CN114306234A - TPGS micelle oral liquid containing gabapentin compound and preparation method thereof - Google Patents
TPGS micelle oral liquid containing gabapentin compound and preparation method thereof Download PDFInfo
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- CN114306234A CN114306234A CN202111570945.3A CN202111570945A CN114306234A CN 114306234 A CN114306234 A CN 114306234A CN 202111570945 A CN202111570945 A CN 202111570945A CN 114306234 A CN114306234 A CN 114306234A
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Abstract
The invention relates to TPGS micelle oral liquid containing a gabapentin compound, wherein the gabapentin compound is prepared from gabapentin and fatty acid or gabapentin, fatty acid salt and hydrochloric acid. The prepared TPGS micelle oral liquid containing the gabapentin compound can effectively reduce the generation of lactam of a condensation compound in gabapentin molecules, improve the stability of the medicine, cover the bitter taste of gabapentin and improve the compliance of patients.
Description
Technical Field
The invention relates to a composition containing gabapentin and a preparation method thereof, in particular to TPGS micelle oral liquid containing a gabapentin compound and a preparation method thereof, belonging to the field of pharmaceutical preparations.
Background
Gabapentin, an agonist of gamma-aminobutyric acid (GABA) receptors, was first successfully developed and marketed by the company picrorhizae, and is used clinically mainly for the treatment of peripheral neuralgia and adjuvant treatment of focal partial seizures, and also for the treatment of pain (such as postherpetic neuralgia) and anxiety. The molecular structural formula of gabapentin is shown below:
gabapentin is currently marketed in several countries and regions, where dosage forms are mainly tablets and oral solutions. Gabapentin is readily soluble in water, but the preparation of oral gabapentin formulations presents the following difficulties: (1) gabapentin is very bitter in taste; (2) the gabapentin has primary amino and carboxyl in molecules, so that the intramolecular condensation is easy to generate lactam, and the damp-heat action can accelerate the intramolecular cyclization of the gabapentin to generate lactam impurities. The molecular structural formula of lactam is shown as follows:
during the preparation and storage of gabapentin, the lactam formed by degradation is toxic and requires strict quality control. The gabapentin oral liquid sold in the market of the pfizer company needs to be refrigerated for storage (2-8 ℃), and is inconvenient to store, transport and carry. The oral liquid is mostly taken by old people and children who have difficulty in swallowing and inconvenience in taking, and the preparation on the market is heavy and lasting in bitter taste, so that the compliance of patients is greatly reduced. Based on the above, the development of the gabapentin oral liquid which is stable, convenient to store, transport and carry and good in taste is of great significance.
Patent CN1303991C provides a method for preparing a stable pharmaceutical formulation of 4-amino-3-substituted butyric acid derivatives, by incorporating an amino acid as a stabilizer, to obtain a stable solid or liquid pharmaceutical formulation of 4-amino-3-substituted butyric acid derivatives including gabapentin. The results of the stability experiments for the disclosed gabapentin formulation after addition of the amino acid show that: the lactam impurity has increased to 0.3 percent in 12 months at normal temperature, which indicates that the effective period is still short.
The polymer micelles (polymeric micelles) are generally composed of a large number of amphiphilic block copolymer molecular chains in an oriented arrangement mode, the hydrophobic chain segments wrap the drugs in cores through weak interaction with drug molecules, and hydrophilic chains outwards stabilize the micelles, so that a typical core-shell structure is presented, and the size of the micelle is in the range of tens to hundreds of nanometers. The polymer micelle oral administration system is used for improving the solubility of insoluble drugs, is beneficial to reducing the irritation of the drugs to gastrointestinal tracts, increasing the drug concentration of absorption parts, improving the stability of the drugs in the gastrointestinal tracts and improving the bioavailability.
Polyethylene glycol 1000 vitamin E succinate (TPGS) is a water-soluble derivative of natural vitamin E, is obtained by esterification reaction of hydrophilic polyethylene glycol and lipophilic vitamin E succinate, has physiological activities of polyethylene glycol and vitamin E, is a self-colored or light yellow waxy solid at normal temperature, has a melting point of 37-41 ℃, and can stably exist in the air. TPGS was first developed and marketed by Eastman corporation of America in 1950, has surfactant properties due to its lipophilic group of tocopherol and hydrophilic group of long chain of polyethylene glycol, and can be used as solubilizer, absorption enhancer, emulsifier, plasticizer, and carrier of liposoluble drug delivery system, such as liposome, micelle, etc. Studies show that TPGS as a high-efficiency emulsifier prepared nanoparticles has high encapsulation efficiency and strong cell uptake capacity on medicaments. TPGS also has the effects of increasing the stability of the medicine, promoting the penetration and absorption of the medicine, and the like. In addition, TPGS, as a water-soluble vitamin E, has a different absorption mechanism in the intestinal tract from that of fat-soluble vitamin E, and can be used as a nutritional supplement for people with malabsorption of fat-soluble vitamin E.
Disclosure of Invention
Through a great deal of research, the water-soluble gabapentin and fatty acid form an oil-soluble gabapentin fatty acid compound, and the compound and TPGS are prepared into a micellar solution to produce the following unexpected effects:
firstly, gabapentin fatty acid complex significantly improves the stability of gabapentin oral liquid. The gabapentin amino and the fatty acid carboxylic acid group are combined through static electricity, so that the condition that primary amino and carboxyl exist in gabapentin molecules and intramolecular condensation is carried out to generate lactam is reduced. The concrete points are as follows: (1) can obviously reduce the generation of lactam impurities and improve the safety of the medicine; (2) the storage can be carried out at normal temperature, so that the storage and transportation cost is obviously reduced; (3) the storage and carrying of the patient are convenient; (4) the effective period can be obviously prolonged.
Secondly, the gabapentin fatty acid compound can be prepared into micelles together with polyethylene glycol 1000 vitamin E succinate (TPGS), and then the micelles are mixed with a flavoring agent and a bacteriostatic agent to prepare the oral liquid. The polymer micelle can prevent the direct contact of the medicine and the oral cavity, cover the bitter taste of gabapentin, improve the taste of the oral liquid and improve the compliance of patients.
The specific technical scheme is as follows:
the invention provides a polyethylene glycol 1000 vitamin E succinate micelle oral liquid containing a gabapentin compound, which is characterized in that: the oral liquid consists of gabapentin fatty acid compound and polyethylene glycol 1000 vitamin E succinate, wherein the weight ratio of the gabapentin fatty acid compound to the polyethylene glycol 1000 vitamin E succinate is 1: 1-1: 5, preferably 1: 2-1: 3.
The gabapentin fatty acid compound provided by the invention is characterized in that: the preparation method comprises the steps of taking gabapentin and fatty acid as raw materials, dissolving the fatty acid and the gabapentin in a solvent to form a solution, standing to form a compound, and removing the solvent to obtain the gabapentin compound.
The invention provides a preparation method of the gabapentin fatty acid compound, which is characterized by comprising the following steps: the molar ratio of gabapentin to fatty acid is 1: 1-1: 5; wherein the fatty acid includes one or more of caprylic acid, capric acid, oleic acid, lauric acid, palmitic acid, linoleic acid, stearic acid, myristic acid, arachidic acid and behenic acid; wherein the organic solvent includes but is not limited to one or a mixture of more than two of ethanol, methanol, acetonitrile and acetone; the standing temperature is 10-40 ℃, and preferably 20-25 ℃; the standing time is 1-7 days, preferably 2-3 days.
The invention provides a preparation method of the gabapentin fatty acid compound, which is characterized by comprising the following steps: the method comprises the following steps of taking gabapentin, sodium fatty acid and hydrochloric acid as raw materials, adding an aqueous solution of the sodium fatty acid into the aqueous solution of the gabapentin under stirring, adjusting the pH value of the solution to 2-6 with the hydrochloric acid, stirring to separate out a precipitate, standing, and filtering to obtain the gabapentin aqueous solution; wherein the molar ratio of gabapentin to sodium fatty acid is 1: 1-1: 5.
The invention also provides a preparation method of the polyethylene glycol 1000 vitamin E succinate micelle of the gabapentin fatty acid compound, which is characterized by comprising the following steps: the preparation method of the polyethylene glycol 1000 vitamin E succinate micelle comprises but is not limited to one of a solvent injection method, a film hydration method, a one-step preparation method and a dialysis method.
The invention also provides a method for preparing polyethylene glycol 1000 vitamin E succinate micelle of gabapentin fatty acid compound by the solvent injection method, which is characterized by comprising the following steps: uniformly mixing the gabapentin fatty acid compound and the polyethylene glycol 1000 vitamin E succinate in an organic solvent to form an organic phase, then adding the organic phase into an aqueous solution to obtain a mixed solution, and removing or not removing the organic solvent to obtain the drug micelle solution.
The invention also provides a method for preparing polyethylene glycol 1000 vitamin E succinate micelle of gabapentin fatty acid compound by the thin film hydration method, which is characterized by comprising the following steps: uniformly mixing gabapentin fatty acid compound and polyethylene glycol 1000 vitamin E succinate in an organic solvent, removing the organic solvent to obtain a drug-loaded membrane, adding an aqueous solution to hydrate the drug-loaded membrane, and completely and uniformly hydrating to obtain a drug micelle solution.
The invention also provides a method for preparing polyethylene glycol 1000 vitamin E succinate micelles of gabapentin fatty acid compound by the one-step method, which is characterized by comprising the following steps: the gabapentin fatty acid compound and the polyethylene glycol 1000 vitamin E succinate are melted and then added into water for dissolution, so as to obtain the drug micelle solution.
The invention also provides a method for preparing polyethylene glycol 1000 vitamin E succinate micelles of gabapentin fatty acid compound by the dialysis method, which is characterized by comprising the following steps: the gabapentin fatty acid compound and the polyethylene glycol 1000 vitamin E succinate are dissolved and mixed uniformly in an organic solvent, and the organic solvent is removed by a dialysis device to obtain a drug micelle solution.
In the above method for preparing polyethylene glycol 1000 vitamin E succinate micelle of gabapentin fatty acid compound of the present invention, the organic solvent used includes but is not limited to one or a mixture of two or more of ethanol, methanol, acetonitrile, acetone, dimethyl sulfoxide, glycerol, and 1, 2-propylene glycol.
The invention also provides a preparation method of the polyethylene glycol 1000 vitamin E succinate micelle oral liquid of the gabapentin fatty acid compound, which is characterized by comprising the following steps: mixing the prepared polyethylene glycol 1000 vitamin E succinate micelle solution of the gabapentin compound with the aqueous solution in which the sweetening agent, the preservative and the essence are dissolved uniformly, fixing the volume, filtering and filling to obtain the gabapentin compound. The sweetener includes but is not limited to one or a mixture of more than two of sorbitol, xylitol, aspartame, saccharin sodium, sucralose, maltitol and erythritol; the preservative used in the method comprises one or a mixture of more than two of benzoic acid and salts thereof, sorbic acid and salts thereof and parabens.
The polyethylene glycol 1000 vitamin E succinate micelle oral liquid containing the gabapentin fatty acid compound, which is prepared by the invention, is stored for 24 months at 25 ℃, and the content of lactam impurities is 0.15 percent, which is obviously superior to the stability of the oral liquid of the gabapentin and amino acid composition provided by the existing preparation oral liquid (stored for 24 months at 5 ℃ and the content of lactam impurities is about 0.23 percent) and the comparison patent CN1303991C (stored for 12 months at 25 ℃ and the content of lactam impurities is about 0.3 percent). The polymer micelle oral liquid containing the gabapentin compound prepared by the invention is tasted by volunteers and basically has no bitter taste.
In conclusion, the polyethylene glycol 1000 vitamin E succinate micelle oral liquid containing the gabapentin fatty acid compound and the preparation method thereof provided by the invention utilize the combination of amino groups in gabapentin molecules and carboxyl groups in fatty acid molecules to form the compound, thereby reducing the generation of lactam of an intramolecular condensation compound of gabapentin and improving the stability of the medicine. The polyethylene glycol 1000 vitamin E succinate micelle has a wrapping effect on the medicine, so that the bitter taste can be covered, and the compliance of a patient is improved.
Detailed Description
The following exemplary embodiments are provided to illustrate the present invention, and simple replacement or improvement of the present invention by those skilled in the art is within the technical scheme of the present invention.
Example 1: gabapentin-lauric acid compound micelle oral liquid
Step 1 preparation of a compound: 20.0g (0.1mol) of lauric acid and 5g (0.03mol) of gabapentin are fully dissolved in 50ml of dimethyl sulfoxide, and the mixture is kept still for 3 days at room temperature, thus obtaining the gabapentin lauric acid compound solution.
Step 2, preparation of compound micelle: adding 50.0g of polyethylene glycol 1000 vitamin E succinate into the gabapentin lauric acid compound solution obtained in the step 1 for dissolution, and removing dimethyl sulfoxide by using a dialysis device to obtain a drug micelle solution.
Step 3, preparing the compound micelle oral liquid: weighing 25g of xylitol, 0.05g of orange essence and 0.1g of potassium sorbate, adding the mixture into 150ml of purified water to dissolve the mixture into a solution, slowly and uniformly mixing the solution with the medicinal micelle solution prepared in the step (2) under a stirring state, fixing the volume to 200ml, filtering and filling the mixture to obtain the polyethylene glycol 1000 vitamin E succinate micelle oral liquid containing the gabapentin compound.
Example 2: gabapentin octanoic acid compound micelle oral liquid
Step 1 preparation of a compound: 4.5g (0.03mol) of octanoic acid and 5g (0.03mol) of gabapentin were dissolved in 100ml of acetone, and the mixture was allowed to stand at about 40 ℃ for 1 day to obtain a gabapentin octanoic acid complex solution.
Step 2, preparation of compound micelle: adding 50.0g of polyethylene glycol 1000 vitamin E succinate into the gabapentin octanoic acid compound solution obtained in the step 1 for dissolving, performing reduced pressure rotary evaporation on the solution in a solanaceous bottle to remove acetone to obtain a uniform film, adding 100ml of purified water, and performing rotary hydration in a water bath kettle at 37 ℃ to obtain a medicinal micelle solution.
Step 3, preparing the compound micelle oral liquid: weighing 20g of sorbitol, 0.01g of banana essence and 0.1g of methyl paraben, adding into 50ml of purified water to be dissolved to prepare a solution, slowly adding into the medicinal micelle solution prepared in the step 2 under the stirring state, uniformly mixing, fixing the volume to 200ml, filtering, and filling to obtain the micelle oral liquid of the gabapentin compound.
Example 3: gabapentin-oleic acid compound micelle oral liquid
Step 1 preparation of a compound: adding 45.7g (0.15mol) of sodium oleate and 5g (0.03mol) of gabapentin into 100ml of water for full dissolution, adjusting the pH of the solution to 3-6 by hydrochloric acid under magnetic stirring at about 20 ℃, stirring for 1 hour, and centrifuging to obtain gabapentin oleic acid compound solid.
Step 2, preparation of compound micelle: heating and melting the gabapentin oleic acid compound obtained in the step 1 and 50.0g of polyethylene glycol 1000 vitamin E succinate, adding 100ml of water, and performing ultrasonic hydration dissolution at 37 ℃ to obtain a mixture micelle solution.
Step 3, preparing the compound micelle oral liquid: weighing 10g of erythritol, 0.01g of strawberry essence and 0.1g of sodium benzoate, adding into 50ml of purified water, dissolving to prepare a solution, slowly adding into the mixture micelle solution obtained in the step 2 under a stirring state, uniformly mixing, fixing the volume to 200ml, filtering, and filling to obtain the micelle oral liquid of the gabapentin compound.
Example 4:
and placing the obtained sample in stabilizing boxes with different temperatures, and sampling at regular time to carry out stability investigation.
And (4) investigation indexes are as follows: content of lactam impurity in the sample.
The content determination method comprises the following steps: HPLC
Chromatographic conditions are as follows: a chromatographic column: agilent ZORBAX Eclipse C18 (4.6X 150mm,3.5 μm)
Column temperature: 40 deg.C
Flow rate: 0.8mL/min
Wavelength: 210nm
Sample introduction amount: 10 μ L
Mobile phase A: 10mM potassium dihydrogen phosphate buffer (pH6.9)
Mobile phase B: acetonitrile
Gradient program:
| Time | phase A (acetonitrile) | Phase B (ultrapure water) |
| 0 | 90 | 10 |
| 3 | 90 | 10 |
| 10 | 45 | 55 |
| 13 | 45 | 55 |
| 14 | 90 | 10 |
| 20 | 90 | 10 |
The results of the examination are shown in the following table:
stability experiment lactam impurity detection result
Experimental results and conclusions:
compared with the oral liquid in the patent CN1303991C, the lactam impurity is increased to 0.3 percent when the oral liquid is placed at normal temperature for 12 months. The lactam impurity of the oral solution of the preparation on the market is increased to 0.23 percent when the oral solution is placed at the temperature of 2-8 ℃ for 24 months.
The experimental results show that: compared with the common gabapentin oral liquid on the market and the preparation described in the patent CN1303991C, the polymer micelle oral liquid containing the gabapentin compound provided by the invention has the advantages that the content of lactam impurities is obviously reduced, and the stability is improved.
The oral liquid prepared from the polymer micelle prepared in example 2 is tasted by 20 volunteers, and is sweet and palatable, almost has no bitter taste, and is acceptable.
Claims (7)
1. The polyethylene glycol 1000 vitamin E succinate micelle oral liquid containing gabapentin compound is characterized by comprising gabapentin fatty acid compound and polyethylene glycol 1000 vitamin E succinate, wherein the weight ratio of the gabapentin fatty acid compound to the polyethylene glycol 1000 vitamin E succinate is 1: 1-1: 5, preferably 1: 2-1: 3.
2. The polyethylene glycol 1000 vitamin E succinate micelle oral liquid containing gabapentin complex as claimed in claim 1, wherein the gabapentin fatty acid complex is prepared by dissolving gabapentin and fatty acid in a solvent to form a solution, standing to form the complex, and removing the solvent.
3. The polyethylene glycol 1000 vitamin E succinate micelle oral liquid containing gabapentin complex according to claims 1 and 2, wherein the molar ratio of gabapentin to fatty acid is 1:1 to 1: 5; fatty acids include, but are not limited to, one or a mixture of two or more of caprylic acid, capric acid, oleic acid, lauric acid, palmitic acid, linoleic acid, stearic acid, myristic acid, arachidic acid, and behenic acid; the solvent includes but is not limited to one or a mixture of more than two of ethanol, methanol, acetonitrile and acetone; the standing temperature is 10-40 ℃, preferably 20-25 ℃; the standing time is 1-7 days, preferably 2-3 days.
4. The polyethylene glycol 1000 vitamin E succinate micelle oral liquid containing gabapentin complex as claimed in claim 1, wherein the gabapentin fatty acid complex is prepared by using gabapentin, sodium fatty acid and hydrochloric acid as raw materials, adding an aqueous solution of sodium fatty acid into the gabapentin aqueous solution under stirring, adjusting the pH value of the solution to 2-6 with hydrochloric acid, stirring to separate out a precipitate, standing, and filtering.
5. The polyethylene glycol 1000 vitamin E succinate micelle oral liquid containing gabapentin complex according to claims 1 and 4, wherein the molar ratio of gabapentin to sodium fatty acid is 1:1 to 1: 5.
6. The polyethylene glycol 1000 vitamin E succinate micelle oral liquid containing gabapentin complex as claimed in claims 1-5, wherein the preparation method of the polymer micelle comprises but is not limited to one of solvent injection method, thin film hydration method, one-step preparation method and dialysis method.
7. The polyethylene glycol 1000 vitamin E succinate micelle oral liquid containing the gabapentin complex as claimed in claims 1-6, wherein the preparation method of the oral liquid comprises the steps of uniformly mixing the prepared polyethylene glycol 1000 vitamin E succinate micelle solution of the gabapentin complex with an aqueous solution in which a sweetening agent, a preservative and essence are dissolved, fixing the volume, filtering and filling; wherein the sweetener includes but is not limited to one or a mixture of more than two of sorbitol, xylitol, aspartame, saccharin sodium, sucralose, maltitol and erythritol; the preservative includes but is not limited to one or a mixture of more than two of benzoic acid and salts thereof, sorbic acid and salts thereof and parabens.
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| CN202111570945.3A CN114306234A (en) | 2021-12-23 | 2021-12-23 | TPGS micelle oral liquid containing gabapentin compound and preparation method thereof |
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020107208A1 (en) * | 2000-10-24 | 2002-08-08 | Chih-Ming Chen | Gabapentin prodrugs and formulations |
| US20030083382A1 (en) * | 2001-06-11 | 2003-05-01 | Cundy Kenneth C. | Orally administered dosage forms of GABA analog prodrugs having reduced toxicity |
| US20030176398A1 (en) * | 2001-06-11 | 2003-09-18 | Gallop Mark A. | Prodrugs of GABA analogs, compositions and uses thereof |
| US20060141034A1 (en) * | 2004-11-04 | 2006-06-29 | Xenoport, Inc. | GABA analog prodrug sustained release oral dosage forms |
| CN101232868A (en) * | 2005-04-19 | 2008-07-30 | 阿尔扎公司 | Combination of tramadol and substances that comprise gabapentin |
| US20110263701A1 (en) * | 2010-04-21 | 2011-10-27 | Sigal Blau | Gabapentin enacarbil compositions |
| WO2020165633A1 (en) * | 2019-02-11 | 2020-08-20 | Glenmark Pharmaceuticals Limited | A pharmaceutical composition of gabapentin enacarbil or salt thereof |
-
2021
- 2021-12-23 CN CN202111570945.3A patent/CN114306234A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020107208A1 (en) * | 2000-10-24 | 2002-08-08 | Chih-Ming Chen | Gabapentin prodrugs and formulations |
| US20030083382A1 (en) * | 2001-06-11 | 2003-05-01 | Cundy Kenneth C. | Orally administered dosage forms of GABA analog prodrugs having reduced toxicity |
| US20030176398A1 (en) * | 2001-06-11 | 2003-09-18 | Gallop Mark A. | Prodrugs of GABA analogs, compositions and uses thereof |
| US20060141034A1 (en) * | 2004-11-04 | 2006-06-29 | Xenoport, Inc. | GABA analog prodrug sustained release oral dosage forms |
| CN101232868A (en) * | 2005-04-19 | 2008-07-30 | 阿尔扎公司 | Combination of tramadol and substances that comprise gabapentin |
| US20110263701A1 (en) * | 2010-04-21 | 2011-10-27 | Sigal Blau | Gabapentin enacarbil compositions |
| WO2020165633A1 (en) * | 2019-02-11 | 2020-08-20 | Glenmark Pharmaceuticals Limited | A pharmaceutical composition of gabapentin enacarbil or salt thereof |
Non-Patent Citations (1)
| Title |
|---|
| 王鸽 等: "聚乙二醇 1000 维生素 E 琥珀酸酯的药剂学应用进展", 《中南药学》 * |
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