CN110870853B - Slow-release pasireotide microspheres and preparation method thereof - Google Patents
Slow-release pasireotide microspheres and preparation method thereof Download PDFInfo
- Publication number
- CN110870853B CN110870853B CN201810996995.XA CN201810996995A CN110870853B CN 110870853 B CN110870853 B CN 110870853B CN 201810996995 A CN201810996995 A CN 201810996995A CN 110870853 B CN110870853 B CN 110870853B
- Authority
- CN
- China
- Prior art keywords
- pasireotide
- microspheres
- release
- sustained
- microsphere
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
-
- 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
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- 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
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
-
- 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
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Inorganic Chemistry (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to a slow-release pasireotide microsphere and a preparation method thereof, and particularly discloses a slow-release pasireotide microsphere, which is prepared from pasireotide serving as an active ingredient, a microsphere carrier polymer, a protective agent, a surfactant and a suspending agent; the microsphere carrier polymer is selected from glycolide-lactide copolymer; the suspending agent is one or the combination of more than two of tragacanth, acacia, carbomer and sodium alginate. The pasireotide microspheres prepared by the multiple emulsion method have simple preparation process, can be prepared into microspheres with uniform particle size, high encapsulation efficiency and stable quality, and release 95% of the pasireotide microspheres from 14 days and release 95% of the pasireotide microspheres from 28 days by adding the suspending agent.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a slow-release pasireotide microsphere and a preparation method thereof.
Background
The pasireotide injection is a somatostatin analogue and is mainly used for treating patients suffering from cushing disease who cannot be treated by an operation. Cushing's disease is a proliferation of pituitary ACTH adenomas or ACTH cells, secreting excess ACTH, causing hyperplasia of the adrenal cortex, producing hypercortisolism, leading to a range of substance metabolism disorders and pathological changes. Pasireotide inhibits ACTH secretion, thereby reducing cortisol secretion.
Pasireotide injection has been approved by the FDA in the united states for marketing, but requires subcutaneous injections twice daily due to the short half-life. The compliance is poor, and thus the development of sustained release microsphere formulations that can be administered once a month can improve patient compliance.
The FDA approved once a month formulation of norghrelin (Signifor) for the treatment of acromegaly, a rare growth hormone disorder that can lead to disfigurement and death.
Nowa shows that the therapeutic drug for intramuscular injection can be combined with somatostatin receptors of human bodies, reduce the production of excessive growth hormone and insulin-like growth factor 1 (the root cause of diseases), reduce the hand and face swelling marked by acromegaly and improve the outcome of patients.
Pasireotide is a cyclohexapeptide somatostatin analogue, and has the following structure:
in the prior art, the medicament is prepared into injection, so that the action time in vivo is short; while the microspheres are relatively slow releasing and have a long action in vivo.
Disclosure of Invention
The invention aims to provide a microsphere capable of effectively prolonging the in vivo release time of pasireotide, which contains an active ingredient pasireotide, and a composition suitable for the requirements of patients is obtained by selecting a proper prescription and a proper process.
One aspect of the invention provides a microsphere of pasireotide with sustained and controlled release, which is prepared from pasireotide as an active ingredient, a microsphere carrier polymer, a protective agent, a surfactant and a suspending agent;
the microsphere carrier polymer is selected from glycolide-lactide copolymer;
the suspending agent is one or the combination of more than two of tragacanth, acacia, carbomer and sodium alginate.
In the technical scheme of the invention, the formula of the microsphere comprises the following components in percentage by mass,
in the technical scheme of the invention, the protective agent is polyhydric alcohol and saccharides which can protect the spatial conformation of polypeptide or protein, and the saccharides are selected from one or more of mannitol, trehalose, hypromellose, sodium carboxymethylcellulose, polyvinylpyrrolidone and human serum albumin; preferably, the protective agent is a combination of human serum albumin and any one of mannitol, trehalose, hypromellose, sodium carboxymethylcellulose and polyvinylpyrrolidone.
In the technical scheme of the invention, the surfactant is selected from one or the combination of any two or more of polyvinyl alcohol, poloxamer, sodium oleate, sodium stearate, tween and span.
In the technical scheme of the invention, the pasireotide sustained-release microsphere preparation is prepared by the following steps:
1) dissolving the microsphere carrier polymer in an organic solvent to form an oil phase;
2) dissolving pasireotide, a protective agent and a suspending agent in water to form an internal water phase;
3) adding a surfactant to water to form an external aqueous phase;
4) mixing the inner aqueous phase with the oil phase to form colostrum, and adding the colostrum into the outer aqueous phase containing the surfactant to form multiple emulsion;
5) and after the organic solvent is volatilized, obtaining the slow release microspheres wrapped with the pasireotide.
The invention also provides a preparation method of the sustained and controlled release pasireotide microspheres, which comprises the following steps:
1) dissolving the microsphere carrier polymer in an organic solvent to form an oil phase;
2) dissolving pasireotide, a protective agent and a suspending agent in water to form an internal water phase;
3) adding a surfactant to water to form an external aqueous phase;
4) mixing the inner aqueous phase with the oil phase to form colostrum, and adding the colostrum into the outer aqueous phase containing the surfactant to form multiple emulsion;
5) and after the organic solvent is volatilized, obtaining the slow release microspheres wrapped with the pasireotide.
In the technical scheme of the invention, the glycolide-lactide copolymer (i.e. PLGA) is a high molecular material formed by block copolymerization of glycolide and lactide in different proportions, has good biocompatibility and degradability, and the final degradation products are carbon dioxide and water.
The glycolide-lactide copolymer disclosed by the invention is glycolide: lactide is 75: 25-25: 75, and the molecular weight of the copolymer is 5000-25000 daltons.
In the technical scheme of the invention, the organic solvent comprises one or a combination of dichloromethane, ethyl acetate and N, N-dimethyl pyrrolidone.
In the technical scheme of the invention, the suspending agent can increase the viscosity of the inner water phase to hinder the migration of the active ingredients, thereby increasing the encapsulation efficiency, slowly releasing the drug-loading rate of the microspheres and improving the stability of the microspheres.
In some embodiments, the glycolide lactide copolymer of the present invention may be 75: 25, or 50: 50, the solvent is dichloromethane and ethyl acetate; the protective agent may be human serum albumin; the suspending agent can be carbomer or one or a combination of sodium alginate; the surfactant may be one or more of polyvinyl alcohol and tween.
The pasireotide microspheres provided by the invention comprise the following components in percentage by weight: 5-12% of pasireotide, 70-90% of PLGA, 1-8% of a suspending agent, 1-10% of a protective agent and 0.5-5% of a surfactant.
In the specific technical scheme of the invention, the formula of the microsphere comprises the following components in percentage by mass,
in the specific technical scheme of the invention, the formula of the microsphere comprises the following components in percentage by mass,
in the specific technical scheme of the invention, the formula of the microsphere comprises the following components in percentage by mass,
in certain embodiments, the pasireotide compositions provided by the present invention consist of (parts by weight): 10% of pasireotide, 80% of PLGA, 5% of a suspending agent, 3% of a protective agent and 2% of a surfactant.
In certain embodiments, the pasireotide compositions provided by the present invention are composed of (parts by weight): 8% of pasireotide, 85% of PLGA, 3% of a suspending agent, 5% of a protective agent and 2% of a surfactant.
The pasireotide sustained-release microspheres are prepared by a multiple emulsion method.
The preparation method comprises the following steps:
(1) dissolving PLGA in an organic solvent to form an oil phase, wherein the organic solvent is one or the combination of dichloromethane, ethyl acetate, N, N-dimethyl pyrrolidone.
(2) Dissolving pasireotide, a protective agent and a suspending agent in water to form an internal water phase.
(3) Mixing the inner aqueous phase with the oil phase to form colostrum, and adding the colostrum to the surfactant-containing outer aqueous phase to form a multiple emulsion.
(4) And after the organic solvent is volatilized, obtaining the slow release microspheres wrapped with the pasireotide.
And (3) performing freeze-drying on the obtained microspheres in an aseptic environment to prepare freeze-dried powder, subpackaging the freeze-dried microspheres into penicillin bottles according to the medicament specification and the medicament loading amount, plugging and capping to obtain the medicine. Before use, the injection water is injected into the penicillin bottle, and the microspheres are uniformly dispersed by shaking.
Advantageous effects
The pasireotide microspheres prepared by the multiple emulsion method have simple preparation process, and can be used for preparing microspheres with uniform particle size, high encapsulation rate and stable quality, and the slow release time is prolonged from 14 days to 28 days.
Detailed Description
The embodiment of the invention discloses pasireotide microspheres and a preparation method thereof. The person skilled in the art can, with the aid of the teachings contained herein, modify the formulation appropriately to achieve this. 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.
Example 1
Preparation of the internal aqueous phase: weighing 100mg of pasireotide and water, carrying out vortex shaking to dissolve, weighing 100mg of mannitol with a prescription amount, adding the mannitol into a pasireotide aqueous solution for dispersion, and carrying out water bath to dissolve to obtain an internal water phase;
preparation of external water phase: weighing a proper amount of purified water, adding 50mg of polyvinyl alcohol, heating and stirring to dissolve, and passing through a gauze to obtain an external water phase solution;
preparation of oil phase: weighing 0.8g of PLGA, and dissolving the PLGA in 30g of dichloromethane to be used as an oil phase;
preparing colostrum: transferring the dissolved oil phase into the internal water phase, and stirring at high speed (2000rpm) for 20 seconds to obtain primary emulsion;
preparing compound milk: adding the primary emulsion into polyvinyl alcohol solution under stirring to obtain multiple emulsion, continuously stirring the multiple emulsion to volatilize the organic solvent, centrifuging, washing and collecting to obtain microspheres, freezing and drying.
Example 2
Preparation of the internal aqueous phase: weighing 120mg of pasireotide and water, carrying out vortex shaking to dissolve, weighing 180mg of hydroxypropyl methylcellulose in a prescription amount, adding the weighed hydroxypropyl methylcellulose into pasireotide aqueous solution for dispersion, and carrying out water bath to dissolve to obtain an internal water phase;
preparation of external water phase: weighing a proper amount of purified water, adding 200mg of Tween, heating and stirring to dissolve, and passing through a gauze to obtain an external water phase solution;
preparation of oil phase: weighing 1.0g of PLGA, and dissolving the PLGA in 30g of ethyl acetate to obtain an oil phase;
preparing colostrum: transferring the dissolved oil phase into the internal water phase, and stirring at high speed (16000rpm) for 30 s to obtain primary emulsion;
preparing compound milk: adding the primary emulsion into 200mg tween solution under stirring to obtain multiple emulsion, continuously stirring the multiple emulsion to volatilize the organic solvent, centrifuging, washing to collect microspheres, freezing, and drying.
Example 3
Preparation of the internal aqueous phase: weighing 120mg of pasireotide and water, carrying out vortex shaking to dissolve, weighing 180mg of mannitol with a prescription amount, adding the solution into pasireotide aqueous solution for dispersion, carrying out water bath to dissolve, adding 100mg of human serum albumin, and adding 100mg of Arabic gum serving as a suspending agent to obtain an inner water phase;
preparation of external water phase: weighing a proper amount of purified water, adding 120mg of polyvinyl alcohol according to the prescription amount, heating and stirring to dissolve, and passing through a gauze to obtain an external water phase solution;
preparation of oil phase: weighing 1.1g of PLGA, and dissolving the PLGA in 30g of dichloromethane to be used as an oil phase;
preparing colostrum: transferring the dissolved oil phase into the internal water phase, and stirring at high speed (16000rpm) for 30 s to obtain primary emulsion;
preparing compound milk: adding the primary emulsion into polyvinyl alcohol solution under stirring to obtain multiple emulsion, continuously stirring the multiple emulsion to volatilize the organic solvent, centrifuging, washing and collecting to obtain microspheres, freezing and drying.
Example 4
Preparation of the internal aqueous phase: weighing 120mg of pasireotide and water, carrying out vortex shaking to dissolve, weighing 180mg of mannitol with a prescription amount, adding the solution into pasireotide aqueous solution for dispersion, carrying out water bath to dissolve, and adding 100mg of human serum albumin to obtain an internal water phase;
preparation of external water phase: weighing a proper amount of purified water, adding 120mg of polyvinyl alcohol according to the prescription amount, heating and stirring to dissolve, and passing through a gauze to obtain an external water phase solution;
preparation of oil phase: weighing 1.1g of PLGA, and dissolving the PLGA in 30g of dichloromethane to be used as an oil phase;
preparing colostrum: transferring the dissolved oil phase into the internal water phase, and stirring at high speed (16000rpm) for 30 s to obtain primary emulsion;
preparing compound milk: adding the primary emulsion into polyvinyl alcohol solution under stirring to obtain multiple emulsion, continuously stirring the multiple emulsion to volatilize the organic solvent, centrifuging, washing and collecting to obtain microspheres, freezing and drying.
Example 5
Preparation of the internal aqueous phase: weighing 120mg of pasireotide and water, carrying out vortex shaking to dissolve, weighing 180mg of mannitol with a prescription amount, adding the solution into pasireotide aqueous solution for dispersion, carrying out water bath to dissolve, adding 100mg of human serum albumin, and adding 20mg of Arabic gum serving as a suspending agent to obtain an inner water phase;
preparation of external water phase: weighing a proper amount of purified water, adding 120mg of polyvinyl alcohol according to the prescription amount, heating and stirring to dissolve, and passing through a gauze to obtain an external water phase solution;
preparation of oil phase: weighing 1.1g of PLGA, and dissolving the PLGA in 30g of dichloromethane to be used as an oil phase;
preparing colostrum: transferring the dissolved oil phase into the internal water phase, and stirring at high speed (16000rpm) for 30 s to obtain primary emulsion;
preparing compound milk: adding the primary emulsion into polyvinyl alcohol solution under stirring to obtain multiple emulsion, continuously stirring the multiple emulsion to volatilize the organic solvent, centrifuging, washing and collecting to obtain microspheres, freezing and drying.
Example 6
Preparation of the internal aqueous phase: weighing 120mg of pasireotide and water, carrying out vortex shaking to dissolve, weighing 180mg of mannitol with a prescription amount, adding the solution into pasireotide aqueous solution for dispersion, carrying out water bath to dissolve, adding 100mg of human serum albumin, and simultaneously adding 100mg of tragacanth serving as a suspending agent to obtain an inner water phase;
preparation of external water phase: weighing a proper amount of purified water, adding 120mg of polyvinyl alcohol according to the prescription amount, heating and stirring to dissolve, and passing through a gauze to obtain an external water phase solution;
preparation of oil phase: weighing 1.1g of PLGA, and dissolving the PLGA in 30g of dichloromethane to be used as an oil phase;
preparing colostrum: transferring the dissolved oil phase into the internal water phase, and stirring at high speed (16000rpm) for 30 s to obtain primary emulsion;
preparing compound milk: adding the primary emulsion into polyvinyl alcohol solution under stirring to obtain multiple emulsion, continuously stirring the multiple emulsion to volatilize the organic solvent, centrifuging, washing and collecting to obtain microspheres, freezing and drying.
Example 7 determination of the in vitro Release of Slow-Release microspheres of pasireotide
The pasireotide sustained release microsphere preparation prepared in the above example is subjected to in vitro release determination, and the determination method comprises the following steps: 20mg of microspheres containing medicine is precisely weighed and placed in a 10ml test tube with a plug, 10ml of phosphate buffer solution with the pH value of 7.4 is taken as a release medium, the test tube is placed in a constant-temperature water bath shaking table, and the in-vitro release degree is measured under the conditions that the oscillation speed is 100rpm and the temperature is 37 +/-0.5 ℃. 0.3ml of release medium was taken at 1d,2d,4d,7d,14d,21d,28d, respectively, for HPLC determination of the pasireotide content and was supplemented with fresh release medium.
Cumulative drug release for different examples
| Time of day | 1d | 2d | 4d | 7d | 14d | 21d | 28d |
| Example 1 | 34.6％ | 48.7％ | 65.5％ | 85.4％ | 98.7％ | 98.8％ | 98.5％ |
| Example 2 | 36.4％ | 50.9％ | 67.8％ | 84.7％ | 97.5％ | 97.8％ | 97.8％ |
| Example 3 | 27.6％ | 32.7％ | 52.5％ | 65.4％ | 80.4％ | 90.3％ | 98.7％ |
| Example 4 | 35.8％ | 49.8％ | 66.5％ | 85.1％ | 98.4％ | 98.3％ | 98.2％ |
| Examples5 | 26.9％ | 32.5％ | 52.2％ | 65.1％ | 80.2％ | 90.1％ | 97.7％ |
| Example 6 | 27.3％ | 32.8％ | 52.6％ | 65.2％ | 80.7％ | 91.3％ | 98.5％ |
When the microspheres prepared by different formulas are analyzed in terms of release degree, the inventor finds that the microspheres prepared in examples 1 and 2 can achieve the effect of about 14 cumulative release, the time of cumulative release of the medicine is greatly prolonged after the suspending agent is added, the release time of examples 3,5 and 6 can reach 28 days, and the comparison between example 3 and example 4 shows that the prolonging of the release time is caused by the addition of the suspending agent, which indicates that the addition of the suspending agent in the examples has a certain effect of hindering the migration of active ingredients, so that the release time is longer.
Example 8 Material Properties and chemical stability results
Drug loading, encapsulation and particle size measurements for the different examples
Different examples have higher drug loading, higher encapsulation efficiency and no obvious difference in particle size compared with 1 and 2 in example 3, and the fact that the suspending agent is added in the examples has a certain effect of hindering the migration of the active ingredients, so that the encapsulation efficiency is increased and the drug loading of the sustained-release microspheres is delayed.
The samples prepared in the examples are placed for 1, 3 and 6 months under different conditions (30 ℃/65 percent and 25 ℃/60 percent), and the changes of the particle size distribution range, the content, the impurity content and the release degree of the sample microspheres are measured.
Stability assay results for different examples
In conclusion, it can be seen that examples 3,5 and 6 have higher content, less impurities, higher encapsulation efficiency and no obvious change in particle size compared with examples 1, 2 and 4 at different times, and the suspending agent is added in the formula to improve the stability of the microspheres.
The pasireotide microspheres prepared by the multiple emulsion method have simple preparation process, and can be used for preparing microspheres with uniform particle size, high encapsulation rate and stable quality.
Claims (7)
1. A microsphere of pasireotide with sustained and controlled release, which is prepared from pasireotide as an active ingredient, a microsphere carrier polymer, a protective agent, a surfactant and a suspending agent;
the microsphere carrier polymer is selected from glycolide-lactide copolymer;
the suspending agent is selected from one or the combination of any two of tragacanth gum and acacia gum;
the pasireotide sustained-release microsphere preparation is prepared by the following steps:
1) dissolving the microsphere carrier polymer in an organic solvent to form an oil phase;
2) dissolving pasireotide, a protective agent and a suspending agent in water to form an internal water phase;
3) adding a surfactant to water to form an external aqueous phase;
4) mixing the inner aqueous phase with the oil phase to form colostrum, and adding the colostrum into the outer aqueous phase containing the surfactant to form multiple emulsion;
5) after the organic solvent is volatilized, obtaining the slow release microspheres wrapped with pasireotide;
the formula of the microsphere comprises the following components in percentage by mass,
the protective agent is one or more selected from mannitol, trehalose, hypromellose, sodium carboxymethylcellulose, polyvinylpyrrolidone, and human serum albumin.
2. The sustained and controlled release pasireotide microspheres of claim 1, wherein the protective agent is a combination of human serum albumin and any one of mannitol, trehalose, hypromellose, sodium carboxymethylcellulose, and polyvinylpyrrolidone.
3. The sustained or controlled release pasireotide microspheres according to any one of claims 1-2, wherein the surfactant is one or a combination of any two or more selected from the group consisting of polyvinyl alcohol, poloxamer, sodium oleate, sodium stearate, tween and span.
4. The microspheres of sustained-release pasireotide according to claim 1, which are formulated by mass,
5. the microspheres of sustained-release pasireotide according to claim 1, which are formulated by mass,
6. the microspheres of sustained-release pasireotide according to claim 1, which are formulated by mass,
7. the method for preparing the sustained and controlled release pasireotide microspheres according to any one of claims 1 to 5, which is obtained by the following steps:
1) dissolving the microsphere carrier polymer in an organic solvent to form an oil phase;
2) dissolving pasireotide, a protective agent and a suspending agent in water to form an internal water phase;
3) adding a surfactant to water to form an external aqueous phase;
4) mixing the inner aqueous phase with the oil phase to form colostrum, and adding the colostrum into the outer aqueous phase containing the surfactant to form multiple emulsion;
5) and after the organic solvent is volatilized, obtaining the microspheres of the sustained and controlled release pasireotide.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810996995.XA CN110870853B (en) | 2018-08-29 | 2018-08-29 | Slow-release pasireotide microspheres and preparation method thereof |
| PCT/CN2018/114524 WO2020042364A1 (en) | 2018-08-29 | 2018-11-08 | Slow release pasireotide microsphere and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810996995.XA CN110870853B (en) | 2018-08-29 | 2018-08-29 | Slow-release pasireotide microspheres and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110870853A CN110870853A (en) | 2020-03-10 |
| CN110870853B true CN110870853B (en) | 2020-12-11 |
Family
ID=69644848
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810996995.XA Active CN110870853B (en) | 2018-08-29 | 2018-08-29 | Slow-release pasireotide microspheres and preparation method thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN110870853B (en) |
| WO (1) | WO2020042364A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1878541A (en) * | 2003-11-14 | 2006-12-13 | 诺瓦提斯公司 | Microparticles comprising somatostatin analogues |
| CN101677965A (en) * | 2007-05-24 | 2010-03-24 | 诺瓦提斯公司 | An extended-release composition comprising a somatostatin derivative in microparticles |
-
2018
- 2018-08-29 CN CN201810996995.XA patent/CN110870853B/en active Active
- 2018-11-08 WO PCT/CN2018/114524 patent/WO2020042364A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1878541A (en) * | 2003-11-14 | 2006-12-13 | 诺瓦提斯公司 | Microparticles comprising somatostatin analogues |
| CN101677965A (en) * | 2007-05-24 | 2010-03-24 | 诺瓦提斯公司 | An extended-release composition comprising a somatostatin derivative in microparticles |
Non-Patent Citations (1)
| Title |
|---|
| 微球制剂质量控制研究进展;郭宁子，等;《中国新药杂志》;20151231;第24卷(第18期);2115-2121 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2020042364A1 (en) | 2020-03-05 |
| CN110870853A (en) | 2020-03-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| FI101677B (en) | Process for preparing an anhydrous transdermal composition | |
| CN1138528C (en) | Peptide/protein suspension formulations | |
| JP5933025B2 (en) | Microspheres for controlled or sustained release of medication | |
| KR102218655B1 (en) | Preparation of peptide loaded plga microspheres with controlled release characteristics | |
| EP2379055B1 (en) | Method of making sustained release microparticles | |
| EP0302582A1 (en) | Drug delivery system and method of making the same | |
| CN104382860A (en) | Liraglutide sustained-release microsphere preparation and preparation method thereof | |
| CN116270486A (en) | Water-insoluble or slightly-soluble medicine slow-release composition and preparation method thereof | |
| Wu et al. | Liraglutide-loaded poly (lactic-co-glycolic acid) microspheres: Preparation and in vivo evaluation | |
| KR20080034838A (en) | Bone morphogenetic protein formulations | |
| Rahmani et al. | Dual release carriers for cochlear delivery | |
| AU2008259411B2 (en) | Slow release pharmaceutical composition made of microparticles | |
| KR20100017904A (en) | An extended-release composition comprising a somatostatin derivative in microparticles | |
| EP3949951A1 (en) | Sustained-release microparticles containing deslorelin, and preparation method therefor | |
| US8206621B2 (en) | Use of ethanol as plasticizer for preparing subcutaneous implants containing thermolabile active principles dispersed in a PLGA matrix | |
| CN110870853B (en) | Slow-release pasireotide microspheres and preparation method thereof | |
| CN109069416A (en) | It is sustained buprenorphine microballoon (SRBM) and its application method | |
| CN114569564B (en) | Goserelin sustained-release microsphere composition | |
| CN108272756B (en) | Amoxicillin soluble powder and preparation method thereof | |
| KR20100042768A (en) | A biodegradable microsphere and production method thereof | |
| JP2017511371A (en) | Exenatide-containing composition and method for producing the same | |
| US20180221451A1 (en) | Long acting liraglutide compositions | |
| JP6151848B2 (en) | Goserelin sustained-release microsphere pharmaceutical composition | |
| JPH05238930A (en) | Long-acting medicine | |
| EP4230194A1 (en) | Composition for sustained-release injection comprising deslorelin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |