CN111973575A - Generation process of fingolimod microcapsules - Google Patents
Generation process of fingolimod microcapsules Download PDFInfo
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- CN111973575A CN111973575A CN201910429683.5A CN201910429683A CN111973575A CN 111973575 A CN111973575 A CN 111973575A CN 201910429683 A CN201910429683 A CN 201910429683A CN 111973575 A CN111973575 A CN 111973575A
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
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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
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- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The invention discloses a process for generating a fingolimod microcapsule, which comprises the following raw materials in parts by weight: 10-20 parts of fingolimod bulk drug, 2-6 parts of surfactant, 1-2 parts of solubilizer, 1-5 parts of ethyl cellulose, 1-10 parts of methyl cellulose, 5-20 parts of microcrystalline cellulose, 1-5 parts of Arabic gum, 1-10 parts of gelatin, 1-5 parts of fructo-oligosaccharide and 1-5 parts of isomaltooligosaccharide; the preparation method of the fingolimod microcapsule preparation comprises the following steps: (1) preparing a capsule material solution; (2) preparing a suspension; (3) preparing a settling solvent; (4) settling; (5) and (5) drying in vacuum. The polymer auxiliary material capsule wall material enables the fingolimod to be slowly released, prolongs the detention time of the medicine in vivo, and obviously improves the medicine absorption rate, thereby realizing the advantages of small taking dosage, long action time, high bioavailability and less adverse reaction.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a process for generating fingolimod microcapsules.
Background
Multiple sclerosis is an autoimmune disease that is specifically directed against the white matter of the central nervous system, leading to its demyelination. It is usually more than green and strong than male. Belongs to flaccidity patent No. 36484. The disease is closely related to kidney and brain. The exact pathogenesis is unknown. Physicians believe autoimmune diseases. The disease is a debilitating nervous system disease, can cause people to lose balance, cause muscle spasm and other motor dysfunction, even cause difficulty in speaking and eating for serious people, and affect breathing for serious people, and the disease seriously affects the life quality of patients.
Fingolimod (Fingolimod), also known as fingolide, has the chemical name 2-amino-2- [2- (4-octylphenyl) ethyl ] -1, 3-propanediol. Fingolimod hydrochloride is the first oral drug for treating multiple sclerosis, is developed by norwalk pharmaceutical company, and is approved to be marketed by FDA in the united states in 2010, and the dosage form is capsule. The recommended dose is 0.5mg, administered orally 1 time per day. Fingolimod is a sphingosine-l-phosphate (S1PR) receptor modulator, and binds to S1P receptors on the surfaces of lymphocytes after phosphorylation in vivo, so as to change migration of the lymphocytes, promote the cells to enter the lymphatic tissues, prevent the cells from leaving the lymphatic tissues to enter a transplant, further prevent the cells from infiltrating the Central Nervous System (CNS), and achieve the effect of immunosuppression.
Tests show that the fingolimod hydrochloride capsule belongs to a small-specification preparation, the drug effect is quickly released after entering a human body, and if the drug effect is required to be maintained, the daily dosage and the frequency are very large, the burden on the kidney is large, and the fingolimod hydrochloride capsule is not easy to accept by patients.
Disclosure of Invention
The invention aims to provide a process for generating fingolimod microcapsules capable of slowly releasing drug properties.
In order to achieve the purpose, the invention provides a process for generating a fingolimod microcapsule, which comprises the following raw materials in parts by weight: 10-20 parts of fingolimod bulk drug, 2-6 parts of surfactant, 1-2 parts of solubilizer, 1-5 parts of ethyl cellulose, 1-10 parts of methyl cellulose, 5-20 parts of microcrystalline cellulose, 1-5 parts of Arabic gum, 1-10 parts of gelatin, 1-5 parts of fructo-oligosaccharide and 1-5 parts of isomaltooligosaccharide;
The preparation method of the fingolimod microcapsule preparation comprises the following steps:
(1) preparation of Capsule Material solution
Adding a volatile solvent into a stirrer, sequentially adding ethyl cellulose, methyl cellulose, microcrystalline cellulose, Arabic gum, gelatin, fructo-oligosaccharide and isomaltose hypgather while stirring, and stirring to obtain a capsule wall material solution a;
(2) preparation of the suspension
Adding the fingolimod bulk drug into a non-polar solvent to obtain a fingolimod oil solution, adding the fingolimod oil solution into the capsule wall material solution, slowly stirring, preserving heat and standing to obtain a suspension b;
(3) preparation of the Settlement solvent
Dissolving a surfactant in a non-volatile high-boiling-point liquid to obtain a solution c;
(4) sedimentation
Adding the solution c into the suspension b, stirring to fully and uniformly mix the fingolimod and the capsule material solution, slowly cooling to fully encapsulate the fingolimod in the capsule material to prepare a microcapsule, then quickly cooling to quickly settle the microcapsule, and filtering to remove a supernatant to obtain a wet microcapsule product;
(5) vacuum drying
And (4) putting the microcapsule wet product into a vacuum drying box, and drying to obtain the fingolimod microcapsule preparation.
The method is further optimized as follows: in the step (1), a solubilizer is also added, and the solubilizer is preferably soybean lecithin or egg yolk lecithin.
The method is further optimized as follows: the non-polar solvent is vegetable oil or animal oil.
The method is further optimized as follows: the vegetable oil is one or more of peanut oil, soybean oil, rapeseed oil, corn oil, olive oil, sunflower seed oil and sesame oil.
The method is further optimized as follows: the animal oil is one or more of lard, beef tallow, mutton fat, chicken fat and duck fat oil.
The method is further optimized as follows: the volatile solvent in the step (1) is 45-50% of ethanol water solution.
The method is further optimized as follows: the stirring speed in the step (1) is 800-1000r/min, the stirring temperature is 60-75 ℃, and the stirring time is 3-5 h.
The method is further optimized as follows: the slow stirring speed in the step (2) is 230-500r/min, the stirring temperature is 60-65 ℃, and the stirring time is 2-3 h.
The method is further optimized as follows: the non-volatile high-boiling-point liquid in the step (3) is water or liquid paraffin.
The method is further optimized as follows: the surfactant is sodium dodecyl sulfate, polysorbate-80, poloxamer, polyethylene glycol caprylic glyceride, polyethylene glycol capric glyceride, polyethylene glycol lauric glyceride or polyethylene glycol stearic glyceride.
The invention has the beneficial effects that:
1. the particle size of the prepared fingolimod microcapsule preparation is 120-200 mu m, the bad smell and taste of fingolimod are covered by the auxiliary material capsule wall material, the effective part can be more completely reserved due to the particularity of the process, the physical property is stable, and the deterioration caused by high temperature influence is not easy to occur;
2. The invention adopts ethyl cellulose as the capsule wall material, and one of ethyl acetate or acetone with proper polarity as the solvent of the capsule wall material, and the medicament is dissolved in the organic solvent of the carrier material, so as to prepare the ideal microcapsule. The microcapsule prepared by the method has round and round capsule shape without adhesion, uniform particle size distribution and good reproducibility, and the obtained microcapsule has higher drug loading rate and encapsulation efficiency; in addition, the method is simple and convenient to operate, low in cost, easy to form and suitable for industrial production;
3. the high molecular auxiliary material capsule wall material enables the fingolimod to be slowly released, the residence time of the medicine in the body is prolonged, the medicine absorption rate is obviously improved, the solubility in intestinal tracts is obviously increased, the absorption rate of a patient on the fingolimod is improved, and the burden of liver to metabolize redundant fingolimod is reduced, so that the advantages of small taking dose, long acting time, high bioavailability and less adverse reaction are realized.
Detailed Description
Example 1
A process for generating fingolimod microcapsules comprises the following raw materials in parts by weight: 10 parts of fingolimod bulk drug, 2 parts of surfactant, 1 part of solubilizer, 1 part of ethyl cellulose, 1 part of methyl cellulose, 5 parts of microcrystalline cellulose, 1 part of Arabic gum, 1 part of gelatin, 1 part of fructo-oligosaccharide and 1 part of isomaltooligosaccharide;
The preparation method of the fingolimod microcapsule preparation comprises the following steps:
(1) preparation of Capsule Material solution
Adding 45-50% ethanol water solution into a stirrer, sequentially adding ethyl cellulose, methyl cellulose, microcrystalline cellulose, acacia, gelatin, fructo-oligosaccharide and isomaltooligosaccharide while stirring, and stirring to obtain capsule wall material solution a;
(2) preparation of the suspension
Adding the fingolimod bulk drug into the peanut oil to obtain a fingolimod oil solution, adding the fingolimod oil solution into the capsule wall material solution, slowly stirring, preserving heat and standing to obtain a suspension b;
(3) preparation of the Settlement solvent
Dissolving sodium dodecyl sulfate in water to obtain a solution c;
(4) sedimentation
Adding the solution c into the suspension b, stirring to fully and uniformly mix the fingolimod and the capsule material solution, slowly cooling to fully encapsulate the fingolimod in the capsule material to prepare a microcapsule, then quickly cooling to quickly settle the microcapsule, and filtering to remove a supernatant to obtain a wet microcapsule product;
(5) vacuum drying
And (4) putting the microcapsule wet product into a vacuum drying box, and drying to obtain the fingolimod microcapsule preparation.
Example 2
The difference between the process for generating the fingolimod microcapsules and the process in the embodiment 1 is that: the fingolimod microcapsule preparation comprises the following raw materials in parts by weight: 20 parts of fingolimod bulk drug, 6 parts of surfactant, 2 parts of solubilizer, 5 parts of ethyl cellulose, 10 parts of methyl cellulose, 20 parts of microcrystalline cellulose, 5 parts of Arabic gum, 10 parts of gelatin, 5 parts of fructo-oligosaccharide and 5 parts of isomaltooligosaccharide.
Comparative example 1
The difference between the process for generating the fingolimod microcapsules and the process in the embodiment 1 is that: the ethyl cellulose and methyl cellulose in the microcapsule preparation components are replaced by 10 parts of sodium alginate.
Comparative example 2
The difference between the process for generating the fingolimod microcapsules and the process in the embodiment 1 is that: the ethyl cellulose and methyl cellulose in the microcapsule preparation components are replaced by 10 parts of polylactic acid-polyethylene glycol copolymer.
The above table shows that the microcapsule preparations of comparative examples 1 and 2 have high dissolution speed, complete release within 3 hours of the experiment, and the cumulative release percentage reaches over 95 percent, and the sustained release effect cannot be achieved.
Examples 1 and 2, which release smoothly within 24 hours in an in vitro dissolution test, may reflect the release process of the formulation in vivo to some extent.
In addition to the above embodiments, the present invention may have other embodiments. All technical solutions formed by adopting equivalent substitutions or equivalent transformations fall within the protection scope of the claims of the present invention.
Claims (10)
1. A process for generating fingolimod microcapsules is characterized in that the fingolimod microcapsule preparation comprises the following raw materials in parts by weight: 10-20 parts of fingolimod bulk drug, 2-6 parts of surfactant, 1-2 parts of solubilizer, 1-5 parts of ethyl cellulose, 1-10 parts of methyl cellulose, 5-20 parts of microcrystalline cellulose, 1-5 parts of Arabic gum, 1-10 parts of gelatin, 1-5 parts of fructo-oligosaccharide and 1-5 parts of isomaltooligosaccharide;
The preparation method of the fingolimod microcapsule preparation comprises the following steps:
(1) preparation of Capsule Material solution
Adding a volatile solvent into a stirrer, sequentially adding ethyl cellulose, methyl cellulose, microcrystalline cellulose, Arabic gum, gelatin, fructo-oligosaccharide and isomaltose hypgather while stirring, and stirring to obtain a capsule wall material solution a;
(2) preparation of the suspension
Adding the fingolimod bulk drug into a non-polar solvent to obtain a fingolimod oil solution, adding the fingolimod oil solution into the capsule wall material solution, slowly stirring, preserving heat and standing to obtain a suspension b;
(3) preparation of the Settlement solvent
Dissolving a surfactant in a non-volatile high-boiling-point liquid to obtain a solution c;
(4) sedimentation
Adding the solution c into the suspension b, stirring to fully and uniformly mix the fingolimod and the capsule material solution, slowly cooling to fully encapsulate the fingolimod in the capsule material to prepare a microcapsule, then quickly cooling to quickly settle the microcapsule, and filtering to remove a supernatant to obtain a wet microcapsule product;
(5) vacuum drying
And (4) putting the microcapsule wet product into a vacuum drying box, and drying to obtain the fingolimod microcapsule preparation.
2. The process for generating fingolimod microcapsules according to claim 1, wherein a solubilizer is added in step (1), wherein the solubilizer is preferably soybean lecithin or egg yolk lecithin.
3. The process for generating fingolimod microcapsules according to claim 1, wherein said non-polar solvent is vegetable oil or animal oil.
4. The process for generating fingolimod microcapsules of claim 3, wherein the vegetable oil is one or more of peanut oil, soybean oil, rapeseed oil, corn oil, olive oil, sunflower seed oil and sesame oil.
5. The process for generating fingolimod microcapsules according to claim 3, wherein the animal oil is one or more of lard, beef tallow, mutton tallow, chicken fat and duck fat oil.
6. The process for generating fingolimod microcapsules according to claim 1, wherein the volatile solvent in step (1) is 45-50% ethanol water solution.
7. The process for generating fingolimod microcapsules according to claim 1, wherein the stirring speed in step (1) is 800-1000r/min, the stirring temperature is 60-75 ℃, and the stirring time is 3-5 h.
8. The process for generating fingolimod microcapsules according to claim 1, wherein the slow stirring speed in step (2) is 230-500r/min, the stirring temperature is 60-65 ℃, and the stirring time is 2-3 h.
9. The process for generating fingolimod microcapsules according to claim 1, wherein said non-volatile high boiling point liquid of step (3) is water or liquid paraffin.
10. The process for generating fingolimod microcapsules according to claim 1, wherein the surfactant is sodium lauryl sulfate, polysorbate-80, poloxamer, glyceryl macrogol caprylate, glyceryl macrogol capric acid, glyceryl macrogol laurate or glyceryl macrogol stearate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910429683.5A CN111973575A (en) | 2019-05-22 | 2019-05-22 | Generation process of fingolimod microcapsules |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201910429683.5A CN111973575A (en) | 2019-05-22 | 2019-05-22 | Generation process of fingolimod microcapsules |
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| CN111973575A true CN111973575A (en) | 2020-11-24 |
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| CN201910429683.5A Pending CN111973575A (en) | 2019-05-22 | 2019-05-22 | Generation process of fingolimod microcapsules |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105560219A (en) * | 2014-11-06 | 2016-05-11 | 中国科学院上海药物研究所 | Application of fingolimod or salts thereof in treatment of cystic diseases |
| CN106063783A (en) * | 2016-06-16 | 2016-11-02 | 浙江爱生药业有限公司 | A kind of Progesterone slow-releasing microcapsule preparation and preparation method thereof |
| CN108066320A (en) * | 2017-12-25 | 2018-05-25 | 安徽永生堂药业有限责任公司 | A kind of preparation method of roxithromycin microcapsule formulation |
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2019
- 2019-05-22 CN CN201910429683.5A patent/CN111973575A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105560219A (en) * | 2014-11-06 | 2016-05-11 | 中国科学院上海药物研究所 | Application of fingolimod or salts thereof in treatment of cystic diseases |
| CN106063783A (en) * | 2016-06-16 | 2016-11-02 | 浙江爱生药业有限公司 | A kind of Progesterone slow-releasing microcapsule preparation and preparation method thereof |
| CN108066320A (en) * | 2017-12-25 | 2018-05-25 | 安徽永生堂药业有限责任公司 | A kind of preparation method of roxithromycin microcapsule formulation |
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