CN112220765A - Oral preparation containing simvastatin and preparation method thereof - Google Patents

Oral preparation containing simvastatin and preparation method thereof Download PDF

Info

Publication number
CN112220765A
CN112220765A CN202011202294.8A CN202011202294A CN112220765A CN 112220765 A CN112220765 A CN 112220765A CN 202011202294 A CN202011202294 A CN 202011202294A CN 112220765 A CN112220765 A CN 112220765A
Authority
CN
China
Prior art keywords
simvastatin
preparation
solution
hydroxypropyl
beta
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.)
Pending
Application number
CN202011202294.8A
Other languages
Chinese (zh)
Inventor
胡健
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nanjing Zhizhong Biotechnology Co ltd
Original Assignee
Nanjing Zhizhong Biotechnology Co ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Nanjing Zhizhong Biotechnology Co ltd filed Critical Nanjing Zhizhong Biotechnology Co ltd
Priority to CN202011202294.8A priority Critical patent/CN112220765A/en
Publication of CN112220765A publication Critical patent/CN112220765A/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention discloses an oral preparation containing simvastatin and a preparation method thereof, wherein the oral preparation is prepared by the following steps: simvastatin is included by hydroxypropyl-beta-cyclodextrin (HP-beta-CD), and the formed inclusion compound is very easy to dissolve in water, so that the stability of the medicine is greatly improved, the release of the medicine in vivo is promoted, the absorption is increased, the bioavailability is improved, and the difference between the individual medicines is reduced. The simvastatin oral preparation prepared by the invention overcomes the problems that the raw materials are difficult to dissolve in water, and the common tablet has low dissolution rate and low bioavailability, and the prepared oral preparation is quick to disintegrate, stable in quality and good in-vivo absorption, improves the product quality and ensures the stability of the product in the long-term storage process.

Description

Oral preparation containing simvastatin and preparation method thereof
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to an oral preparation containing simvastatin and a preparation method thereof.
Background
Statin drugs are the most popular blood lipid regulating drugs in the world at present, can be used for treating primary hypercholesterolemia and the like, and currently, simvastatin has become one of the first-choice drugs for treating hyperlipidemia. Simvastatin was developed by the American merck corporation, and its trade name is Shu-Jiang (specifications are many, 5mg, 10mg, 20mg, 40 mg), and there are many manufacturers at home and abroad. Because simvastatin raw material is easy to degrade, the prescription of the commercial product mostly contains components such as butyl hydroxy anisole (BHA antioxidant), ascorbic acid (antioxidant), citric acid monohydrate and the like. Wherein the ascorbic acid is unstable and is easy to oxidize and deteriorate after being exposed to light and damp heat to generate yellow substances; the citric acid has strong hygroscopicity, and can stimulate the gastrointestinal tract of a human body to secrete excessive gastric juice after long-term use, so that the Wenchang becomes a burden, and the discomfort of a patient is caused; butylated Hydroxyanisole (BHA) has certain carcinogenicity, and experiments show that the substances are easy to introduce new impurities, so that the related substances are increased. Therefore, if the acidic protective agent and the antioxidant in the product can be removed, the safety of the medicine is greatly improved.
In the prior art, patent CN103191072B discloses a simvastatin tablet, which is prepared by directly tabletting a liposome clathrate and pharmaceutically acceptable auxiliary materials, lecithin is used in the actual production process, and is very easily oxidized, so that the stability of the medicine is affected, and meanwhile, great difficulty is brought to equipment cleaning, and mass production is difficult to realize. Patent CN105106198B discloses a highly stable simvastatin tablet and a preparation method thereof, wherein an antioxidant butylated hydroxyanisole is added into a prescription, and a wet granulation low-temperature drying mode is adopted to obtain the highly stable simvastatin tablet, but the butylated hydroxyanisole has certain carcinogenicity, wet granulation is adopted, low temperature and high temperature are combined, the process operation is complex, the requirement on production equipment is high, and great inconvenience is brought to production. In addition, simvastatin is very low in solubility in water and almost insoluble, and only 5% of drugs enter human body circulation as active ingredients in the oral route, so how to improve bioavailability on the premise of ensuring drug stability is a problem which needs to be solved urgently at present.
The hydroxypropyl-beta-cyclodextrin is amorphous, is very easy to dissolve in water, has wide application in the aspect of pharmaceutical preparation, is mainly applied to the solubilization of insoluble drugs and the improvement of the stability of the drugs, can promote the release of the drugs in vivo, increase the absorption, improve the bioavailability and cover up unpleasant odor.
In view of the above problems, the simvastatin is innovatively included by hydroxypropyl-beta-cyclodextrin (HP-beta-CD), and is very soluble in water after inclusion, so that the stability of the simvastatin is greatly improved, the release of the simvastatin in vivo is promoted, the absorption is increased, the bioavailability is improved, and the difference between the individual medicines is reduced.
Disclosure of Invention
The invention provides an oral preparation containing simvastatin and a preparation method thereof. The process is simple and feasible, ensures the stability of the medicine, promotes the release of the medicine in vivo, increases the absorption and improves the bioavailability. The purpose of the invention is realized by the following steps:
the simvastatin-containing oral preparation and the preparation method thereof are characterized in that the simvastatin-containing oral preparation comprises simvastatin, hydroxypropyl-beta-cyclodextrin, a filling agent, a disintegrating agent, a binding agent and a lubricating agent.
The simvastatin-containing oral preparation and the preparation method thereof are characterized in that the filler is one of mannitol, microcrystalline cellulose, corn starch and porous starch.
The simvastatin-containing oral preparation and the preparation method thereof are characterized in that the disintegrating agent is one of microcrystalline cellulose, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, hydroxypropyl starch and the like.
The simvastatin-containing oral preparation and the preparation method thereof are characterized in that the lubricant is one of talcum powder and magnesium stearate.
The simvastatin-containing oral preparation and the preparation method thereof are characterized in that the adhesive is 2% of polyvinylpyrrolidone aqueous solution.
1. The simvastatin-containing oral preparation is characterized by comprising 1 part of simvastatin, 1-3 parts of hydroxypropyl-beta-cyclodextrin, 30-70 parts of an adhesive, 10-50 parts of a filling agent, 2-10 parts of a disintegrating agent and 0.05-3 parts of a lubricating agent.
The oral preparation containing simvastatin and the preparation method thereof are characterized in that the preparation method of the inclusion compound comprises the following steps:
(1) dissolving hydroxypropyl-beta-cyclodextrin in water to prepare a saturated solution to obtain a solution A;
(2) and dissolving simvastatin in absolute ethyl alcohol to obtain a solution B.
Slowly dripping the solution B into the solution A under magnetic stirring, continuously stirring at room temperature for 2-4h after all the solution B is added, standing for 12h, filtering, drying under reduced pressure or freeze drying to obtain the clathrate compound.
The oral preparation containing simvastatin is characterized by comprising the following steps: forming an inclusion compound by using hydroxypropyl-beta-cyclodextrin and simvastatin, uniformly mixing the obtained inclusion compound with a filling agent and a disintegrating agent, adding an adhesive to prepare a soft material, sieving and granulating, drying, adding a lubricating agent, and tabletting to obtain the tablet.
The simvastatin raw material is difficult to dissolve in water, and the problems of low dissolution rate and low bioavailability exist in common tablets.
Detailed Description
The following examples are intended to further illustrate the invention and are not to be construed as limiting the invention in any way.
Example 1
This example provides an oral formulation containing simvastatin and a method for preparing the same, wherein the oral formulation is prepared by the following steps:
name (R) Dosage per gram
Simvastatin 10
Hydroxypropyl-beta-cyclodextrin 50
2% of polyvinylpyrrolidone 300
Microcrystalline cellulose 200
Cross-linked polyvidone 50
Magnesium stearate 2
The preparation method comprises the following steps:
dissolving hydroxypropyl-beta-cyclodextrin in water to prepare a saturated solution to obtain a solution A; and dissolving simvastatin in absolute ethyl alcohol to obtain a solution B. Slowly dripping the solution B into the solution A under magnetic stirring, continuously stirring at room temperature for 2-4h after all the solution B is added, standing for 12h, filtering, drying under reduced pressure or freeze drying to obtain the clathrate compound.
Mixing the clathrate with microcrystalline cellulose and crospovidone, adding 2% polyvinylpyrrolidone water solution to obtain soft mass, sieving, granulating, drying, adding magnesium stearate, and tabletting.
Example 2
This example provides an oral formulation containing simvastatin and a method for preparing the same, wherein the oral formulation is prepared by the following steps:
name (R) Dosage per gram
Simvastatin 10
Hydroxypropyl-beta-cyclodextrin 30
2% of polyvinylpyrrolidone 500
Porous starch 100
Croscarmellose sodium 30
Talcum powder 8
The preparation method comprises the following steps:
dissolving hydroxypropyl-beta-cyclodextrin in water to prepare a saturated solution to obtain a solution A; and dissolving simvastatin in absolute ethyl alcohol to obtain a solution B. Slowly dripping the solution B into the solution A under magnetic stirring, continuously stirring at room temperature for 2-4h after all the solution B is added, standing for 12h, filtering, drying under reduced pressure or freeze drying to obtain the clathrate compound.
Mixing the obtained clathrate with porous starch and croscarmellose sodium, adding 2% polyvinylpyrrolidone water solution to obtain soft material, sieving, granulating, drying, adding pulvis Talci, and tabletting.
Example 3
This example provides an oral formulation containing simvastatin and a method for preparing the same, wherein the oral formulation is prepared by the following steps:
name (R) Dosage per gram
Simvastatin 10
Hydroxypropyl-beta-cyclodextrin 60
2% of polyvinylpyrrolidone 600
Mannitol 300
Hydroxypropyl starch 60
Talcum powder 15
The preparation method comprises the following steps:
dissolving hydroxypropyl-beta-cyclodextrin in water to prepare a saturated solution to obtain a solution A; and dissolving simvastatin in absolute ethyl alcohol to obtain a solution B. Slowly dripping the solution B into the solution A under magnetic stirring, continuously stirring at room temperature for 2-4h after all the solution B is added, standing for 12h, filtering, drying under reduced pressure or freeze drying to obtain the clathrate compound.
Mixing the obtained clathrate with mannitol and hydroxypropyl starch, adding 2% polyvinylpyrrolidone water solution to obtain soft material, sieving, granulating, drying, adding pulvis Talci, and tabletting.
COMPARATIVE EXAMPLE 1 (refer to patent CN110051636A)
Name (R) Dosage per gram
Simvastatin 10
Microcrystalline cellulose 50
Lactose 30.15
Pregelatinized starch 5.75
Magnesium stearate 2
Tert-butyl-4-hydroxyanisole (BHA) 0.1
Low-substituted hydroxypropyl cellulose 2
The preparation method comprises the following steps:
mixing simvastatin and lactose in equal amount, atomizing, adding an isopropanol solution of BHA, adding the rest of lactose, mixing, drying with hot air, and pulverizing the rest; adding pregelatinized starch, mixing, atomizing, adding isopropanol, granulating by wet method, drying with hot air, and grading; adding low-substituted hydroxypropyl cellulose, microcrystalline cellulose and magnesium stearate, mixing, and tabletting. COMPARATIVE EXAMPLE 2 (refer to patent 103191072B)
Name (R) Dosage per gram
Simvastatin 10
Lecithin 10
Hydroxypropyl-beta-cyclodextrin 120
Anhydrous ethanol 1000
Lactose 400
Cross-linked polyvidone 15
Magnesium stearate 6
The preparation method comprises the following steps:
dissolving simvastatin, hydroxypropyl-beta-cyclodextrin and lecithin in absolute ethyl alcohol, stirring, decompressing and drying, and removing ethyl alcohol to obtain a simvastatin liposome clathrate compound; adding lactose, crospovidone and magnesium stearate, mixing, and directly tabletting.
Verification examples
1. Release test
Taking the product, according to the dissolution determination method of Chinese pharmacopoeia (appendix XD first method), taking 900ml of 0.01mol/L sodium dihydrogen phosphate buffer solution containing 0.5% sodium dodecyl sulfate as dissolution medium, rotating at 50 r/min, operating according to the method, taking 10ml of solution after 30min, filtering, and taking the subsequent filtrate as the test solution.
TABLE 1 Release measurement results
Figure RE-GDA0002824994990000051
2. Stability test
Table 2 summary of stability survey results
Figure RE-GDA0002824994990000061
3. Pharmacokinetic testing
Examples 1-3 and comparative examples 1-2 pharmacokinetic experiments were carried out on 6 male SD rats per group weighing 190-@) Comparing, further calculating for ease and decline@The ratio of Cmax to AUC of (c).
TABLE 3 pharmacokinetic determination results
Examples Cmax ratio AUC (0-t) ratio
Example 1 9.1 9.1
Example 2 9.8 9.6
Example 3 10.2 10.7
Comparative example 1 1.2 1.8
Comparative example 2 3.1 3.4
The results show that the release of the inventive examples 1-3 within 30min of in vitro dissolution is complete and is obviously superior to that of the comparative examples 1-2; stability tests show that the substances and contents in examples 1-3 of the invention have no obvious change in the acceleration process, while the substances in comparative examples 1-2 have reduced contents and increased contents in the acceleration process, and the stability is not as good as that of the invention; pharmacokinetic studies show that the bioavailability of the drug can be significantly improved in examples 1-3 of the present invention, and the effect is significantly inferior to that of comparative examples 1-2.
According to the data, simvastatin is included by hydroxypropyl-beta-cyclodextrin (HP-beta-CD), so that the formed inclusion compound is very soluble in water, the stability of the medicine is greatly improved, and the problems that the raw material is difficult to dissolve in water, and the common tablet is low in dissolution rate and low in bioavailability are solved. The simvastatin oral preparation prepared by the invention is quick in disintegration, stable in quality and good in vivo absorption, improves the product quality and ensures the stability of the product in the long-term storage process.

Claims (8)

1. The simvastatin-containing oral preparation is characterized by comprising simvastatin, hydroxypropyl-beta-cyclodextrin, a filling agent, a disintegrating agent, a binding agent and a lubricating agent.
2. The oral formulation comprising simvastatin according to claim 1, wherein the filler is one of mannitol, microcrystalline cellulose, corn starch, and porous starch.
3. The oral preparation and the preparation method thereof according to claim 1, wherein the disintegrant is one of carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, hydroxypropyl starch, and the like.
4. The oral formulation containing simvastatin according to claim 1, wherein the lubricant is one of talc and magnesium stearate.
5. The oral formulation comprising simvastatin according to claim 1, wherein the binder is a 2% aqueous solution of polyvinylpyrrolidone.
6. The oral preparation containing simvastatin according to claim 1, wherein the simvastatin comprises 1 part of simvastatin, 1-6 parts of hydroxypropyl-beta-cyclodextrin, 30-70 parts of a binder, 10-50 parts of a filler, 2-10 parts of a disintegrant and 0.05-3 parts of a lubricant.
7. The oral preparation containing simvastatin according to claim 1, wherein the preparation method of the clathrate comprises the following steps: (1) dissolving hydroxypropyl-beta-cyclodextrin in water to prepare a saturated solution to obtain a solution A; (2) dissolving simvastatin in absolute ethyl alcohol to obtain a solution B; slowly dripping the solution B into the solution A under magnetic stirring, continuously stirring at room temperature for 2-4h after all the solution B is added, standing for 12h, filtering, drying under reduced pressure or freeze drying to obtain the clathrate compound.
8. The oral formulation comprising simvastatin according to claim 1, wherein the preparation method comprises: forming an inclusion compound by using hydroxypropyl-beta-cyclodextrin and simvastatin, uniformly mixing the obtained inclusion compound with a filling agent and a disintegrating agent, adding an adhesive to prepare a soft material, sieving and granulating, drying, adding a lubricating agent, and tabletting to obtain the tablet.
CN202011202294.8A 2020-11-02 2020-11-02 Oral preparation containing simvastatin and preparation method thereof Pending CN112220765A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202011202294.8A CN112220765A (en) 2020-11-02 2020-11-02 Oral preparation containing simvastatin and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202011202294.8A CN112220765A (en) 2020-11-02 2020-11-02 Oral preparation containing simvastatin and preparation method thereof

Publications (1)

Publication Number Publication Date
CN112220765A true CN112220765A (en) 2021-01-15

Family

ID=74121880

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202011202294.8A Pending CN112220765A (en) 2020-11-02 2020-11-02 Oral preparation containing simvastatin and preparation method thereof

Country Status (1)

Country Link
CN (1) CN112220765A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113244410A (en) * 2021-05-28 2021-08-13 哈尔滨工业大学 Preparation method of clathrate compound based on porous starch and used for increasing cannabidiol water solubility

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SEOUNG WOOK JUN等: "Preparation and characterization of simvastatin/hydroxypropyl-b-cyclodextrin inclusion complex using supercritical antisolvent (SAS) process", 《EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113244410A (en) * 2021-05-28 2021-08-13 哈尔滨工业大学 Preparation method of clathrate compound based on porous starch and used for increasing cannabidiol water solubility

Similar Documents

Publication Publication Date Title
RU2624236C2 (en) Pharmaceutical composition containing tetrahydropholic acid
CN102946869B (en) The quick releasing formulation of gamma-hydroxybutyric acid and dosage form
US11617751B2 (en) Pharmaceutical composition containing a tetrahydrofolic acid
JP6151727B2 (en) Ulipristal acetate ester tablets
EP1397133B1 (en) Rapid onset formulation
JP2000511170A (en) Pharmaceutical composition
NZ532491A (en) Oral pharmaceutical products containing 17beta-estradiol-3-lower alkanoate, method of administering the same and process of preparation
EP2777696A1 (en) Preparation of stable pharmaceutical dosage forms
AU2004275469A1 (en) HRT formulations
US20060240101A1 (en) Orally disintegrating pharmaceutical tablet formulations of olanzapine
KR20070045247A (en) Pharmaceutical composition comprising drospirenone and ethynylestradiol
US20090088424A1 (en) Methods and compositions for controlling the bioavailability of poorly soluble drugs
CN112220765A (en) Oral preparation containing simvastatin and preparation method thereof
KR20160026714A (en) Choline alfoscerate-containing tablet and process for preparing the same
KR20190062260A (en) Dutasteride-embeded solubilized nanoporous complexes, pharmaceutical compositions comprising the same, and methods for preparing the same
US20180344648A1 (en) Clobazam tablet formulation and process for its preparation
CN105596304B (en) Novel formulation of cilostazol being a quinolinone derivative for alleviating the symptoms of intermittent claudication in patients with peripheral vascular disease
CN114588124B (en) Delayed release pharmaceutical composition
CN115463104A (en) EBTP-containing tablet and preparation method thereof
AU2013202756B2 (en) Pharmaceutical composition containing a tetrahydrofolic acid
CN112516097A (en) Levamlodipine besylate composition
WO2017163268A2 (en) A sustained release pharmaceutical dosage form of divalproex

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
RJ01 Rejection of invention patent application after publication

Application publication date: 20210115

RJ01 Rejection of invention patent application after publication