * | 2014-06-05 | 2015-12-30 | 华东理工大学 | Sirolimus sustained-release nano-microspheres and preparation method thereof |
| CN104666298A (en) * | 2015-02-06 | 2015-06-03 | 义乌市中医医院 | Compound rapamycin suppository and preparation method thereof |
| EP3496712A1 (en) * | 2016-08-10 | 2019-06-19 | The Board of Regents of The University of Texas System | Topical rapamycin therapy |
| CN108771656A (en) * | 2018-07-10 | 2018-11-09 | 白晓春 | Rapamycin sustained-release dosage type and preparation method, rapamycin it is slow-release injected and application |
| CN108815160A (en) * | 2018-07-18 | 2018-11-16 | 严鹏科 | A kind of rapamycin liposome nano granule and preparation method thereof |
| CN109498547B (en) * | 2018-12-20 | 2022-04-12 | 武汉科福新药有限责任公司 | Pingyangmycin local injection preparation and preparation method thereof |
| CN109431977A (en) * | 2018-12-20 | 2019-03-08 | 武汉科福新药有限责任公司 | A kind of rapamycin ointment and preparation method thereof for treating vascular malformation |
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