CN111053755B - Preparation method of high-permeability cefixime capsule preparation - Google Patents
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- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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- 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
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- 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
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Abstract
The invention relates to a preparation method of cefixime preparation for improving bioavailability, belonging to the technical field of medicines. The invention co-crystallizes cefixime and at least one transmembrane reinforcing agent to prepare a thermally stable co-crystal, the co-crystal is mixed with proper auxiliary materials and filled to prepare the capsule preparation, and the co-crystal can improve the transmembrane operation capability of cefixime in the body, thereby increasing the permeability in the body and achieving the effect of improving the bioavailability in the body.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of a cefixime capsule preparation with high permeability.
Background
Cefixime, also known as cefotaxime carboximes, is a third-generation cephalosporin, has the characteristics of broad spectrum, high efficiency, wide in-vivo distribution and good in-vivo tissue penetrability, but has high oral administration dosage due to lower bioavailability, can achieve better treatment effect only by taking the cefixime for multiple times a day, and is accompanied with high risk of adverse reaction, so that the bioavailability of cefixime is improved, and the cefixime is of great significance for improving the curative effect, economy and safety of cefixime preparations.
Cefixime is a BCS class IV (low dissolution-low permeability) drug, classified according to the Biopharmaceutics Classification System (BCS), because it is poorly soluble in water and gastric acid solutions and has low permeability in the body's intestinal tract (Caco-2 cell model), thus resulting in low absolute bioavailability. Cefixime is a weakly acidic drug which is difficult to dissolve in water and gastric acid solution but has high solubility in the alkaline environment of intestinal juice, and has high stability to beta-lactamase, and the main factor restricting the bioavailability is low gastrointestinal permeability.
Research on influence of pharmaceutic adjuvants on cefixime intestinal absorption [ C ] latest scientific research results exchange meeting of national youth pharmaceutical workers [ 2012 ]) in literature research (Schochyten, Liuying, Li Chan, et al.) influence of pharmaceutic adjuvants on cefixime intestinal absorption and transportation is researched by adopting an outward turning intestinal vesicle method, and influence of twelve pharmaceutic adjuvants on cefixime intestinal absorption and transportation is investigated, wherein the influences of the twelve pharmaceutic adjuvants on cefixime intestinal absorption and transportation comprise acrylic resins, PEG (polyethylene glycol) surfactants, non-ionic surfactants, celluloses, polyoxyethylene and the like. The result shows that Eudragit L100 has obvious effect of promoting absorption of cefixime in each intestinal section, PVP K30 has obvious effect of promoting absorption in jejunum and ileum, carbomer 934P, PEG400, Pd-140, F68, water-soluble chitosan, polysorbate 80 and EL35 only have obvious effect of promoting absorption in ileum, samples related in experiments in documents are that cefixime and various auxiliary materials are dissolved in Krebs solution and are in a prepared liquid state, and cefixime is not suitable for being prepared into an oral liquid preparation due to poor stability in water.
In order to solve the problem, the invention provides a preparation method of a cefixime capsule oral solid preparation with high permeability.
CN 102119025B (chinese patent application No. 200980114260.9, entitled improved formulation of a poorly permeable active pharmaceutical ingredient) provides a pharmaceutical oral dosage form comprising a poorly permeable active pharmaceutical ingredient and at least one permeability improving substance, wherein the permeability improving substance is heat-stably embedded in a water-soluble matrix of a water-soluble carrier, and a heat-stable formulation useful for enhancing bioavailability. According to this patent claim, the following compounds are used as penetration modifiers or transmembrane enhancers: polysorbate, caprylic capric polyethylene glycol-8 glyceride, PEG- (8-50) stearate, PEG-32 glyceryl laurate and d-alpha tocopheryl polyethylene glycol 1,000 succinate, and according to claim 11 thereof an aqueous solution of the heat stable solid composition is sprayed onto the active pharmaceutical ingredient formulated as a granulate, pellet, microsphere or tablet.
However, when this patent is applied to a compound of the BCS IV class, such as cefixime described in this patent, there is a problem of premature separation of the transmembrane enhancer from the cefixime, i.e. in human gastric juice, the water-soluble transmembrane enhancer dissolves from the surface of the cefixime particles and flows with the gastric juice into the duodenum and intestinal lumen, whereas the poorly soluble cefixime particles in gastric juice continue to reside in the gastric lumen and enter the intestinal lumen later, the water-soluble transmembrane enhancer cannot co-act with cefixime on the villi of the small intestine and assist in cefixime absorption.
The invention provides a preparation method of a high-permeability cefixime capsule preparation, which comprises the steps of co-crystallizing cefixime and at least one transmembrane reinforcing agent, wrapping the cefixime and the transmembrane reinforcing agent to prepare a thermostable co-crystal, wherein the obtained co-crystal has the same dissolution rate in gastric juice and intestinal juice, so that the transmembrane reinforcing agent is not separated from the cefixime in gastric juice, and is dissolved out simultaneously with the cefixime in the intestinal juice to assist the absorption of the cefixime in small intestinal villus.
Disclosure of Invention
The invention mainly aims to provide a preparation method of a cefixime capsule preparation with high permeability, which is characterized in that cefixime and at least one transmembrane reinforcing agent are subjected to cocrystallization to prepare a thermally stable cocrystal, the cocrystal is mixed with proper auxiliary materials to be filled to prepare the capsule preparation, and the cocrystal can improve the transmembrane operation capacity of cefixime in a body, so that the in-vivo permeability is increased, and the effect of improving the in-vivo bioavailability is achieved.
In order to achieve the purpose, the invention adopts the following technical scheme:
a process for preparing the high-penetrability cefixime capsule includes such steps as dissolving cefixime in proper solvent, co-crystallizing with at least one transmembrane reinforcing agent to obtain thermally stable co-crystal, mixing it with proper auxiliaries, and filling in capsules.
A method for preparing a high-permeability cefixime capsule preparation, which uses at least one transmembrane enhancer dissolved in a proper amount of water to prepare a transmembrane enhancer solution, wherein the transmembrane enhancer is selected from the group consisting of: polyoxyl (8-50) stearate, sodium lauryl sulfate, preferably polyoxyl 40 stearate.
A process for preparing the high-permeability cefixime capsule includes such steps as dissolving the coarse cefixime product in water, mechanically stirring for dispersing it uniformly, slowly adding alkaline solution while stirring for dissolving cefixime, adding activated carbon for decolouring, filtering and loading in crystallizer.
Controlling the temperature of the thermostatic bath to 15-25 ℃, slowly adding dilute hydrochloric acid, controlling the adding flow rate, adding cefixime crystal seeds when the pH value is 3.0-3.5, slowly separating out the cefixime and rebounding along with the pH value when the cefixime begins to be slowly separated out, adding a transmembrane reinforcing agent solution into the cefixime solution when the pH value is 3.5-4.0 due to the rebounding, and uniformly stirring. Continuously dropwise adding dilute hydrochloric acid to make the pH value reach 3.0-3.5, continuously and slowly stirring the solution to slowly separate out the cefixime-transmembrane enhancer cocrystal, dropwise adding dilute hydrochloric acid to make the pH value reach 2.0-2.3 when the second bounce makes the pH value reach 3.5-4.0, and growing the crystals for two hours. Filtering, washing and drying to obtain the cefixime-transmembrane enhancer cocrystal.
A preparation method of a high-permeability cefixime capsule preparation is disclosed, wherein the cefixime-transmembrane enhancer cocrystal is prepared from the following components in parts by weight: 100 parts of cefixime and 0.1-5 parts of transmembrane enhancer, preferably 100 parts of cefixime and 2 parts of transmembrane enhancer.
A preparation method of a cefixime capsule preparation with high permeability comprises the following steps of: one or more of carboxymethyl cellulose calcium, low-substituted hydroxypropyl cellulose and crospovidone, and a lubricant: magnesium stearate, glidant: mixing one or more of silicon dioxide and colloidal silicon dioxide, and filling into capsule.
The prescription of the formula comprises the following components: 100 parts of cefixime-transmembrane enhancer cocrystal, 1-10 parts of disintegrant, 0.1-2 parts of lubricant and 0.1-2 parts of glidant.
The prescription of the formula is preferably as follows: 100 parts of cefixime-transmembrane enhancer cocrystal, 5 parts of disintegrant, 0.5 part of lubricant and 0.5 part of glidant.
The above formula is prepared by mixing and filling into No. 4 capsules, wherein the filling amount is 110-150 mg, preferably 130mg, and the cefixime content is 100 mg.
The above formula is prepared by mixing and filling into No. 5 gelatin empty capsules, wherein the filling amount is 55-70 mg, preferably 60mg, and the cefixime content is 50 mg.
Detailed Description
EXAMPLE A preparation of cefixime-transmembrane enhancer cocrystal
100g of polyoxyl [ 40 ] stearate is weighed and dissolved in 5kg of water to prepare a transmembrane enhancer solution.
Dissolving 5kg of cefixime crude product in 100kg of water, uniformly dispersing the cefixime crude product by mechanical stirring, slowly adding an alkaline solution, simultaneously stirring to completely dissolve the cefixime, adding activated carbon for decoloring, filtering, and transferring to a crystallizer.
Controlling the temperature of the thermostatic bath to 15-25 ℃, slowly adding dilute hydrochloric acid, controlling the adding flow rate, dropwise adding cefixime crystal seeds when the pH value is 3.0-3.5, slowly separating out the cefixime and rebounding along with the pH value when the cefixime begins to be slowly separated out, adding the prepared transmembrane enhancer solution into the cefixime solution when the pH value is 3.5-4.0 due to the rebounding, and uniformly stirring. Continuously dropwise adding dilute hydrochloric acid to make the pH value reach 3.0-3.5, continuously and slowly stirring the solution to slowly separate out the cefixime-transmembrane enhancer cocrystal, dropwise adding dilute hydrochloric acid to make the pH value reach 2.0-2.3 when the second bounce makes the pH value reach 3.5-4.0, and growing the crystals for two hours. Filtering, washing and drying to obtain the cefixime-transmembrane enhancer cocrystal.
EXAMPLE two preparation of high Permeability cefixime Capsule formulation-100 mg specification
110 parts by weight of the cefixime-transmembrane enhancer cocrystal prepared in example one was mixed with 5 parts by weight of carboxymethylcellulose calcium, 0.5 part by weight of magnesium stearate, and 0.5 part by weight of colloidal silicon dioxide, and the mixture was filled into a size 4 capsule to prepare a capsule with a content of 120 mg.
EXAMPLE III preparation of high Permeability cefixime Capsule formulation-50 mg Scale
110 parts by weight of the cefixime-transmembrane enhancer cocrystal prepared in example one was mixed with 5 parts by weight of carboxymethylcellulose calcium, 0.5 part by weight of magnesium stearate, and 0.5 part by weight of colloidal silicon dioxide, and the mixture was filled into a size 5 capsule to obtain a 60mg content.
Claims (10)
1. A method for preparing cefixime capsule preparation with high permeability is characterized in that cefixime is dissolved in a proper solvent, and is cocrystallized with at least one transmembrane reinforcing agent to prepare a thermally stable cocrystal, and the thermally stable cocrystal is mixed with proper auxiliary materials and filled to prepare a capsule preparation; specifically, at least one transmembrane enhancer is dissolved in a proper amount of water to prepare a transmembrane enhancer solution, wherein the transmembrane enhancer is polyoxyl 40 stearate;
dissolving cefixime crude product in water, uniformly dispersing the cefixime crude product by mechanical stirring, slowly adding an alkaline solution, simultaneously stirring to completely dissolve the cefixime, adding activated carbon for decoloring, filtering, and transferring the cefixime crude product into a crystallizer;
controlling the temperature of a constant temperature bath to 15-25 ℃, slowly adding dilute hydrochloric acid, controlling the adding flow rate, adding cefixime seed crystal when the pH value is 3.0-3.5 by dropwise adding, when cefixime begins to slowly separate out and is accompanied with pH rebound, adding the prepared transmembrane enhancer solution into the cefixime solution when the pH value is 3.5-4.0 by rebound, uniformly stirring, continuously adding dilute hydrochloric acid to make the pH value be 3.0-3.5 by dropwise adding, continuously and slowly stirring the solution to slowly separate out the cefixime-transmembrane enhancer cocrystal, adding dilute hydrochloric acid to make the pH value be 2.0-2.3 by dropwise adding when the pH value is 3.5-4.0 by rebound for the second time, and after crystal growth for two hours, filtering, washing and drying to obtain the cefixime-transmembrane enhancer cocrystal.
2. The method for preparing the highly permeable cefixime capsule preparation according to claim 1, wherein: the cefixime-transmembrane enhancer cocrystal is prepared from the following components in parts by weight: 100 parts of cefixime and 0.1-5 parts of transmembrane enhancer.
3. The method for preparing the cefixime capsule preparation with high permeability according to claim 2, wherein: the cefixime-transmembrane enhancer cocrystal is prepared from the following components in parts by weight: 100 parts of cefixime and 2 parts of transmembrane enhancer.
4. The method for preparing the highly permeable cefixime capsule preparation according to claim 1, wherein: the cefixime-transmembrane enhancer cocrystal is mixed with a disintegrating agent: one or more of carboxymethyl cellulose calcium, low-substituted hydroxypropyl cellulose and crospovidone, and a lubricant: magnesium stearate, glidant: mixing silicon dioxide, and filling into gelatin hollow capsule.
5. The method for preparing cefixime capsule preparation with high permeability according to claim 4, wherein: the formula comprises the following components: 110 parts of cefixime-transmembrane enhancer cocrystal, 1-10 parts of disintegrant, 0.1-2 parts of lubricant and 0.1-2 parts of glidant.
6. The method for preparing cefixime capsule formulation with high permeability according to claim 5, wherein: the formula comprises the following components: 110 parts of cefixime-transmembrane enhancer cocrystal, 5 parts of disintegrant, 0.5 part of lubricant and 0.5 part of glidant.
7. A process for preparing highly permeable cefixime capsule formulation according to any one of claims 4 to 6, which comprises the steps of: mixing, and filling into No. 4 gelatin empty capsule with filling amount of 110-140 mg, containing cefixime 100 mg.
8. The process for preparing cefixime capsule formulation with high permeability according to claim 7, wherein: the loading was 120 mg.
9. A process for preparing highly permeable cefixime capsule formulation according to any one of claims 4 to 6, which comprises the steps of: mixing, and filling into No. 5 gelatin hollow capsule with filling amount of 55-70 mg and cefixime content of 50 mg.
10. A process for preparing cefixime capsule formulation with high permeability according to claim 9, wherein: the loading was 60 mg.
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