CN117338724A - Phloroglucinol release-regulating preparation and preparation method thereof - Google Patents
Phloroglucinol release-regulating preparation and preparation method thereof Download PDFInfo
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- CN117338724A CN117338724A CN202210752307.1A CN202210752307A CN117338724A CN 117338724 A CN117338724 A CN 117338724A CN 202210752307 A CN202210752307 A CN 202210752307A CN 117338724 A CN117338724 A CN 117338724A
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- phloroglucinol
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- QCDYQQDYXPDABM-UHFFFAOYSA-N phloroglucinol Chemical compound OC1=CC(O)=CC(O)=C1 QCDYQQDYXPDABM-UHFFFAOYSA-N 0.000 title claims abstract description 76
- JPYHHZQJCSQRJY-UHFFFAOYSA-N Phloroglucinol Natural products CCC=CCC=CCC=CCC=CCCCCC(=O)C1=C(O)C=C(O)C=C1O JPYHHZQJCSQRJY-UHFFFAOYSA-N 0.000 title claims abstract description 74
- 229960001553 phloroglucinol Drugs 0.000 title claims abstract description 74
- 238000002360 preparation method Methods 0.000 title abstract description 40
- 239000000463 material Substances 0.000 claims abstract description 51
- 239000000314 lubricant Substances 0.000 claims abstract description 16
- 239000000945 filler Substances 0.000 claims abstract description 12
- 239000000853 adhesive Substances 0.000 claims abstract description 9
- 230000001070 adhesive effect Effects 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 3
- 239000008187 granular material Substances 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 19
- 238000009472 formulation Methods 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 14
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 12
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 12
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 10
- 229940079593 drug Drugs 0.000 claims description 9
- 229920000609 methyl cellulose Polymers 0.000 claims description 8
- 239000001923 methylcellulose Substances 0.000 claims description 8
- 235000010981 methylcellulose Nutrition 0.000 claims description 8
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 5
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 5
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 5
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 5
- 229960003943 hypromellose Drugs 0.000 claims description 5
- 235000019359 magnesium stearate Nutrition 0.000 claims description 5
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 4
- 238000007908 dry granulation Methods 0.000 claims description 4
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 4
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 4
- 230000002048 spasmolytic effect Effects 0.000 claims description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 3
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 3
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000000812 cholinergic antagonist Substances 0.000 claims description 2
- 239000008119 colloidal silica Substances 0.000 claims description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 239000011159 matrix material Substances 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 2
- 229940069328 povidone Drugs 0.000 claims description 2
- 229910021487 silica fume Inorganic materials 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 208000002193 Pain Diseases 0.000 abstract description 18
- 230000000694 effects Effects 0.000 abstract description 16
- 239000002245 particle Substances 0.000 abstract 2
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 239000011812 mixed powder Substances 0.000 abstract 1
- 239000003826 tablet Substances 0.000 description 10
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 7
- 238000004090 dissolution Methods 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 238000003825 pressing Methods 0.000 description 5
- 238000007873 sieving Methods 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- 230000001154 acute effect Effects 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 230000007547 defect Effects 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 210000002460 smooth muscle Anatomy 0.000 description 4
- 230000000202 analgesic effect Effects 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000003405 delayed action preparation Substances 0.000 description 3
- 208000004998 Abdominal Pain Diseases 0.000 description 2
- 230000001078 anti-cholinergic effect Effects 0.000 description 2
- 230000002921 anti-spasmodic effect Effects 0.000 description 2
- MPYXTIHPALVENR-UHFFFAOYSA-N benzene-1,3,5-triol;dihydrate Chemical compound O.O.OC1=CC(O)=CC(O)=C1 MPYXTIHPALVENR-UHFFFAOYSA-N 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000006191 orally-disintegrating tablet Substances 0.000 description 2
- 230000008058 pain sensation Effects 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000007939 sustained release tablet Substances 0.000 description 2
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010017999 Gastrointestinal pain Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 208000008238 Muscle Spasticity Diseases 0.000 description 1
- 206010038419 Renal colic Diseases 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000009084 cardiovascular function Effects 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Rheumatology (AREA)
- Neurology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a phloroglucinol release-regulating preparation and a preparation method thereof. The modified release preparation comprises phloroglucinol with effective treatment amount, and pharmaceutically acceptable framework materials, adhesives, fillers, lubricants and the like. The preparation method of the modified release preparation comprises the following steps: a. uniformly mixing the prescription amount of framework material, adhesive and filler; b. uniformly mixing the mixed powder obtained in the step a with the raw materials, and preparing dry particles by a dry-method granulator; c. and (3) uniformly mixing the dry particles prepared in the step (b) with a lubricant. The phloroglucinol release-regulating preparation can realize rapid pain relieving and high-efficiency cramping relieving effects, can clinically maintain the long-time pain relieving effect, and has stable product quality; simple process steps, low cost, convenient administration for patients and suitability for commercial production and popularization.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and relates to a phloroglucinol modified release preparation and a preparation method thereof.
Background
The modified release preparation is a general preparation for adjusting the release rate, the release position or the release time of the medicine by technical means compared with the common preparation. The release-regulating preparation can be classified into sustained release, controlled release, delayed release preparation and the like. Compared with common preparations, the sustained-release and controlled-release preparation has lasting drug treatment effect, reduced toxic and side effects, reduced administration times and improved medication compliance of patients. The delayed release preparation can delay release of the drug, thereby playing the roles of enteric solubility, colon positioning or pulse release.
The phloroglucinol can directly act on smooth muscle of gastrointestinal tract and genitourinary tract, relieve smooth muscle spasm, and is suitable for acute spasmodic pain, acute spasmodic urethra, bladder, renal colic, gynecological spasmodic pain, etc. caused by digestive system and biliary tract dysfunction. Compared with other smooth muscle spasmolytics, the phloroglucinol has the characteristics of no anticholinergic effect, and can relieve smooth muscle spasticity without generating a series of anticholinergic side effects. The phloroglucinol can not cause symptoms such as hypotension, heart rate acceleration, arrhythmia and the like, has no influence on cardiovascular functions, and has wide application in the clinical spasmolytic and analgesic fields.
At present, the clinical common dosage forms of phloroglucinol are injection and orally disintegrating tablets, and the injection has the defects of short administration frequency, harsh use conditions and the like, so that the patient compliance is poor; the phloroglucinol orally disintegrating tablet has the advantages of rapid disintegration and dissolution and good taste, but has short biological half-life, more administration times (2-3 times per day for an adult) and poor clinical compliance, and can not continuously relieve pain, and the development of the once-a-day modified release preparation can not only improve the compliance of patients, but also reduce the C of the drug in blood max Alleviating or avoiding association withThe side effects related to the dosage and the increase of the curative effect of the medicine by prolonging the effective concentration of the medicine in the blood plasma have obvious advantages. Therefore, in order to solve the requirements of rapid pain relief and long-term action in clinic, development of a phloroglucinol modified release preparation is needed.
The phloroglucinol has larger clinical dosage (320 mg-480 mg of adult daily) and better water solubility, and the proper release characteristic in vivo is difficult to realize by the prior conventional technology, thus seriously affecting the in vivo curative effect. At present, no document report on phloroglucinol sustained release preparation exists, and in the prior art (such as patent CN113616607A, CN 105560202B), when hydrophilic gel skeleton materials such as hydroxypropyl methylcellulose, hydroxypropyl cellulose and the like are adopted to prepare sustained release tablets, the skeleton materials are used in a large amount, the release degree of the prepared gel skeleton sustained release tablets is faster in the early stage, and the long-acting effect in the later stage cannot be maintained; in addition, the bulk drug is easily soluble and has larger clinical administration specification, and when hypromellose is used as a slow release framework material, the release speed is difficult to control. The existing slow release technology aims at the defect of the effective framework slow release material of large-scale high water-soluble active ingredients, and development and improvement are urgently needed. Analyzing the above techniques has certain defects, and the phloroglucinol release-regulating preparation with quick action and long-term action cannot be prepared; therefore, the development of the phloroglucinol modified release preparation with rapid and long-acting clinical application has remarkable advantages in the aspects of pharmaceutical quality and market prospect.
Disclosure of Invention
In view of the shortcomings of the prior art, the invention aims to provide a phloroglucinol modified release preparation.
It is another object of the present invention to provide a method for preparing a phloroglucinol modified release formulation.
The inventors have conducted intensive studies in order to develop a phloroglucinol modified release preparation which has a rapid release effect and can be stabilized for a long time, and have found that the phloroglucinol modified release preparation can be more stably released and effective by dry granulation using a combined matrix material mainly comprising high-viscosity hypromellose and secondarily comprising low-viscosity hypromellose, thereby completing the present invention.
The aim of the invention can be achieved by the following technical scheme:
the phloroglucinol modified release preparation comprises the following components in total weight:
the content of the phloroglucinol is 10 to 50 percent,
the content of the framework material A is 20% -80%,
the content of the framework material B is 4% -25%;
the total mass percentage of the phloroglucinol and the framework material A and the framework material B is less than or equal to 100 percent;
wherein the phloroglucinol is selected from phloroglucinol or phloroglucinol hydrate;
the framework material A is selected from hydroxypropyl methylcellulose;
the framework material B is selected from hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose or a combination thereof.
As a preferred embodiment of the present invention, the phloroglucinol modified release formulation comprises the following components by total weight:
the content of the phloroglucinol is 20 to 40 percent,
the content of the framework material A is 20% -60%,
the content of the framework material B is 4% -15%.
The total mass percentage of the phloroglucinol and the framework material A and the framework material B is less than or equal to 100 percent.
As a further preferred aspect of the present invention, the phloroglucinol modified release formulation comprises, by total weight:
the content of the phloroglucinol is 20 to 40 percent,
the content of the framework material A is 20% -60%,
the content of the framework material B is 4-15%,
the content of the adhesive is 2% -20%,
the content of the filler is 10% -30%,
the content of the lubricant is 0.5% -2.5%;
and the total mass percent of the components is equal to 100 percent.
As a still further preferred aspect of the present invention, the phloroglucinol modified release formulation comprises, by total weight:
the content of the phloroglucinol is 30 to 45 percent,
the content of the framework material A is 28% -40%,
the content of the framework material B is 4-15%,
the content of the adhesive is 2% -15%,
the content of the filler is 15-30%,
the content of the lubricant is 0.5% -1.5%;
and the total mass percent of the components is equal to 100 percent.
Preferably, the viscosity of the skeleton material is 75000 to 140000 mPas; the viscosity of the framework material B is 3000-5600 mPa.s.
Preferably, the binder is selected from sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, povidone, or a combination thereof; the filler is selected from microcrystalline cellulose, lactose, starch, mannitol or a combination thereof; the lubricant is selected from colloidal silica, silica fume, magnesium stearate, talcum powder or a combination thereof.
In some preferred embodiments of the invention, the phloroglucinol modified release formulation comprises, by total weight:
the content of the phloroglucinol is 30 to 35 percent,
the content of the framework material A is 30% -37%,
the content of the framework material B is 4-10%,
the content of the adhesive is 2% -6%,
the content of the filler is 21% -25%,
the content of the lubricant is 0.8% -1.2%;
and the total mass percentage of the components is equal to 100 percent;
wherein the framework material A is selected from hypromellose, the framework material B and the binder are selected from sodium hydroxymethyl cellulose or methylcellulose, and the filler is selected from microcrystalline cellulose.
As a further preferred aspect of the present invention, the phloroglucinol modified release preparation is prepared into tablets or capsules by a dry granulation process.
The preparation method of the phloroglucinol release-regulating preparation comprises the following steps:
a. uniformly mixing the prescription amount of framework material A, framework material B, adhesive and filler;
b. adding phloroglucinol raw material medicines into the a, uniformly mixing, and putting into a dry granulator to prepare dry granules;
c. mixing the dry granules obtained in step b with lubricant uniformly, tabletting or encapsulating.
The phloroglucinol modified release preparation is applied to the medicament with rapid onset and long-acting spasmolytics in clinic.
In the medicament, each tablet contains 240mg to 400mg of phloroglucinol or phloroglucinol hydrate.
The phloroglucinol release-regulating preparation can realize quick effect and pain relief after clinical administration, can realize long-time antispasmodic effect, and can be stably released for 4-12h after administration. After the phloroglucinol release-regulating preparation is orally administrated, single dose T max For 4-12h, and/or steady state T ma x is 4h-10h.
The invention has the main advantages that:
1) The invention provides a phloroglucinol release-regulating preparation which can realize quick effect clinically and can achieve the effect of spasmolysis and pain relief for a long time, and the defects of short pain relief effect and frequent administration for many times in the clinical use of the existing phloroglucinol preparation are greatly overcome.
2) The invention combines the physical and chemical properties of the phloroglucinol bulk drug, realizes quick effect after administration by adopting a combined framework material and a dry granulation process, can maintain the antispasmodic effect for a long time, and has remarkable clinical advantages.
Drawings
FIG. 1 comparative example 1 Release Curve
FIG. 2 example 1 Release Curve
FIG. 3 example 2 Release Curve
FIG. 4 example 3 Release Curve
FIG. 5 example 4 Release Curve
FIG. 6 example 6 in vivo drug administration Curve
Detailed Description
Comparative example 1
1. Prescription composition
Hydroxypropyl methylcellulose has a viscosity in the range of 75000 to 140000 mPa.s
2. Preparation method
Weighing all auxiliary materials except phloroglucinol and lubricant, mixing by a three-dimensional mixer for 15 minutes, adding phloroglucinol, mixing for 10 minutes, preparing dry granules by a dry granulator, sieving the dry granules with a 20-mesh sieve, granulating, uniformly mixing the dry granules with magnesium stearate, and pressing into tablets.
Example 1
1. Prescription composition
Hydroxypropyl methylcellulose has a viscosity in the range of 75000 to 140000 mPa.s
Methyl cellulose viscosity range of 3000-5000 mPa.s
2. Preparation method
Weighing all auxiliary materials except phloroglucinol and lubricant, mixing by a three-dimensional mixer for 10-20 minutes, adding phloroglucinol, mixing for 10 minutes, preparing dry granules by a dry granulator, sieving the dry granules with a 20-mesh sieve, granulating, uniformly mixing the dry granules with magnesium stearate, and pressing into tablets.
Example 2
1. Prescription composition
Hydroxypropyl methylcellulose has a viscosity in the range of 75000 to 140000 mPa.s
Methyl cellulose viscosity range of 3000-5000 mPa.s
2. Preparation method
Weighing all auxiliary materials except phloroglucinol and lubricant, mixing by a three-dimensional mixer for 10 minutes, adding phloroglucinol, mixing for 10 minutes, preparing dry granules by a dry granulator, sieving the dry granules with a 20-mesh sieve, granulating, uniformly mixing the dry granules with talcum powder, and pressing into tablets.
Example 3
1. Prescription composition
Hydroxypropyl methylcellulose has a viscosity in the range of 75000 to 140000 mPa.s
Carboxymethyl cellulose viscosity range 4000-5600 mPa.s
2. Preparation method
Weighing all auxiliary materials except phloroglucinol and lubricant, mixing by a three-dimensional mixer for 20 minutes, adding phloroglucinol, mixing for 10 minutes, preparing dry granules by a dry granulator, sieving the dry granules with a 20-mesh sieve, granulating, uniformly mixing the dry granules with aerosil, and pressing into tablets.
Example 4
Hydroxypropyl methylcellulose has a viscosity in the range of 75000 to 140000 mPa.s
Methyl cellulose viscosity range of 3000-5000 mPa.s
2. Preparation method
Weighing all auxiliary materials except phloroglucinol and lubricant, mixing by a three-dimensional mixer for 15 minutes, adding phloroglucinol, mixing for 10 minutes, preparing dry granules by a dry granulator, sieving the dry granules with a 20-mesh sieve, granulating, uniformly mixing the dry granules with magnesium stearate, and pressing into tablets.
Example 5
The samples prepared in comparative example 1 and examples 1 to 4 were subjected to in vitro dissolution behavior studies, and the dissolution curves of the samples in examples 1 to 4 under different conditions of pH1.2, pH4.5, pH6.8 and the like were examined, and the studies showed that the dissolution experiments were carried out in different media at 100rpm, the dissolution behavior was consistent, the release amount was 32mg or more in 30 minutes, 50% was released in 3 to 6 hours, 90% was released in 8 to 12 hours, and 50% was released in 30 minutes, without significant slow release effect, and the results were shown in FIG. 1 to 4.
Example 6
Study purposes: the analgesic effect of the invention on spasmodic pain was examined and the pharmacokinetic profile in vivo was examined.
The research method comprises the following steps:
1) Pharmacokinetic studies: 20 patients with acute gastrointestinal cramp abdominal pain were selected as volunteers according to the present invention, and divided into 2 groups of 10 persons, and 1 self-made sample (sample of example 4) and 4 phloroglucinol freeze-dried tablets (Spasfon, 80 mg) were respectively given 1 time a day, and blood was collected at 10min, 20min, 30min, 45min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 16h, 24h, and blood concentration in the body was measured.
2) Pain intensity assessment: 20 patients with acute gastrointestinal cramping abdominal pain were selected as volunteers according to the invention, and divided into 2 groups of 10 persons, and 1 self-made sample (using the sample of example 4) and 4 phloroglucinol freeze-dried tablets (Spasfon, 80 mg) were given respectively, using the visual analog pain scale (VAS), painless: score 0, mild pain: 1-3 minutes, moderate pain: 4-6 minutes, severe pain: 7-9 minutes, severe pain: the pain sensation was scored and collected at 15min, 30min, 1h, 2h, 4h, 8h, 12h, and 16h after the administration of the drug for 10 min.
Study results: the evaluation of pain intensity after administration is shown in Table 1, and the results show that the pain sensation of the volunteer is significantly reduced after administration for 30min, and the analgesic effect of 8 to 12 hours can be basically maintained, and the blood concentration in the body is shown in FIG. 5.
Table 1 pain intensity assessment
TABLE 2 in vivo pharmacokinetic data
| Pharmacokinetic parameters | Example 4 | Phloroglucinol freeze-dried tablet |
| AUC (0-t) (ng·h·mL -1 ) | 10248.12 | 2553 |
| AUC (0-∞) (ng·h·mL -1 ) | 11046.26 | 2560 |
| C max (ng·mL -1 ) | 2110.22 | 3540 |
| t 1/2 (h) | 3.85 | 0.635 |
| T max (h) | 2.96 | 0.5 |
Claims (9)
1. A phloroglucinol modified release formulation comprising, by total weight:
the content of the phloroglucinol is 10 to 50 percent,
the content of the framework material A is 20% -80%,
the content of the framework material B is 4% -25%;
and the total mass percentage of the phloroglucinol and the framework material A and the framework material B is less than or equal to 100 percent;
wherein the framework material A is selected from hypromellose;
the framework material B is selected from hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose or a combination thereof.
2. The phloroglucinol modified release formulation of claim 1, comprising the following components by total weight:
the content of the phloroglucinol is 20 to 40 percent,
the content of the framework material A is 20% -60%,
the content of the framework material B is 4% -15%.
And the total mass percentage of the phloroglucinol and the framework material A and the framework material B is less than or equal to 100 percent.
3. The phloroglucinol modified release formulation of claim 1, comprising the following components by total weight:
the content of the phloroglucinol is 20 to 40 percent,
the content of the framework material A is 20% -60%,
the content of the framework material B is 4-15%,
the content of the adhesive is 2% -20%,
the content of the filler is 10% -30%,
the content of the lubricant is 0.5% -2.5%;
and the total mass percent of the components is equal to 100 percent.
4. A phloroglucinol modified release formulation according to claim 3, comprising the following components by total weight:
the content of the phloroglucinol is 30 to 45 percent,
the content of the framework material A is 28% -40%,
the content of the framework material B is 4-15%,
the content of the adhesive is 2% -15%,
the content of the filler is 15-30%,
the content of the lubricant is 0.5% -1.5%;
and the total mass percent of the components is equal to 100 percent.
5. The phloroglucinol modified release formulation of any of claims 1-4, wherein the matrix material has a viscosity ranging from 75000 to 140000 mPa-s; the viscosity of the framework material B is 3000-5600 mPa.s.
6. The phloroglucinol modified release formulation of claim 5, wherein the binder is selected from sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, povidone, or combinations thereof; the filler is selected from microcrystalline cellulose, lactose, starch, mannitol or a combination thereof; the lubricant is selected from colloidal silica, silica fume, magnesium stearate, talcum powder or a combination thereof.
7. The phloroglucinol modified release formulation of claim 6, wherein the phloroglucinol modified release formulation is formulated into a tablet or capsule using a dry granulation process.
8. The method for preparing the phloroglucinol modified release formulation of claim 5, comprising the steps of:
a. uniformly mixing the prescription amount of framework material A, framework material B, adhesive and filler;
b. adding phloroglucinol raw material medicines into the a, uniformly mixing, and putting into a dry granulator to prepare dry granules;
c. mixing the dry granules obtained in step b with lubricant uniformly, tabletting or encapsulating.
9. The use of the phloroglucinol modified release formulation of claim 5 in a fast acting and long acting spasmolytic in the clinic.
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