CN112439054A - Teriparatide sustained-release gel injection and preparation method thereof - Google Patents
Teriparatide sustained-release gel injection and preparation method thereof Download PDFInfo
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- CN112439054A CN112439054A CN201910804352.5A CN201910804352A CN112439054A CN 112439054 A CN112439054 A CN 112439054A CN 201910804352 A CN201910804352 A CN 201910804352A CN 112439054 A CN112439054 A CN 112439054A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/29—Parathyroid hormone (parathormone); Parathyroid hormone-related peptides
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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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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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
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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
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
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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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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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
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
Abstract
The invention relates to a teriparatide sustained-release gel injection and a preparation method thereof, and particularly discloses a teriparatide sustained-release gel injection which is prepared from the following components: teriparatide, a pH buffer component, a biological adhesion material, a temperature sensitive gel material, a pH regulator and a solvent; preferably, the temperature-sensitive gel material is selected from a combination of temperature-sensitive poloxamer and glycerol, and the bioadhesive material is selected from chitosan, hyaluronic acid, cellulose derivatives, polyacrylic acid or a combination thereof; the solvent is water. The teriparatide sustained-release gel injection disclosed by the invention is sustained-released for several days, so that the administration times can be obviously reduced, the compliance of a patient is improved, the treatment effect is improved, meanwhile, the use of a bacteriostatic agent is avoided, and the same effect is achieved.
Description
Technical Field
The invention relates to a preparation process of teriparatide sustained-release gel injection, belonging to the field of pharmaceutical preparations.
Background
Osteoporosis is a metabolic bone disease in which the balance between bone absorption and bone formation is disrupted after the physical function of the human body is reduced, resulting in increased bone fragility. Osteoporosis is classified into postmenopausal osteoporosis in women and senile osteoporosis. China is the country with the most population in the world, and people have also stepped into the elderly society, so that the development of medicines for preventing and treating osteoporosis has wide market demand and social significance.
Parathyroid hormone (PTH) regulates calcium and phosphorus metabolism in bone, increases serum calcium levels, decreases calcium clearance from the kidneys, and promotes bone absorption and release of calcium, thereby promoting new bone formation. Teriparatide is a chemically synthesized parathyroid hormone, can promote the formation of new bones, increase the mineral density of bones, and improve the bone density and microstructure of patients with osteoporosis, thereby reducing the risk of fracture, and is suitable for various types of osteoporosis.
The FDA approved teriparatide injection developed by American Gift corporation in 2002
Becomes the first drug approved by the FDA for treating osteoporosis. In 3 months 2011, teriparatide injection is approved by SFDA to enter the china market for the treatment of osteoporosis in postmenopausal women.
Currently, teriparatide injection developed by American Gift company
The prescription is as follows: glacial acetic acid, sodium acetate (anhydrous), mannitol, m-cresol, hydrochloric acid, sodium hydroxide and water for injection. M-cresol is a bacteriostatic agent and is easy to oxidize, so that unknown impurities are easy to generate in the preparation process of the existing teriparatide injection, and the stability of the injection is poor. The specification is 20 mug: 80 μ l, 2.4 mL/arm, with a recommended dose of 20 μ g per day by subcutaneous injection, the injection site being selected in the thigh or abdomen. The maximum time for total treatment was 24 months. The patient may receive only 1 treatment for a 24-month period for life. Futaiao is a prefilled pen type injector, and each pen is only used by one patient. The injection is administered with a new oneThe fungus injection needle is used for storing Futaiao in a refrigerator after each injection.
In the original preparation, the gel is a common injection, a patient needs to be injected subcutaneously every day, but the treatment period of osteoporosis is long, and long-time injection administration brings great pain and inconvenience to the patient, so that the compliance of the patient is poor, therefore, the development of the teriparatide preparation with long effect and slow release effect has important practical significance, the slow release of the gel injection is as long as several days, the administration times can be obviously reduced, the compliance of the patient can be improved, and the treatment effect can be improved.
The temperature sensitive slow release gel has a gelation mechanism of in-situ gel formed by the change of environmental temperature, contains temperature sensitive high molecular material, and forms non-chemical cross-linked gel due to the change of in vivo and in vitro temperature after administration. The injection is in a liquid state in vitro, has low viscosity, can be injected for administration, and after entering a joint cavity, the liquid medicine quickly forms uniform semisolid gel due to the rise of temperature, so that the retention time of the medicine in the joint cavity is prolonged, the full absorption of the medicine is facilitated, and the bioavailability of the teriparatide is improved.
Poloxamers are the most studied and used class of gel materials, and there are patents published: an amphiphilic polysaccharide derivative/poloxamer temperature-sensitive in-situ hydrogel and a preparation method thereof (patent number: CN 104888224B), the prepared in-situ hydrogel has higher stability and longer drug slow-release time, provides possibility for realizing injection administration and improving the bioavailability of drugs, and can be applied to a mucosal administration system, a transdermal administration system and an injection administration system.
Disclosure of Invention
The invention aims to overcome the defects of the dosage form in the prior art and provides a teriparatide sustained-release gel injection and a preparation method thereof, which are convenient to use, form a drug reservoir in muscle or joint cavity, have long drug action time and obviously reduce the drug administration times.
In order to achieve the above objects, one aspect of the present invention provides a teriparatide sustained-release gel injection, which is prepared from the following components: teriparatide, a pH buffer component, a biological adhesion material, a temperature sensitive gel material, a pH regulator and a solvent;
preferably, the temperature-sensitive gel material is selected from a combination of temperature-sensitive poloxamer and glycerol, and the bioadhesive material is selected from chitosan, hyaluronic acid, cellulose derivatives, polyacrylic acid or a combination thereof; the solvent is water.
In the technical scheme of the invention, the biological adhesive material refers to natural or synthetic high molecular substances with the capacity of adhering to the surface of cavity mucus or epithelial cells.
In the technical scheme of the invention, each 100ml of the teriparatide sustained-release gel injection is prepared from the following components:
in the technical scheme of the invention, the pH buffering component is selected from a buffering pair with a pH value of 3.5-5.5 after a buffering pair and a pH value regulator are added, preferably a glacial acetic acid and sodium acetate buffering pair, sodium dihydrogen phosphate and disodium hydrogen phosphate, citric acid and sodium citrate, and succinic acid.
In the technical scheme of the invention, the temperature-sensitive poloxamer is selected from poloxamer 407, poloxamer 188, a mixture of poloxamer 407 and poloxamer 188, preferably a mixture of poloxamer 407 and poloxamer 188 or more than 15g of poloxamer 407 in each 100ml of teriparatide slow-release gel injection; more preferably, the mass ratio of the poloxamer 407 to the poloxamer 188 is 1-6:1 or more than 16g of poloxamer 407 is contained in each 100ml of teriparatide sustained-release gel injection.
In the technical scheme of the invention, the addition amount of the glycerol is 50mg/ml-100mg/ml of the final concentration of the glycerol in the gel injection.
In the technical scheme of the invention, the biological adhesive material is selected from chitosan, hyaluronic acid, cellulose derivatives, polyacrylic acid or a combination thereof, and chitosan is preferred.
In the technical scheme of the invention, the pH regulator is selected from phosphoric acid, acetic acid, citric acid, hydrochloric acid and sodium hydroxide, preferably acetic acid.
In the technical scheme of the invention, the pH value buffering range of the pH buffer solution is 3.5-5.0.
In the technical scheme of the invention, the pH value of the teriparatide sustained-release gel injection is 3.8-4.5.
The invention also provides a preparation method of the teriparatide sustained-release gel injection, which comprises the following steps:
1) dissolving a teriparatide bulk drug in water for injection to obtain a first solution;
2) dissolving the biological adhesion material by using a pH buffer solution to obtain a second solution;
3) adding the temperature-sensitive gel material into the second solution, stirring and dissolving, and controlling the stirring temperature to be 0-10 ℃ to obtain a third solution;
4) uniformly mixing the first solution and the third solution at 0-10 deg.C, adjusting pH to 3.5-5.5 with pH regulator, and diluting to desired volume with injectable water;
5) sterilizing and filtering with 0.22 μm filter under aseptic condition, and controlling the filtering temperature at 0-15 deg.C;
6) and (5) subpackaging the filtered and sterilized liquid medicine.
In the technical scheme of the invention, sterile liquid medicine is subpackaged in penicillin bottles, prefilled syringes or snap bottles, preferably prefilled syringes.
In the technical scheme of the invention, the concentration of acetic acid is different from that of glacial acetic acid, the concentration of acetic acid is 36%, and the concentration of glacial acetic acid is 98%.
Advantageous effects
1. The common teriparatide injection has no slow release effect, and patients need to inject the injection every day, so that great pain and inconvenience are brought to the patients; the teriparatide sustained-release gel injection disclosed by the invention has sustained release for several days, so that the administration times can be obviously reduced, the compliance of a patient is improved, and the treatment effect is improved.
2. The prescription process of the invention avoids using bacteriostatic agents and achieves the same effect.
Detailed Description
The embodiment of the invention discloses a preparation method of teriparatide sustained-release gel injection. Those skilled in the art can modify the process recipe implementation appropriately based on the contents provided herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the method of the present invention has been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the formulations and processes described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention without departing from the spirit and scope of the invention.
For a further understanding of the present invention, reference will now be made in detail to the following examples. The following examples will help understanding of the present invention, but the following examples are only for illustrating the implementation of the present invention more specifically and are not intended to limit the technical scheme of the present invention.
Comparative example 1 teriparatide sustained Release gel injection
1) Dissolving teriparatide 25mg in 10ml of water for injection;
2) dissolving 41mg of glacial acetic acid in 50ml of water for injection, adding 10mg of sodium acetate, stirring and dissolving, adding 4.54g of mannitol, stirring and dissolving;
3) adding 0.3g of m-cresol into the mixture obtained in the step 2), and stirring and dissolving to obtain an auxiliary material solution;
4) adding the Chinese medicinal liquid in the step 1) into the step 3), stirring uniformly, adjusting the pH value to 4.0 by using acetic acid, and fixing the volume to 100ml by using water for injection;
5) sterile filtration through a 0.22 μm filter.
6) The filtrate is filled into pre-filled glass syringe (1.05ml) and stored in refrigerator at 2-8 deg.C. Comparative example 2 teriparatide sustained Release gel injection
1) Dissolving teriparatide 25mg in 10ml of water for injection;
2) dissolving 41mg of glacial acetic acid in 50ml of water for injection, adding 10mg of sodium acetate, and stirring for dissolving;
3) adding 15g of poloxamer 407 into the mixture obtained in the step 2), stirring and dissolving the mixture in ice bath, and controlling the stirring temperature to be 0-10 ℃ to obtain an auxiliary material solution;
4) adding the Chinese medicinal liquid of 1) into the liquid of 3), stirring uniformly, controlling the stirring temperature at 0-10 ℃, adjusting the pH value to 4.0 by using acetic acid, and fixing the volume to 100ml by using water for injection;
5) sterilizing and filtering with 0.22 μm filter, and controlling the filtering temperature at 0-10 deg.C.
6) The filtrate is filled into pre-filled glass syringe (1.05ml) and stored in refrigerator at 2-8 deg.C. Comparative example 3 teriparatide sustained Release gel injection
1) Dissolving teriparatide 25mg in 10ml of water for injection;
2) dissolving 41mg of glacial acetic acid in 50ml of water for injection, adding 500mg of chitosan, stirring and dissolving, and then adding 10mg of sodium acetate, stirring and dissolving;
3) adding 5g of glycerol, 14g of poloxamer 407 and 0.5g of poloxamer 188 into the mixture obtained in step 2), stirring and dissolving in ice bath, and controlling the stirring temperature to be 0-10 ℃ to obtain an auxiliary material solution;
4) adding the Chinese medicinal liquid of 1) into the liquid of 3), stirring uniformly, controlling the stirring temperature at 0-10 ℃, adjusting the pH value to 4.0 by using acetic acid, and fixing the volume to 100ml by using water for injection;
5) sterilizing and filtering with 0.22 μm filter, and controlling the filtering temperature at 0-10 deg.C.
6) The filtrate is filled into pre-filled glass syringe (1.05ml) and stored in refrigerator at 2-8 deg.C.
Example 1 sustained Release gel injection of teriparatide
1) Dissolving teriparatide 25mg in 10ml of water for injection;
2) dissolving 41mg of glacial acetic acid in 50ml of water for injection, adding 800mg of chitosan, stirring and dissolving, and then adding 10mg of sodium acetate, stirring and dissolving;
3) adding 7.5g of glycerol, 18g of poloxamer 407 and 3g of poloxamer 188 into the mixture obtained in step 2), stirring and dissolving in ice bath, and controlling the stirring temperature to be 0-10 ℃ to obtain an auxiliary material solution;
4) adding the Chinese medicinal liquid of 1) into the liquid of 3), stirring uniformly, controlling the stirring temperature at 0-10 ℃, adjusting the pH value to 4.0 by using acetic acid, and fixing the volume to 100ml by using water for injection;
5) sterilizing and filtering with 0.22 μm filter, and controlling the filtering temperature at 0-10 deg.C.
6) The filtrate is filled into pre-filled glass syringe (1.05ml) and stored in refrigerator at 2-8 deg.C.
Example 2 sustained Release gel injection of teriparatide
1) Dissolving teriparatide 25mg in 10ml of water for injection;
2) dissolving 41mg of glacial acetic acid in 50ml of water for injection, adding 200mg of hyaluronic acid, stirring and dissolving, and then adding 10mg of sodium acetate, stirring and dissolving;
3) adding 5g of glycerol, 18g of poloxamer 407 and 3g of poloxamer 188 into the mixture obtained in step 2), stirring and dissolving in ice bath, and controlling the stirring temperature to be 0-10 ℃ to obtain an auxiliary material solution;
4) adding the Chinese medicinal liquid of 1) into the liquid of 3), stirring uniformly, controlling the stirring temperature at 0-10 ℃, adjusting the pH value to 4.0 by using acetic acid, and fixing the volume to 100ml by using water for injection;
5) sterilizing and filtering with 0.22 μm filter, and controlling the filtering temperature at 0-10 deg.C.
6) And (3) subpackaging the filtered and sterilized liquid medicine into 2mL penicillin bottles (1.15mL), and storing in a refrigerator at the temperature of 2-8 ℃ to obtain the drug. Example 3 sustained Release gel injection of teriparatide
1) Dissolving teriparatide 5mg in 10ml of water for injection;
2) dissolving 41mg of glacial acetic acid in 50ml of water for injection, adding 5000mg of chitosan, stirring and dissolving, and then adding 10mg of sodium acetate, stirring and dissolving;
3) adding 10g of glycerol, 12g of poloxamer 407 and 3g of poloxamer 188 into the mixture obtained in step 2), stirring and dissolving in ice bath, and controlling the stirring temperature to be 0-10 ℃ to obtain an auxiliary material solution;
4) adding the Chinese medicinal liquid of 1) into the liquid of 3), stirring uniformly, controlling the stirring temperature at 0-10 ℃, adjusting the pH value to 4.0 by using acetic acid, and fixing the volume to 100ml by using water for injection;
5) sterilizing and filtering with 0.22 μm filter, and controlling the filtering temperature at 10-15 deg.C.
6) The filtrate is packaged into card bottle (3.3ml), and stored in refrigerator at 2-8 deg.C.
Example 4 sustained Release gel injection of teriparatide
1) Dissolving teriparatide 75mg in 10ml of water for injection;
2) dissolving 41mg of glacial acetic acid in 30ml of water for injection, adding 500mg of chitosan, stirring and dissolving, and then adding 10mg of sodium acetate, stirring and dissolving;
3) adding 5g of glycerol, 29.17g of poloxamer 407 and 5.83g of poloxamer 188 into the mixture obtained in step 2), stirring and dissolving in ice bath, and controlling the stirring temperature to be 0-10 ℃ to obtain an auxiliary material solution;
4) adding the Chinese medicinal liquid of 1) into the liquid of 3), stirring uniformly, controlling the stirring temperature at 0-10 ℃, adjusting the pH value to 4.0 by using acetic acid, and fixing the volume to 100ml by using water for injection;
5) sterilizing and filtering with 0.22 μm filter, and controlling the filtering temperature at 0-10 deg.C.
6) The filtrate is filled into pre-filled glass syringe (1.05ml) and stored in refrigerator at 2-8 deg.C.
Example 5 sustained Release gel injection of teriparatide
1) Dissolving teriparatide 15mg in 10ml of water for injection;
2) dissolving 41mg of glacial acetic acid in 50ml of water for injection, adding 500mg of chitosan, stirring and dissolving, and then adding 10mg of sodium acetate, stirring and dissolving;
3) adding 7.5g of glycerol, 20g of poloxamer 407 and 5g of poloxamer 188 into the mixture obtained in step 2), stirring and dissolving in ice bath, and controlling the stirring temperature to be 0-10 ℃ to obtain an auxiliary material solution;
4) adding the Chinese medicinal liquid of 1) into the liquid of 3), stirring uniformly, controlling the stirring temperature at 0-10 ℃, adjusting the pH value to 3.5 with acetic acid, and fixing the volume to 100ml with water for injection;
5) sterilizing and filtering with 0.22 μm filter, and controlling the filtering temperature at 0-10 deg.C.
6) The filtrate is filled into pre-filled glass syringe (1.05ml) and stored in refrigerator at 2-8 deg.C.
Example 6 sustained Release gel injection of teriparatide
1) Dissolving teriparatide 15mg in 10ml of water for injection;
2) dissolving 41mg of glacial acetic acid in 50ml of water for injection, adding 1000mg of hyaluronic acid, stirring and dissolving, and then adding 10mg of sodium acetate, stirring and dissolving;
3) adding 5g of glycerol, 20g of poloxamer 407 and 5g of poloxamer 188 into the mixture obtained in step 2), stirring and dissolving in ice bath, and controlling the stirring temperature to be 0-10 ℃ to obtain an auxiliary material solution;
4) adding the Chinese medicinal liquid of 1) into the liquid of 3), stirring uniformly, controlling the stirring temperature at 0-10 ℃, adjusting the pH value to 5.5 with acetic acid, and fixing the volume to 100ml with water for injection;
5) sterilizing and filtering with 0.22 μm filter, and controlling the filtering temperature at 0-10 deg.C.
6) The filtrate is filled into pre-filled glass syringe (1.05ml) and stored in refrigerator at 2-8 deg.C.
Example 7 sustained Release gel injection of teriparatide
1) Dissolving teriparatide 10mg in water for injection 10 ml;
2) dissolving 2.5g of sodium dihydrogen phosphate dihydrate in 50ml of water for injection, adding 800mg of chitosan, stirring and dissolving, and then adding 10mg of sodium acetate, stirring and dissolving;
3) adding 7.5g of glycerol, 18g of poloxamer 407 and 3g of poloxamer 188 into the mixture obtained in step 2), stirring and dissolving in ice bath, and controlling the stirring temperature to be 0-10 ℃ to obtain an auxiliary material solution;
4) adding the Chinese medicinal liquid of 1) into the liquid of 3), stirring uniformly, controlling the stirring temperature at 0-10 ℃, adjusting the pH value to 5.0 by using acetic acid, and fixing the volume to 100ml by using water for injection;
5) sterilizing and filtering with 0.22 μm filter, and controlling the filtering temperature at 0-10 deg.C.
6) The filtrate is filled into pre-filled glass syringe (1.05ml) and stored in refrigerator at 2-8 deg.C.
Example 8 sustained Release gel injection of teriparatide
1) Dissolving teriparatide 20mg in 10ml of water for injection;
2) dissolving 1.0g of citric acid monohydrate in 50ml of water for injection, adding 800mg of chitosan, stirring and dissolving, and then adding 10mg of sodium acetate, stirring and dissolving;
3) adding 7.5g of glycerol, 20g of poloxamer 407 and 10g of poloxamer 188 into the mixture obtained in step 2), stirring and dissolving in ice bath, and controlling the stirring temperature to be 0-10 ℃ to obtain an auxiliary material solution;
4) adding the Chinese medicinal liquid of 1) into the liquid of 3), stirring uniformly, controlling the stirring temperature at 0-10 ℃, adjusting the pH value to 4.0 by using acetic acid, and fixing the volume to 100ml by using water for injection;
5) sterilizing and filtering with 0.22 μm filter, and controlling the filtering temperature at 0-10 deg.C.
6) The filtrate is filled into pre-filled glass syringe (1.05ml) and stored in refrigerator at 2-8 deg.C.
Example 9 sustained Release gel injection of teriparatide
1) Dissolving teriparatide 25mg in 10ml of water for injection;
2) dissolving 1.0g of citric acid monohydrate in 50ml of water for injection, adding 2000mg of chitosan, stirring and dissolving, then adding 10mg of sodium acetate, stirring and dissolving;
3) adding 7.5g of glycerol, 10g of poloxamer 407 and 10g of poloxamer 188 into the mixture obtained in step 2), stirring and dissolving in ice bath, and controlling the stirring temperature to be 0-10 ℃ to obtain an auxiliary material solution;
4) adding the Chinese medicinal liquid of 1) into the liquid of 3), stirring uniformly, controlling the stirring temperature at 0-10 ℃, adjusting the pH value to 4.0 by using acetic acid, and fixing the volume to 100ml by using water for injection;
5) sterilizing and filtering with 0.22 μm filter, and controlling the filtering temperature at 0-10 deg.C.
6) The filtrate is filled into pre-filled glass syringe (1.05ml) and stored in refrigerator at 2-8 deg.C.
Example 10 sustained Release gel injection of teriparatide
1) Dissolving teriparatide 25mg in 10ml of water for injection;
2) dissolving 41mg of glacial acetic acid in 50ml of water for injection, adding 800mg of chitosan, stirring and dissolving, and then adding 10mg of sodium acetate, stirring and dissolving;
3) adding 7.5g of glycerol and 20g of poloxamer 407 into the mixture obtained in the step 2), stirring and dissolving the mixture in ice bath, and controlling the stirring temperature to be 0-10 ℃ to obtain an auxiliary material solution;
4) adding the Chinese medicinal liquid of 1) into the liquid of 3), stirring uniformly, controlling the stirring temperature at 0-10 ℃, adjusting the pH value to 4.0 by using acetic acid, and fixing the volume to 100ml by using water for injection;
5) sterilizing and filtering with 0.22 μm filter, and controlling the filtering temperature at 0-10 deg.C.
6) The filtrate is filled into pre-filled glass syringe (1.05ml) and stored in refrigerator at 2-8 deg.C.
Example 11 phase transition temperature and reversibility measurement of teriparatide sustained-Release gel injection
Test samples: teriparatide sustained-release gel injection or teriparatide injection prepared according to the formulation and preparation method described in examples 1-10 and comparative example 1.
The phase transition temperature measuring method comprises the following steps: placing 1mL teriparatide sustained-release gel injection in a 10mL test tube, gradually heating in a constant temperature water bath kettle to 0.1 deg.C for 1min, stabilizing after reaching a given temperature, judging according to flow-no-flow principle, and recording temperature. And after the phase change occurs, taking out the liquid crystal, putting the liquid crystal in a refrigerator, observing whether the liquid crystal is recovered after 10min, and judging whether the phase change is reversible.
The test results are shown in the following table:
TABLE 1 results of liquid phase transition temperature and reversibility of teriparatide sustained-release gel injection
The average temperature of human body is 36-37 deg.C, so that the sample can be changed into semisolid gel at body temperature as long as it is liquid at normal temperature, i.e. the sample with gelation temperature of 20-37 deg.C is satisfactory, and is more excellent for sample with temperature of 25-33 deg.C.
Test results show that the teriparatide sustained-release gel injection is liquid at the gelation temperature of 20-37 ℃, is convenient to administer and good in patient compliance, can form semisolid gel at the gelation temperature of 1-3 min after being injected into muscles or joint cavities, has high gelation speed, forms a drug storage, slowly releases active substance teriparatide and exerts curative effect. And when the mass ratio of the poloxamer 407 to the poloxamer 188 is 1-6:1 or more than 16g of poloxamer 407 is contained in each 100ml of teriparatide sustained-release gel injection, the effect is better.
EXAMPLE 12 examination of in vitro Release degree of teriparatide sustained-Release gel injection
The in vitro release behavior of the teriparatide sustained-release gel injection is examined by adopting a constant temperature shaking table method: taking 2g of teriparatide sustained-release gel injection or teriparatide injection into a penicillin bottle (phi 13mm), placing the teriparatide sustained-release gel injection or the teriparatide injection into a constant-temperature shaking table at 37 ℃ for 10min, then adding 2mL of acetic acid-sodium acetate buffer solution (pH4.0) and vibrating at 37 ℃ at 50rpm, respectively sampling 0.5mL in 4h, 8h, 12h, 24h, 48h, 72h, 120h, 168h and 240h, supplementing 0.5mL of acetic acid-sodium acetate buffer solution (pH4.0), treating 0.5mL of a sample taken out each time, taking 20 mu L of the sample to inject into a high-performance liquid chromatograph, obtaining the concentration of the sample solution, calculating the cumulative release degree Q, and drawing a curve result shown as the following formula:
c in formula 1-1nThe drug concentration (mg/mL), C, was determined for the nth time sampling pointiThe drug concentration (mg/mL) was determined for the ith time sampling point, and M was the total amount of drug in 2g of teriparatide sustained release gel injection.
TABLE 2 cumulative release results for teriparatide sustained release gel injections
Note 1 because it did not gel at 37 deg.C, this set of experiments was done with constant temperature shaking (50rpm) at 39 deg.C
The teriparatide sustained-release gel injection in the embodiment 1-10 has an obvious sustained-release effect, avoids the peak-valley phenomenon of the drug concentration, has long drug action time, reduces the administration times, and greatly improves the compliance of patients.
Claims (10)
1. A teriparatide sustained-release gel injection is prepared from the following components: teriparatide, a pH buffer component, a biological adhesion material, a temperature sensitive gel material, a pH regulator and a solvent;
preferably, the temperature-sensitive gel material is selected from a combination of temperature-sensitive poloxamer and glycerol, and the bioadhesive material is selected from chitosan, hyaluronic acid, cellulose derivatives, polyacrylic acid or a combination thereof; the solvent is water.
2. The teriparatide sustained-release gel injection according to claim 1, wherein each 100ml of the injection is prepared from the following components:
3. the teriparatide sustained release gel injection according to any one of claims 1 to 2, wherein the pH buffering component is selected from the group consisting of a buffer pair having a pH of between 3.5 and 5.5 after addition of a buffer pair and a pH adjusting agent, preferably a glacial acetic acid and sodium acetate buffer pair, sodium dihydrogen phosphate and disodium hydrogen phosphate, citric acid and sodium citrate, succinic acid.
4. The teriparatide sustained-release gel injection according to any one of claims 1 to 3, wherein the temperature-sensitive poloxamer is selected from poloxamer 407, poloxamer 188, a mixture of poloxamer 407 and poloxamer 188, preferably a mixture of poloxamer 407 and poloxamer 188 or more than 15g of poloxamer 407 in each 100ml of teriparatide sustained-release gel injection; more preferably, the mass ratio of the poloxamer 407 to the poloxamer 188 is 1-6:1 or more than 16g of poloxamer 407 is contained in each 100ml of teriparatide sustained-release gel injection.
5. The sustained-release gel injection of teriparatide according to any one of claims 1 to 4, wherein glycerol is added in an amount such that the final concentration thereof in the gel injection is 50mg/ml to 100 mg/ml.
6. The teriparatide sustained-release gel injection according to any one of claims 1 to 5, wherein the pH regulator is selected from phosphoric acid, acetic acid, citric acid, hydrochloric acid and sodium hydroxide, preferably acetic acid.
7. The teriparatide sustained release gel injection according to any one of claims 1 to 6, wherein the pH buffer has a pH value buffering range of 3.5 to 5.0.
8. The teriparatide sustained-release gel injection according to any one of claims 1 to 7, which has a pH value of 3.8 to 4.5.
9. The method for preparing teriparatide sustained release gel injection according to any one of claims 1 to 8, which comprises the following steps:
1) dissolving a teriparatide bulk drug in water for injection to obtain a first solution;
2) dissolving the biological adhesion material by using a pH buffer solution to obtain a second solution;
3) adding the temperature-sensitive gel material into the second solution, stirring and dissolving, and controlling the stirring temperature to be 0-10 ℃ to obtain a third solution;
4) uniformly mixing the first solution and the third solution at 0-10 deg.C, adjusting pH to 3.5-5.5 with pH regulator, and diluting to desired volume with injectable water;
5) sterilizing and filtering with 0.22 μm filter under aseptic condition, and controlling the filtering temperature at 0-15 deg.C;
6) and (5) subpackaging the filtered and sterilized liquid medicine.
10. The method of claim 9, wherein the sterile pharmaceutical solution is dispensed into a vial, pre-filled syringe or cartridge, preferably a pre-filled syringe.
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| CN201910804352.5A CN112439054B (en) | 2019-08-28 | 2019-08-28 | Teriparatide sustained-release gel injection and preparation method thereof |
| PCT/CN2019/121291 WO2021036058A1 (en) | 2019-08-28 | 2019-11-27 | Teriparatide sustained release gel injection solution and preparation method therefor |
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| CN201910804352.5A CN112439054B (en) | 2019-08-28 | 2019-08-28 | Teriparatide sustained-release gel injection and preparation method thereof |
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| CN115634234B (en) * | 2022-10-24 | 2024-03-22 | 山西医科大学 | Poloxamer 407 antibacterial anti-inflammatory temperature-sensitive hydrogel containing chlorhexidine/gardenin/hyaluronic acid and preparation and application thereof |
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| WO2021036058A1 (en) | 2021-03-04 |
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