CN106902097B - A pharmaceutical composition for improving bioavailability of medicine - Google Patents
A pharmaceutical composition for improving bioavailability of medicine Download PDFInfo
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- CN106902097B CN106902097B CN201510961582.4A CN201510961582A CN106902097B CN 106902097 B CN106902097 B CN 106902097B CN 201510961582 A CN201510961582 A CN 201510961582A CN 106902097 B CN106902097 B CN 106902097B
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 14
- 239000003814 drug Substances 0.000 title abstract description 35
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- 238000009505 enteric coating Methods 0.000 claims abstract description 8
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- AYIRNRDRBQJXIF-NXEZZACHSA-N (-)-Florfenicol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)C=C1 AYIRNRDRBQJXIF-NXEZZACHSA-N 0.000 claims description 17
- 229960003760 florfenicol Drugs 0.000 claims description 17
- MGCCHNLNRBULBU-WZTVWXICSA-N flunixin meglumine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.C1=CC=C(C(F)(F)F)C(C)=C1NC1=NC=CC=C1C(O)=O MGCCHNLNRBULBU-WZTVWXICSA-N 0.000 claims description 13
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- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 4
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 4
- 239000004925 Acrylic resin Substances 0.000 claims 2
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 claims 2
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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
- A61K9/50—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
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- 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
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- Public Health (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a pharmaceutical composition capable of improving the bioavailability of a medicament, and belongs to the technical field of medicines. The composition is formed by compounding an enteric composite composition I and a gastric composite composition II; the enteric composite composition I consists of an enteric pellet core and an enteric coating, and the gastric composite composition II consists of a gastric pellet core and a gastric coating.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition capable of improving the bioavailability of a medicament.
Background
Bioavailability (F) refers to the relative amount and rate of absorption of a drug by the body into the systemic circulation. Bioavailability of a pharmaceutical formulation is typically measured as the ratio of the area under the drug-time curve (AUC) for administration by a non-vascular route (e.g. oral, intramuscular, etc.) to the ratio of the area after administration of a reference formulation of the drug (e.g. intravenous (iv) or the same route (po)), expressed as the percentage of absorption. Depending on the difference in the administration routes of the test agent (t) and the reference agent (r), there can be a distinction between absolute bioavailability and relative bioavailability. Considering that the dosage may be different, the formula is calculated as follows:
absolute bioavailability: f ═ 100% (AUCpo · Div)/(AUCiv · Dpo) ×;
relative bioavailability: f ═ 100% (AUCt · Dr)/(AUCr · Dt) ×;
if the drug is excreted mainly as it is through the kidney in vivo, the total amount of excretion of the drug in urine can also be used for estimation.
The bioavailability is closely related to the curative effect of the medicine, particularly, the change of the bioavailability of the medicine for emergency treatment, which has narrow therapeutic index, small dosage and small solubility, has serious influence on the clinical curative effect, and the low bioavailability can cause poisoning and even endanger life when the bioavailability is changed from high to low. Otherwise, the treatment effect cannot be achieved and the treatment is delayed. The effect of bioavailability should be considered when clinically analyzing the reasons for drug therapy ineffectiveness, poor efficacy or toxicity.
Many factors affect the bioavailability, including the size of the drug particles, the crystal form, the compactness of the filling agent, the excipient, the production process and the like. Depending on factors affecting solubility and dissolution rate, there are generally drug micronization routes, prodrug routes, and routes for solubilizing, salifying, or partially changing the molecular structure of a drug.
In the existing method for improving the bioavailability of the drug, the overall effect of a plurality of homogeneous molecules with the same structure of the same drug is considered. Similar drug clusters have high consistency in absorption, distribution, metabolism and excretion in animals, so that the blood concentration of the drug after administration is very high in the early stage and even approaches or exceeds the toxic dose, and the blood concentration is insufficient in the later stage and cannot reach the minimum effective treatment concentration, so that the maintenance time of the effective blood concentration is greatly shortened, and the therapeutic effect of the drug is directly influenced.
Disclosure of Invention
In order to better solve the problems, the invention provides a pharmaceutical composition which can improve the bioavailability of a drug and can more reasonably regulate the blood concentration of the drug in a body from the viewpoints of whole to local and macro to micro.
The composition is formed by compounding an enteric composite composition I and a gastric composite composition II;
the enteric composite composition I is composed of an enteric pellet core and an enteric coating, the enteric pellet core is composed of a main drug and a pharmaceutical excipient, and the thickness of the enteric coating is 0.01-2 mm.
The gastric soluble composite composition II consists of a gastric soluble pill core and a gastric soluble coating, wherein the gastric soluble pill core consists of a main drug and a pharmaceutical adjuvant, and the thickness of the gastric soluble coating is 0.01-2 mm.
The mass ratio of the enteric composite composition I to the gastric composite composition II in the composition is 5: 95-95: 5.
The preparation method of the enteric composite composition I comprises the following steps:
(1) the main medicine and the pharmaceutic adjuvant are respectively sieved by a 80-mesh sieve, and the raw materials and the adjuvant are weighed according to the prescription for standby.
(2) Preparing a binder solution by taking the binder, adding the main drug and other auxiliary materials, and preparing the enteric-coated pellet core.
(3) And (3) preparing a pharmaceutically acceptable coating material to obtain the enteric coating solution.
(4) And mixing the pellet core with the enteric coating solution and coating to obtain the enteric composite composition I.
The preparation method of the gastric-soluble composite composition II comprises the following steps:
(1) the main medicine and the pharmaceutic adjuvant are respectively sieved by a 80-mesh sieve, and the raw materials and the adjuvant are weighed according to the prescription for standby.
(2) Preparing an adhesive solution by taking the adhesive, adding the main drug and other auxiliary materials, and preparing the gastric-dissolving pellet core.
(3) And (3) preparing a pharmaceutically acceptable coating material to obtain the gastric-soluble coating solution.
(4) And mixing the pill core with the gastric-soluble coating solution, and coating to obtain the enteric-coated composite II.
The composition is prepared by uniformly mixing an enteric composite composition I and a gastric composite composition II according to the mass ratio of 5: 95-95: 5 by an equivalent incremental method. Detecting the intermediate product, checking the characters, granularity, fluidity, dissolution rate or release rate, drying weight loss, related substances, contents and the like, and packaging the qualified product to obtain the pharmaceutical composition capable of improving the bioavailability of the medicine. The solid pharmaceutical composition can be prepared into various preparation forms, including granules, oral tablets, capsules, premixes, dry suspensions and the like or other forms of preparations. The invention has the beneficial effects that:
the gastric soluble part of the pharmaceutical composition provided by the invention can be effectively and rapidly released and takes effect rapidly; the enteric-coated part can effectively delay the release and absorption of the enteric-coated part, thereby achieving the effect of slow release and long acting; the effective combination of the two can make the main drug achieve the effective combination effect of quick acting, long acting, slow release and controlled release, compared with the common preparation, the bioavailability of the drug can be improved under the condition of the same dosage, or better treatment effect can be achieved under the condition of relatively smaller dosage, and the obtained treatment effect is better than that of single preparation respectively containing each drug. Simultaneously, the Chinese medicinal composition is favorable for reducing toxic and side effects and relieving the stimulation of medicaments to gastrointestinal tracts, and has no bitter taste.
Description of the drawings:
FIG. 1: time curve of the first and second inventive examples
The numbering in the figures represents: A. florfenicol powder B and sample prepared in the first embodiment of the invention
FIG. 2 is a drawing: the invention has a structure schematic diagram.
The numbering in the figures represents: 1. a gastric coating, 2, a main drug, 3, auxiliary materials a and 4, auxiliary materials b and 5, auxiliary materials c and 6, auxiliary materials d and 7, auxiliary materials e and 8, auxiliary materials f and 9, other auxiliary materials, 10 and an enteric coating.
Detailed Description
The following examples are provided to further illustrate the invention, but are not meant to limit the invention in any way, and all techniques that can be implemented based on the teachings of the invention are within the scope of the invention.
Example 1: a pharmaceutical composition for improving the bioavailability of florfenicol and flunixin meglumine.
Prescription:
the formula of the enteric composite composition I comprises the following components:
the preparation method of the enteric composite composition I comprises the following steps:
(1) respectively sieving florfenicol, flunixin meglumine, sodium carboxymethylcellulose, magnesium stearate, dextrin, microcrystalline cellulose sodium, malic acid, starch and sodium sulfite with a 80-mesh sieve, and weighing raw and auxiliary materials according to the prescription for later use.
(2) Preparing an adhesive solution by taking the adhesive, adding florfenicol, flunixin meglumine and other auxiliary materials, and preparing the enteric-coated pill core.
(3) And (3) preparing a coating solution from a pharmaceutically acceptable coating material.
(4) And mixing the enteric pellet core with the enteric coating solution and coating to obtain the enteric composite composition I.
The formula of the gastric-soluble composite composition II comprises the following components:
the preparation method of the gastric-soluble composite composition II comprises the following steps:
(1) respectively sieving florfenicol, flunixin meglumine, sodium carboxymethylcellulose, maltitol, microcrystalline cellulose sodium, malic acid, lactose and sodium citrate with a 80-mesh sieve, and weighing raw and auxiliary materials according to the prescription for later use.
(2) Preparing an adhesive solution by taking the adhesive, adding florfenicol, flunixin meglumine and other auxiliary materials, and preparing the gastric-soluble pill core.
(3) And (3) preparing a pharmaceutically acceptable coating material to obtain the gastric-soluble coating solution.
(4) And mixing the gastric-soluble pill core and the gastric-soluble coating solution, and coating to obtain a gastric-soluble composite composition II.
Mixing the enteric composite composition I and the gastric composite composition II according to the mass ratio of 50: and mixing by 50 equivalent incremental method. Detecting the intermediate product, checking the characters, granularity, fluidity, dissolution rate or release rate, drying weight loss, related substances, contents and the like, and packaging the qualified products to obtain the solid pharmaceutical composition containing the florfenicol and the flunixin meglumine.
Example 2: pharmaceutical composition capable of improving bioavailability of florfenicol and flunixin meglumine
Taking the composition prepared in example 1, and mixing the enteric composite composition I and the gastric composite composition II according to the mass ratio of 5:95 equal amount increasing method.
Example 3: pharmaceutical composition capable of improving bioavailability of florfenicol and flunixin meglumine
Taking the composition prepared in example 1, and mixing the enteric composite composition I and the gastric composite composition II according to the mass ratio of 95:5 and mixing by equivalent incremental method.
Example 4: pharmacokinetic testing
12 healthy New Zealand white rabbits were randomly divided into A, B groups, and the group A was administered with florfenicol powder in a single dose, and the group B was administered with the drug prescribed one in example 1 above in a single dose, each group being administered with 20mg/kg (in terms of florfenicol). The drug concentration in plasma was determined by high performance liquid chromatography and plasma concentration-time data were processed by Winnonlin pharmacokinetic program software. The results are shown in tables 1-2 below, FIG. 1.
Table 1 mean blood concentration (μ g/ml) n ═ 6 at different time points
TABLE 2 pharmacokinetic parameters
Test results show that compared with florfenicol powder, the half-life elimination of the first prescription for filling is prolonged by 0.86h, the time of peak arrival is delayed by 1.7h, and the bioavailability is 108% of that of common powder.
Claims (1)
1. A pharmaceutical composition capable of improving the bioavailability of florfenicol and flunixin meglumine is characterized by being prepared by compounding an enteric composition I and a gastric composition II:
the formulation of the enteric composition I is as follows:
the enteric coating material is enteric polyacrylic resin: enteric polyacrylic resin: polysorbate 80: ethanol = 10:5:2:200, w/w/w;
the preparation method of the enteric composition I comprises the following steps:
(1) respectively sieving florfenicol, flunixin meglumine, sodium carboxymethylcellulose, magnesium stearate, dextrin, microcrystalline cellulose sodium, malic acid, starch and sodium sulfite with a 80-mesh sieve, and weighing raw and auxiliary materials according to the prescription for later use;
(2) preparing an adhesive solution by taking an adhesive, adding florfenicol, flunixin meglumine and other auxiliary materials, and preparing an enteric-coated pill core;
(3) preparing a coating solution by using a pharmaceutically acceptable coating material;
(4) mixing the enteric-coated pill core with the enteric-coated liquid and coating to obtain an enteric-coated composition I;
the formula of the gastric-soluble composition II comprises the following components:
the gastric coating material is hydroxyethyl cellulose: polyvinylpyrrolidone: polyethylene glycol 4000: dibutyl phthalate: ethanol =20:10:10:2:200, w/w/w;
the preparation method of the gastric-soluble composition II comprises the following steps:
(1) respectively sieving florfenicol, flunixin meglumine, sodium carboxymethylcellulose, maltitol, microcrystalline cellulose sodium, malic acid, lactose and sodium citrate with a 80-mesh sieve, and weighing raw and auxiliary materials according to the prescription for later use;
(2) preparing an adhesive solution by taking the adhesive, adding florfenicol, flunixin meglumine and other auxiliary materials, and preparing to obtain a gastric soluble pill core;
(3) preparing a pharmaceutically acceptable coating material to obtain gastric-soluble coating solution;
(4) mixing the gastric-soluble pill core with the gastric-soluble coating solution, and coating to obtain a gastric-soluble composition II;
mixing the enteric-coated composition I and the gastric-coated composition II uniformly according to the equivalent increasing method with the mass ratio of 50: 50.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510961582.4A CN106902097B (en) | 2015-12-21 | 2015-12-21 | A pharmaceutical composition for improving bioavailability of medicine |
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| CN113288876B (en) * | 2021-03-25 | 2022-09-27 | 华南农业大学 | A kind of quality evaluation and control method of florfenicol sustained-release granules |
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| CN1969834A (en) * | 2005-11-25 | 2007-05-30 | 天津市润拓生物技术有限公司 | Method for preparing colon targeted pill of florfenicol used for poultry and livestock |
| CN101011395A (en) * | 2007-02-02 | 2007-08-08 | 东南大学 | Sustained release preparation of licardipine hydrochloride and its preparing process |
| CN201426855Y (en) * | 2009-07-13 | 2010-03-24 | 上海恒丰强动物药业有限公司 | Florfenicol enteric coated granule |
| CN101693012A (en) * | 2009-08-21 | 2010-04-14 | 天津生机集团股份有限公司 | Preparation and application of florfenicol slowly-releasing micropill for treating animal digestive canal infection |
| CN101909600A (en) * | 2007-11-09 | 2010-12-08 | 英特维特国际股份有限公司 | Fast release solid formulation, preparation and use thereof |
| CN104257614A (en) * | 2014-09-26 | 2015-01-07 | 郑州福源动物药业有限公司 | Flunixin meglumine coated granule and preparation method thereof |
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| CN1969834A (en) * | 2005-11-25 | 2007-05-30 | 天津市润拓生物技术有限公司 | Method for preparing colon targeted pill of florfenicol used for poultry and livestock |
| CN101011395A (en) * | 2007-02-02 | 2007-08-08 | 东南大学 | Sustained release preparation of licardipine hydrochloride and its preparing process |
| CN101909600A (en) * | 2007-11-09 | 2010-12-08 | 英特维特国际股份有限公司 | Fast release solid formulation, preparation and use thereof |
| CN201426855Y (en) * | 2009-07-13 | 2010-03-24 | 上海恒丰强动物药业有限公司 | Florfenicol enteric coated granule |
| CN101693012A (en) * | 2009-08-21 | 2010-04-14 | 天津生机集团股份有限公司 | Preparation and application of florfenicol slowly-releasing micropill for treating animal digestive canal infection |
| CN104257614A (en) * | 2014-09-26 | 2015-01-07 | 郑州福源动物药业有限公司 | Flunixin meglumine coated granule and preparation method thereof |
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