CN112439054B - 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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- CN112439054B CN112439054B CN201910804352.5A CN201910804352A CN112439054B CN 112439054 B CN112439054 B CN 112439054B CN 201910804352 A CN201910804352 A CN 201910804352A CN 112439054 B CN112439054 B CN 112439054B
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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 in particular discloses a teriparatide sustained-release gel injection which is prepared from the following components: teriparatide, a pH buffer component, a bioadhesive 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 glycerin, 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 of the invention can be sustained-release for a plurality of days, can obviously reduce the times of administration, improve the compliance of patients, improve the treatment effect, avoid using bacteriostatic agent and achieve the same effect.
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 bone resorption and bone formation are disrupted after the body's function is reduced, resulting in increased bone fragility. Osteoporosis is classified as postmenopausal female osteoporosis and senile osteoporosis. China is the most populated country in the world, and people have already stepped into the aged society, so that development of medicaments for preventing and treating osteoporosis has wide market demands and social significance.
Parathyroid hormone (PTH) regulates calcium-phosphorus metabolism in bone, increases serum calcium concentration levels, reduces clearance of calcium from the kidneys, and promotes bone absorption and release of calcium, thereby promoting new bone formation. Teriparatide is a chemically synthesized parathyroid hormone, and can promote the formation of new bones, increase the density of bone mineral substances, improve the bone density and microstructure of patients suffering from osteoporosis, thereby reducing the risk of fracture, and being suitable for various types of osteoporosis.
Teriparatide injection developed by American Gift company approved by FDA in 2002
Become the first FDA approved medicament for treating osteoporosis. Teriparatide injection was approved by SFDA into the chinese market 3 months 2011 for the treatment of osteoporosis in postmenopausal women.
Currently, teriparatide injection developed by Gift corporation of America
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 μl,2.4 mL/count, is recommended at a daily subcutaneous injection of 20 μg, with the injection site selected on the thigh or abdomen. The maximum duration of the total treatment was 24 months. Patients can only receive 1 treatment for 24 months throughout their life. Futaiao is a preloaded pen type injector, and each pen is used by only one patient. A new sterile injection needle is needed for each injection, and the compound tai ao is put back into a refrigerator for storage after each injection.
In the original preparation, the preparation is a common injection, a patient needs to be subcutaneously injected every day, but the treatment period of osteoporosis is longer, and long-time injection administration brings great pain and inconvenience to the patient, so that the patient has poor compliance, so that the development of the long-acting teriparatide preparation with a slow release effect has important practical significance, and the slow release gel injection can obviously reduce the administration times, improve the patient compliance and improve the treatment effect for a plurality of days.
The gelation mechanism of the temperature-sensitive slow release gel is in-situ gel formed by the change of the ambient temperature, the slow release gel contains a temperature-sensitive high polymer material, and the gel is formed by non-chemical crosslinking due to the change of the in-vivo and in-vitro temperature after administration. The medicine liquid is in a liquid state in vitro, has small viscosity, can be injected and administrated, and can quickly form uniform semisolid gel due to the temperature rise after entering the joint cavity, so that the residence time of the medicine in the joint cavity is prolonged, the medicine is fully absorbed, and the bioavailability of teriparatide is improved.
Poloxamers are one type of gel material most studied and used, and the published patent: an amphipathic polysaccharide derivative/poloxamer temperature-sensitive in-situ hydrogel and a preparation method thereof (patent number: CN 104888224B), wherein the prepared in-situ hydrogel has higher stability and longer drug release time, provides possibility for realizing injection administration and improving the bioavailability of the drug, and can be applied to mucous membrane administration, percutaneous administration and injection administration systems.
Disclosure of Invention
The invention aims to solve the defects of the dosage form in the prior art and provide a teriparatide sustained-release gel injection and a preparation method thereof, which are convenient to use, and meanwhile, a medicine reservoir is formed in muscle or joint cavity, so that the medicine has long acting time and the medicine using times are obviously reduced.
In order to achieve the above purpose, 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 bioadhesive 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 glycerin, 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 adhesion material refers to natural or synthetic high molecular substances with the capability of adhering to the surfaces of airway 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 buffer component is selected from buffer pairs with pH value between 3.5 and 5.5 after the buffer pairs and the pH value regulator are added, preferably glacial acetic acid and sodium acetate buffer pairs, 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 every 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 glycerol is added in an amount that the final concentration of the glycerol in the gel injection is 50mg/ml-100mg/ml.
In the technical scheme of the invention, the bioadhesive 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 buffer range of the pH buffer solution is 3.5-5.0.
In the technical scheme of the invention, the pH value of the teriparatide slow-release gel injection is 3.8-4.5.
In another aspect, the invention provides a preparation method of teriparatide sustained-release gel injection, which comprises the following steps:
1) Dissolving teriparatide bulk drug in water for injection to obtain a first solution;
2) Dissolving the bioadhesive material with a pH buffer 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, regulating the pH value to 3.5-5.5 by using a pH regulator at the mixing temperature of 0-10 ℃, and fixing the volume by using water for injection;
5) Sterilizing and filtering with 0.22 μm filter under aseptic condition, and controlling the filtering temperature at 0-15deg.C;
6) And subpackaging the liquid medicine after filtering and sterilizing.
In the technical scheme of the invention, the sterile liquid medicine is packaged in penicillin bottles, prefilled syringes or card type bottles, and is preferably packaged in prefilled syringes.
In the technical scheme of the invention, the acetic acid and the glacial acetic acid have different concentrations, the acetic acid concentration is 36%, and the glacial acetic acid concentration is 98%.
Advantageous effects
1. The teriparatide common injection has no slow release effect, and patients need daily injection, so that great pain and inconvenience are brought to the patients; the teriparatide sustained-release gel injection of the invention can be sustained for a plurality of days, thus obviously reducing the times of administration, improving the compliance of patients and improving the treatment effect.
2. The prescription process of the invention avoids using bacteriostat 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, with the benefit of this disclosure, suitably modify the recipe implementation. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included in the present invention. While the method of the present invention has been described in terms of preferred embodiments, it will be apparent to those skilled in the relevant art that the invention can be practiced and practiced with modification and alteration of the formulation or process described herein, or with suitable modification and combination, without departing from the spirit and scope of the invention.
The present invention will be described in detail with reference to examples. The invention will be further understood by the following examples, which are provided only for more specific illustration of the practice of the invention and are not intended to limit the technical solution thereof.
Comparative example 1 teriparatide sustained-release gel injection
1) 25mg of teriparatide is dissolved in 10ml of water for injection;
2) 41mg of glacial acetic acid is dissolved in 50ml of water for injection, then 10mg of sodium acetate is added, stirring is carried out for dissolution, and 4.54g of mannitol is added, stirring is carried out for dissolution;
3) Adding 0.3g of m-cresol into the step 2), and stirring and dissolving to obtain an auxiliary material solution;
4) Adding the traditional Chinese medicine liquid in the step 1) into the step 3), uniformly stirring, adjusting the pH value to 4.0 by using acetic acid, and fixing the volume to 100ml by using water for injection;
5) The mixture was sterilized and filtered through a 0.22 μm filter.
6) The filtered and sterilized liquid medicine is packaged in pre-filled glass syringes (1.05 ml) and stored in a refrigerator at 2-8 ℃. Comparative example 2 teriparatide sustained-release gel injection
1) 25mg of teriparatide is dissolved in 10ml of water for injection;
2) 41mg of glacial acetic acid is dissolved in 50ml of water for injection, and 10mg of sodium acetate is added for stirring and dissolution;
3) Adding 15g of poloxamer 407 into the 2), stirring and dissolving in ice bath, and controlling the stirring temperature to be 0-10 ℃ to obtain auxiliary material solution;
4) Adding the Chinese medicinal liquid in the step 1) into the step 3), uniformly stirring, controlling the stirring temperature to be 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 0-10deg.C.
6) The filtered and sterilized liquid medicine is packaged in pre-filled glass syringes (1.05 ml) and stored in a refrigerator at 2-8 ℃. Comparative example 3 teriparatide sustained-release gel injection
1) 25mg of teriparatide is dissolved in 10ml of water for injection;
2) Dissolving 41mg of glacial acetic acid in 50ml of water for injection, adding 500mg of chitosan, stirring for dissolving, and then adding 10mg of sodium acetate, stirring for dissolving;
3) Adding 5g of glycerol, 14g of poloxamer 407 and 0.5g of poloxamer 188 into the solution 2), stirring and dissolving in an ice bath, and controlling the stirring temperature to be 0-10 ℃ to obtain an auxiliary material solution;
4) Adding the Chinese medicinal liquid in the step 1) into the step 3), uniformly stirring, controlling the stirring temperature to be 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 0-10deg.C.
6) The filtered and sterilized liquid medicine is packaged in pre-filled glass syringes (1.05 ml) and stored in a refrigerator at 2-8 ℃.
EXAMPLE 1 teriparatide sustained-release gel injection
1) 25mg of teriparatide is dissolved in 10ml of water for injection;
2) Dissolving 41mg of glacial acetic acid in 50ml of water for injection, adding 800mg of chitosan, stirring for dissolving, and then adding 10mg of sodium acetate, stirring for dissolving;
3) Adding 7.5g of glycerol, 18g of poloxamer 407 and 3g of poloxamer 188 into the solution 2), stirring and dissolving in an ice bath, and controlling the stirring temperature to be 0-10 ℃ to obtain an auxiliary material solution;
4) Adding the Chinese medicinal liquid in the step 1) into the step 3), uniformly stirring, controlling the stirring temperature to be 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 0-10deg.C.
6) The filtered and sterilized liquid medicine is packaged in pre-filled glass syringes (1.05 ml) and stored in a refrigerator at 2-8 ℃.
EXAMPLE 2 teriparatide sustained-release gel injection
1) 25mg of teriparatide is dissolved in 10ml of water for injection;
2) 41mg of glacial acetic acid is dissolved in 50ml of water for injection, 200mg of hyaluronic acid is added, and after stirring and dissolving, 10mg of sodium acetate is added, stirring and dissolving are carried out;
3) Adding 5g of glycerol, 18g of poloxamer 407 and 3g of poloxamer 188 into the solution 2), stirring and dissolving in an ice bath, and controlling the stirring temperature to be 0-10 ℃ to obtain an auxiliary material solution;
4) Adding the Chinese medicinal liquid in the step 1) into the step 3), uniformly stirring, controlling the stirring temperature to be 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 0-10deg.C.
6) Packaging the filtered and sterilized liquid medicine in 2mL penicillin bottles (1.15 mL), and storing in a refrigerator at 2-8deg.C. EXAMPLE 3 teriparatide sustained-release gel injection
1) 5mg of teriparatide is dissolved in 10ml of water for injection;
2) Dissolving 41mg of glacial acetic acid in 50ml of water for injection, adding 5000mg of chitosan, stirring for dissolving, and then adding 10mg of sodium acetate, stirring for dissolving;
3) Adding 10g of glycerol, 12g of poloxamer 407 and 3g of poloxamer 188 into the solution 2), stirring and dissolving in an ice bath, and controlling the stirring temperature to be 0-10 ℃ to obtain an auxiliary material solution;
4) Adding the Chinese medicinal liquid in the step 1) into the step 3), uniformly stirring, controlling the stirring temperature to be 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 10-15deg.C.
6) Packaging the sterilized liquid medicine in card bottle (3.3 ml), and storing in refrigerator at 2-8deg.C.
EXAMPLE 4 teriparatide sustained-release gel injection
1) Dissolving 75mg of teriparatide in 10ml of water for injection;
2) Dissolving 41mg of glacial acetic acid in 30ml of water for injection, adding 500mg of chitosan, stirring for dissolving, and then adding 10mg of sodium acetate, stirring for dissolving;
3) Adding 5g of glycerol, 29.17g of poloxamer 407 and 5.83g of poloxamer 188 into the solution 2), stirring and dissolving in an ice bath, and controlling the stirring temperature at 0-10 ℃ to obtain an auxiliary material solution;
4) Adding the Chinese medicinal liquid in the step 1) into the step 3), uniformly stirring, controlling the stirring temperature to be 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 0-10deg.C.
6) The filtered and sterilized liquid medicine is packaged in pre-filled glass syringes (1.05 ml) and stored in a refrigerator at 2-8 ℃.
EXAMPLE 5 teriparatide sustained-release gel injection
1) 15mg of teriparatide is dissolved in 10ml of water for injection;
2) Dissolving 41mg of glacial acetic acid in 50ml of water for injection, adding 500mg of chitosan, stirring for dissolving, and then adding 10mg of sodium acetate, stirring for dissolving;
3) Adding 7.5g of glycerol, 20g of poloxamer 407 and 5g of poloxamer 188 into the solution 2), stirring and dissolving in an ice bath, and controlling the stirring temperature to be 0-10 ℃ to obtain an auxiliary material solution;
4) Adding the Chinese medicinal liquid in 1) into 3), stirring uniformly, controlling the stirring temperature to be 0-10 ℃, regulating the pH value to 3.5 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 0-10deg.C.
6) The filtered and sterilized liquid medicine is packaged in pre-filled glass syringes (1.05 ml) and stored in a refrigerator at 2-8 ℃.
EXAMPLE 6 teriparatide sustained-release gel injection
1) 15mg of teriparatide is dissolved in 10ml of water for injection;
2) 41mg of glacial acetic acid is dissolved in 50ml of water for injection, 1000mg of hyaluronic acid is added, and after stirring and dissolving, 10mg of sodium acetate is added, stirring and dissolving are carried out;
3) Adding 5g of glycerin, 20g of poloxamer 407 and 5g of poloxamer 188 into the solution 2), stirring and dissolving in an ice bath, and controlling the stirring temperature to be 0-10 ℃ to obtain an auxiliary material solution;
4) Adding the Chinese medicinal liquid in the step 1) into the step 3), uniformly stirring, controlling the stirring temperature to be 0-10 ℃, adjusting the pH value to 5.5 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 0-10deg.C.
6) The filtered and sterilized liquid medicine is packaged in pre-filled glass syringes (1.05 ml) and stored in a refrigerator at 2-8 ℃.
EXAMPLE 7 teriparatide sustained-release gel injection
1) Dissolving 10mg of teriparatide in 10ml of water for injection;
2) 2.5g of sodium dihydrogen phosphate dihydrate is dissolved in 50ml of water for injection, 800mg of chitosan is added, and after stirring and dissolution, 10mg of sodium acetate is added, and stirring and dissolution are carried out;
3) Adding 7.5g of glycerol, 18g of poloxamer 407 and 3g of poloxamer 188 into the solution 2), stirring and dissolving in an ice bath, and controlling the stirring temperature to be 0-10 ℃ to obtain an auxiliary material solution;
4) Adding the Chinese medicinal liquid in the step 1) into the step 3), uniformly stirring, controlling the stirring temperature to be 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 0-10deg.C.
6) The filtered and sterilized liquid medicine is packaged in pre-filled glass syringes (1.05 ml) and stored in a refrigerator at 2-8 ℃.
EXAMPLE 8 teriparatide sustained-release gel injection
1) Dissolving teriparatide 20mg in 10ml of water for injection;
2) 1.0g citric acid monohydrate is dissolved in 50ml water for injection, 800mg chitosan is added, and after stirring and dissolving, 10mg sodium acetate is added, stirring and dissolving are carried out;
3) Adding 7.5g of glycerin, 20g of poloxamer 407 and 10g of poloxamer 188 into the solution 2), stirring and dissolving in an ice bath, and controlling the stirring temperature to be 0-10 ℃ to obtain an auxiliary material solution;
4) Adding the Chinese medicinal liquid in the step 1) into the step 3), uniformly stirring, controlling the stirring temperature to be 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 0-10deg.C.
6) The filtered and sterilized liquid medicine is packaged in pre-filled glass syringes (1.05 ml) and stored in a refrigerator at 2-8 ℃.
EXAMPLE 9 teriparatide sustained-release gel injection
1) 25mg of teriparatide is dissolved in 10ml of water for injection;
2) 1.0g citric acid monohydrate is dissolved in 50ml water for injection, 2000mg chitosan is added, and after stirring and dissolving, 10mg sodium acetate is added, stirring and dissolving are carried out;
3) Adding 7.5g of glycerin, 10g of poloxamer 407 and 10g of poloxamer 188 into the solution 2), stirring and dissolving in an ice bath, and controlling the stirring temperature to be 0-10 ℃ to obtain an auxiliary material solution;
4) Adding the Chinese medicinal liquid in the step 1) into the step 3), uniformly stirring, controlling the stirring temperature to be 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 0-10deg.C.
6) The filtered and sterilized liquid medicine is packaged in pre-filled glass syringes (1.05 ml) and stored in a refrigerator at 2-8 ℃.
EXAMPLE 10 teriparatide sustained-release gel injection
1) 25mg of teriparatide is dissolved in 10ml of water for injection;
2) Dissolving 41mg of glacial acetic acid in 50ml of water for injection, adding 800mg of chitosan, stirring for dissolving, and then adding 10mg of sodium acetate, stirring for dissolving;
3) Adding 7.5g of glycerol and 20g of poloxamer 407 into the 2), stirring and dissolving in an ice bath, and controlling the stirring temperature at 0-10 ℃ to obtain an auxiliary material solution;
4) Adding the Chinese medicinal liquid in the step 1) into the step 3), uniformly stirring, controlling the stirring temperature to be 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 0-10deg.C.
6) The filtered and sterilized liquid medicine is packaged in pre-filled glass syringes (1.05 ml) and stored in a refrigerator at 2-8 ℃.
Example 11 determination of the phase transition temperature and reversibility of a teriparatide sustained-release gel injection
Test sample: teriparatide slow-release gel injection or teriparatide injection prepared according to the prescriptions and the preparation methods described in examples 1-10 and comparative example 1.
The phase transition temperature measuring method comprises the following steps: taking 1mL of teriparatide slow-release gel injection, placing the injection in a 10mL test tube, placing the test tube in a constant-temperature water bath kettle, gradually heating to 0.1 ℃ in each step, stabilizing for 1min after reaching a specified temperature, judging according to a flowing-non-flowing principle, and recording the temperature. After the phase change, taking out the mixture and placing the mixture in a refrigerator, observing whether the mixture is recovered to be liquid after 10 minutes, and judging whether the phase change is reversible.
The test results are shown in the following table:
TABLE 1 teriparatide sustained release gel injection phase transition temperature and reversibility results
The average temperature of the human body is 36-37 ℃, so that the temperature in the body temperature state can be changed into semisolid gel as long as the sample is liquid at normal temperature, namely, the sample with the gelation temperature of 20-37 ℃ meets the requirements, and the sample with the gelation temperature of 25-33 ℃ is more preferable.
The test result shows that the teriparatide slow-release gel injection is liquid at the gelation temperature of 20-37 ℃, is convenient to administer, has good patient compliance, can form semisolid gel at the gelation temperature for 1-3 min after being injected and administered through muscle or joint cavity, has high gelation speed, forms a drug reservoir, slowly releases the active substance teriparatide and plays a role. The effect is better when the mass ratio of the poloxamer 407 to the poloxamer 188 is 1-6:1 or more than 16g of the poloxamer 407 is contained in each 100ml of teriparatide slow-release gel injection.
EXAMPLE 12 investigation of the 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 slow-release gel injection or teriparatide injection in a penicillin bottle (phi 13 mm), placing in a constant-temperature shaking table at 37 ℃ for 10min, adding 2mL of acetic acid-sodium acetate buffer solution (pH4.0) and shaking at 37 ℃ at constant temperature (50 rpm), sampling 0.5mL at 4h, 8h, 12h, 24h, 48h, 72h, 120h, 168h and 240h respectively, adding 0.5mL of acetic acid-sodium acetate buffer solution (pH4.0), treating 0.5mL of each extracted sample, taking 20 mu L of the sample, injecting 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 in the following formula:
c in 1-1 n Drug concentration (mg/mL) was measured for the nth time sampling point, C i Drug concentration (mg/mL) was measured for the ith time sampling point, and M was the total drug amount of 2g teriparatide sustained release gel injection.
TABLE 2 accumulated Release results of teriparatide sustained-release gel injection
Note 1 since it does not gel at 37 ℃, this set of experiments was performed with constant temperature shaking (50 rpm) at 39 ℃
The teriparatide sustained-release gel injection of the embodiments 1 to 10 has obvious sustained-release effect, avoids peak valley phenomenon of drug concentration, has long drug action time, reduces the administration times and greatly improves the patient compliance.
Claims (11)
1. A teriparatide sustained release gel injection is prepared from the following components: teriparatide, a pH buffer component, a bioadhesive material, a temperature sensitive gel material, a pH regulator and a solvent;
the temperature-sensitive gel material is selected from a combination of temperature-sensitive poloxamer and glycerin, and the bioadhesive material is selected from chitosan, hyaluronic acid, cellulose derivatives, polyacrylic acid or a combination thereof; the solvent is water;
the temperature-sensitive poloxamer is selected from poloxamer 407 and poloxamer 188 with the mass ratio of 1-6:1 or more than 16g of poloxamer 407 is contained in every 100ml of teriparatide slow-release gel injection.
2. The teriparatide sustained-release gel injection according to claim 1, wherein the pH buffering component is selected from the group consisting of a buffering pair and a buffering pair having a pH value of 3.5-5.5 after the addition of the pH adjustor.
3. The teriparatide sustained release gel injection according to claim 2, wherein the pH buffering component is selected from the group consisting of 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 glycerol is added in such an amount that the final concentration thereof in the gel injection is 50mg/ml to 100mg/ml.
5. A teriparatide sustained release gel injection according to any one of claims 1-3 wherein the pH adjuster is selected from phosphoric acid, acetic acid, citric acid, hydrochloric acid and sodium hydroxide.
6. The teriparatide sustained-release gel injection according to claim 4, wherein the pH regulator is selected from acetic acid.
7. A teriparatide sustained release gel injection according to any one of claims 1-3 wherein the pH buffer has a pH buffering range of 3.5-5.0.
8. The teriparatide sustained-release gel injection according to claim 7, wherein the pH value of the teriparatide sustained-release gel injection is 3.8-4.5.
9. The method for preparing a teriparatide sustained-release gel injection according to any one of claims 1 to 8, comprising the following steps:
1) Dissolving teriparatide bulk drug in water for injection to obtain a first solution;
2) Dissolving the bioadhesive material with a pH buffer 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, regulating the pH value to 3.5-5.5 by using a pH regulator at the mixing temperature of 0-10 ℃, and fixing the volume by using water for injection;
5) Sterilizing and filtering with 0.22 μm filter under aseptic condition, and controlling the filtering temperature at 0-15deg.C;
6) And subpackaging the liquid medicine after filtering and sterilizing.
10. The preparation method as claimed in claim 9, wherein the sterile liquid medicine is dispensed in penicillin bottles, prefilled syringes or cartridge bottles.
11. The method of claim 10, wherein the sterile liquid medicine is dispensed into a prefilled 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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| CN112439054A (en) | 2021-03-05 |
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