CN114224850A - Solid pharmaceutical composition, preparation method thereof and pharmaceutical preparation - Google Patents

Solid pharmaceutical composition, preparation method thereof and pharmaceutical preparation Download PDF

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Publication number
CN114224850A
CN114224850A CN202210154646.XA CN202210154646A CN114224850A CN 114224850 A CN114224850 A CN 114224850A CN 202210154646 A CN202210154646 A CN 202210154646A CN 114224850 A CN114224850 A CN 114224850A
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solid pharmaceutical
pharmaceutical composition
parts
preparation
weight
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CN114224850B (en
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魏世峰
汪鹤龄
李勇
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Innovaco Pharmaceuticals Inc
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Innovaco Pharmaceuticals Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • 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
    • A61K9/146—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
    • 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
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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

Abstract

The application relates to a solid pharmaceutical composition, a preparation method thereof and a pharmaceutical preparation. In particular to a solid pharmaceutical composition in the form of granules comprising: 50 parts of active drug, 200-600 parts of poly (methyl) acrylic resin and 50-150 parts of organic acid. Also relates to a process for the preparation of the solid pharmaceutical composition in particulate form and to pharmaceutical formulations prepared therefrom. The compositions of the present invention exhibit excellent technical effects as described in the specification.

Description

Solid pharmaceutical composition, preparation method thereof and pharmaceutical preparation
Technical Field
The invention belongs to the technical field of medicines, and relates to a solid pharmaceutical composition, in particular to a solid pharmaceutical composition in a fine particle form, in particular to a solid pharmaceutical composition containing ibuprofen and other active medicines.
Background
Solid pharmaceutical compositions in the form of fine particles, which are usually orally administered immediately after dissolution and/or suspension in water, are in some cases not dissolved in the liquid in which they are dissolved/suspended, but dissolved and then absorbed after entering the gastrointestinal tract. Furthermore, dissolution of the active substance is not desired at this dissolution/suspension stage, and it is expected that the smaller the amount of the active substance dissolved in the liquid medicine obtained by suspending the above solid pharmaceutical composition with water, the better.
For example, it would be highly desirable to those skilled in the art to formulate ibuprofen or other active agents as a solid pharmaceutical composition in particulate form for oral administration to a patient, for example, by suspension in water, and to solubilize as little of the active agent as possible in the molecular state in the suspension resulting from the suspension in water. However, the prior art does not provide any solution to achieve the above-mentioned objectives.
Disclosure of Invention
The present invention aims to provide a solid pharmaceutical composition in the form of fine particles in which the active drug is ibuprofen or the like, which is expected to dissolve as little as possible in a molecular state in a suspension obtained by adding water to the suspension when administered orally after the suspension is added with water.
To this end, a first aspect of the present invention relates to a solid pharmaceutical composition in the form of a fine particle comprising:
50 parts by weight of active drug,
200 to 600 parts by weight, for example 250 to 550 parts by weight, for example 300 to 500 parts by weight, for example 350 to 450 parts by weight, of a poly (meth) acrylic resin,
50 to 150 parts by weight, for example 75 to 125 parts by weight, for example 80 to 120 parts by weight, for example 90 to 110 parts by weight of an organic acid.
The solid pharmaceutical composition according to the first aspect of the invention, the active drug is selected from the group consisting of: berberine hydrochloride, ibuprofen, azithromycin, atorvastatin calcium, loratadine, finasteride, tacrolimus, alfacalcidol, sodium ritathioninate, clopidogrel, ozagrel, donepezil, huperzine A, memantine, famotidine, topiramate, escitalopram, nimodipine, amlodipine, dipyridamole, simvastatin, pravastatin, sildenafil, celecoxib, itraconazole, posaconazole, nateglinide, repaglinide. According to the solid pharmaceutical composition of the first aspect of the present invention, the organic acid is selected from citric acid, tartaric acid.
The solid pharmaceutical composition according to the first aspect of the invention, wherein the poly (meth) acrylic resin is Eudragit (also known as Eudragit or Eudragit).
The solid pharmaceutical composition according to the first aspect of the invention, wherein the ewing is selected from the group consisting of ewing L100, ewing L100-55, ewing S100, ewing RL100, ewing E100, ewing RL PO, ewing RS100, ewing RS PO and combinations thereof.
The solid pharmaceutical composition according to the first aspect of the invention, wherein the ewing is selected from the group consisting of ewing L100, ewing L100-55, ewing S100, ewing RL100 and combinations thereof.
The solid pharmaceutical composition according to the first aspect of the invention, wherein said ewing is ewing L100, ewing L100-55, ewing S100, ewing RL100, in a weight ratio of 1: 0.8-1.2: 0.8-1.2: 0.8 to 1.2, for example, in the range of 1: 0.9-1.1: 0.9-1.1: 0.9 to 1.1.
A solid pharmaceutical composition according to the first aspect of the present invention, which is prepared as follows:
(1) adding poly (meth) acrylic resin to ethanol such as 90-99% ethanol such as 95% ethanol, stirring to dissolve, adding active drug, and stirring to dissolve;
(2) spray drying the solution obtained in the step (1) to obtain a fine granular material A;
(3) adding organic acid into ethanol such as 90-99% ethanol such as 95% ethanol, stirring to dissolve to obtain organic acid solution, spraying the material A into the organic acid solution in fluidized boiling state in a fluidized bed spray dryer, and continuously fluidizing and boiling to dry the material after spraying to obtain fine granular material B, thus obtaining the solid material composition.
The solid pharmaceutical composition according to the first aspect of the present invention, wherein the concentration of the poly (meth) acrylic resin in ethanol in step (1) is 10 to 30%, for example, 15 to 25%.
The solid pharmaceutical composition according to the first aspect of the present invention, wherein the concentration of the organic acid in ethanol in step (3) is 10 to 20%, for example, 13 to 17%.
Further, the second aspect of the present invention relates to a process for preparing the solid pharmaceutical composition according to the first aspect of the present invention, comprising the steps of:
(1) adding poly (meth) acrylic resin to ethanol such as 90-99% ethanol such as 95% ethanol, stirring to dissolve, adding active drug, and stirring to dissolve;
(2) spray drying the solution obtained in the step (1) to obtain a fine granular material A;
(3) adding organic acid into ethanol such as 90-99% ethanol such as 95% ethanol, stirring to dissolve to obtain organic acid solution, spraying the material A into the organic acid solution in fluidized boiling state in a fluidized bed spray dryer, and continuously fluidizing and boiling to dry the material after spraying to obtain fine granular material B, thus obtaining the solid material composition.
The method according to the second aspect of the present invention, wherein the concentration of the poly (meth) acrylic resin in ethanol in the step (1) is 10 to 30%, for example, 15 to 25%.
The process according to the second aspect of the present invention, wherein the concentration of the organic acid in ethanol in step (3) is 10 to 20%, for example, 13 to 17%.
Further, a third aspect of the present invention relates to a pharmaceutical formulation in the form of granules comprising: solid pharmaceutical compositions, fillers, flavoring agents, binders according to the first aspect of the invention.
The pharmaceutical formulation according to the third aspect of the present invention, wherein the filler is selected from the group consisting of glucose, lactose, mannitol and combinations thereof.
The pharmaceutical formulation according to the third aspect of the invention, wherein the flavoring agent is selected from the group consisting of sucrose, sucralose, sodium saccharin, flavors, and combinations thereof.
The pharmaceutical formulation according to the third aspect of the present invention, wherein the binder is selected from hydroxypropyl methylcellulose, povidone, polyethylene glycol and combinations thereof.
The pharmaceutical preparation in the form of granules is a conventional preparation in the field of pharmacy, and various auxiliary material selections, auxiliary material addition amounts, preparation methods and the like are easily prepared by the skilled person according to experience. For example, the filler may be present in an amount and/or type based on the final weight and/or volume of the granule; for another example, the binder can be dissolved in water or diluted ethanol to obtain a binder solution, and the binder solution is wet granulated and dried to bind the materials, wherein the amount of the solid binder added to the granule preparation is usually 2-5%, for example 2-4%, for example, when hydroxypropylmethylcellulose is used as the binder, the amount of the solid binder added to the granule preparation is 2-4%; as another example, the flavoring agent comprises a flavor, which can be added to the granule formulation in an amount of 0.05-0.2%, e.g., 0.1%; as another example, the flavoring agent comprises sucralose, which may be added to the granule formulation in an amount of 2-5%, such as 2-4%; as another example, the flavoring agent includes sucrose, which can be added to the granule formulation in an amount of 10-50%, such as 20-40%. The formulation and preparation process of the granules are readily accomplished by one skilled in the art based on routine experience.
It has been surprisingly found that when the active substance is mixed with a poly (meth) acrylic resin for dissolution, spray-dried and sprayed with an organic acid, the resulting particulate material exhibits a considerably low drug dissolution amount when retained in water or saliva for a relatively short period of time, and the present invention has been completed based on such a finding.
Detailed Description
The invention is further illustrated by the following specific examples. In preparing a particular composition, the total amount of solid material per charge is not less than 1kg, expressed in parts by weight when describing the formulation.
Example 1: preparation of solid pharmaceutical compositions in particulate form
Prescription: berberine hydrochloride: 50 parts by weight, ewt, L100: 100 parts by weight, ewt, L100-55: 100 parts by weight, yutecqi S100: 100 parts by weight, ewt RL 100: 100 parts by weight, citric acid: 100 parts by weight, 95% ethanol: appropriate amount (removed in the preparation process).
The preparation method comprises the following steps: (1) adding poly (meth) acrylic resin into ethanol, stirring to dissolve (solid concentration is 20%), adding active drug, and stirring to dissolve; (2) spray drying the solution obtained in the step (1) to obtain a fine granular material A; (3) adding citric acid into ethanol, stirring to dissolve to obtain citric acid solution (solid concentration is 15%), spraying citric acid solution into material A in fluidized boiling state in fluidized bed spray dryer, and continuously fluidizing and boiling to dry material after spraying to obtain fine granular material B, to obtain solid material composition.
Example 2: preparation of solid pharmaceutical compositions in particulate form
Prescription: berberine hydrochloride: 50 parts by weight, ewt, L100: 100 parts by weight, ewt, L100-55: 110 parts by weight, yutecqi S100: 90 parts by weight, ewt RL 100: 110 parts by weight, citric acid: 90 parts by weight, 95% ethanol: appropriate amount (removed in the preparation process).
The preparation method comprises the following steps: (1) adding poly (meth) acrylic resin into ethanol, stirring to dissolve (solid concentration is 25%), adding active drug, and stirring to dissolve; (2) spray drying the solution obtained in the step (1) to obtain a fine granular material A; (3) adding citric acid into ethanol, stirring to dissolve to obtain citric acid solution (solid concentration is 13%), spraying citric acid solution into material A in fluidized boiling state in fluidized bed spray dryer, and continuously fluidizing and boiling to dry material after spraying to obtain fine granular material B, to obtain solid material composition.
Example 3: preparation of solid pharmaceutical compositions in particulate form
Prescription: berberine hydrochloride: 50 parts by weight, ewt, L100: 100 parts by weight, ewt, L100-55: 90 parts by weight, yutecqi S100: 110 parts by weight, ewt RL 100: 90 parts by weight, citric acid: 110 parts by weight, 98% ethanol: appropriate amount (removed in the preparation process).
The preparation method comprises the following steps: (1) adding poly (meth) acrylic resin into ethanol, stirring to dissolve (solid content is 15%), adding active drug, and stirring to dissolve; (2) spray drying the solution obtained in the step (1) to obtain a fine granular material A; (3) adding citric acid into ethanol, stirring to dissolve to obtain citric acid solution (solid concentration is 17%), spraying citric acid solution into material A in fluidized boiling state in fluidized bed spray dryer, and continuously fluidizing and boiling to dry material after spraying to obtain fine granular material B, to obtain solid material composition.
Example 4: preparation of solid pharmaceutical compositions in particulate form
Prescription: berberine hydrochloride: 50 parts by weight, ewt, L100: 100 parts by weight, ewt, L100-55: 120 parts by weight, yutecqi S100: 80 parts by weight, Esterqi RL 100: 120 parts by weight, citric acid: 120 parts by weight, 99% ethanol: appropriate amount (removed in the preparation process).
The preparation method comprises the following steps: (1) adding poly (meth) acrylic resin into ethanol, stirring to dissolve (solid concentration is 10%), adding active drug, and stirring to dissolve; (2) spray drying the solution obtained in the step (1) to obtain a fine granular material A; (3) adding citric acid into ethanol, stirring to dissolve to obtain citric acid solution (solid concentration is 20%), spraying citric acid solution into material A in fluidized boiling state in fluidized bed spray dryer, and continuously fluidizing and boiling to dry material after spraying to obtain fine granular material B, to obtain solid material composition.
Example 5: preparation of solid pharmaceutical compositions in particulate form
Prescription: berberine hydrochloride: 50 parts by weight, ewt, L100: 100 parts by weight, ewt, L100-55: 80 parts by weight, yutecqi S100: 120 parts by weight, ewt RL 100: 80 parts by weight, citric acid: 80 parts by weight, 90% ethanol: appropriate amount (removed in the preparation process).
The preparation method comprises the following steps: (1) adding poly (meth) acrylic resin into ethanol, stirring to dissolve (solid concentration is 30%), adding active drug, and stirring to dissolve; (2) spray drying the solution obtained in the step (1) to obtain a fine granular material A; (3) adding citric acid into ethanol, stirring to dissolve to obtain citric acid solution (solid concentration is 10%), spraying citric acid solution into material A in fluidized boiling state in fluidized bed spray dryer, and continuously fluidizing and boiling to dry material after spraying to obtain fine granular material B, to obtain solid material composition.
Example 6: preparation of solid pharmaceutical compositions in particulate form
Referring to the formulation and preparation method of examples 1-5, respectively, except that citric acid was dissolved in the poly (meth) acrylic resin solution of step (1) (concentration based on poly (meth) acrylic resin) to obtain 5 kinds of material A as solid pharmaceutical compositions.
Example 7: preparation of solid pharmaceutical compositions in particulate form
Referring to the formulation and preparation method of examples 1-5, respectively, except that citric acid was not added and the operation of step (3) was not performed, 5 materials a were obtained as solid pharmaceutical compositions.
Example 8: preparation of solid pharmaceutical compositions in particulate form
Referring to the formulation and preparation method of examples 1-5 respectively, except that citric acid was replaced by equal amount of tartaric acid, 5 materials A were obtained as solid pharmaceutical compositions.
Formulation example 1: preparation of pharmaceutical preparations in the form of granules
Prescription: the solid pharmaceutical compositions of examples 1-8: 50 parts by weight of active drug, glucose: 800 parts by weight, sucrose: 500 parts by weight, hydroxypropyl methylcellulose: 60 parts by weight, sucralose: 40 parts by weight of essence (orange): 2 parts by weight.
The preparation method comprises the following steps: (a) weighing a half amount of hydroxypropyl methyl cellulose to prepare a 5% aqueous solution, and then adding sucralose to stir and dissolve to obtain an adhesive solution; (b) weighing the solid pharmaceutical composition of example 1-8, glucose, sucrose powder (pre-crushed) and the rest hydroxypropyl methylcellulose, quickly mixing, and then adding a binder solution for wet granulation; drying and granulating; (c) weighing essence, sieving with 60 mesh sieve, and mixing with the above dry granules; (d) packaging with aluminum plastic composite film bags containing 50mg active drug.
The content of berberine hydrochloride in each solid pharmaceutical composition of examples 1 to 8 or each granule of preparation example 1 was determined by HPLC method for determining the content of berberine hydrochloride capsules on page 1054 of the second part of the Chinese pharmacopoeia, 2020 edition, and the results were consistent with the theoretical dosage of each sample preparation.
Test example 1: the amount of the composition dissolved in water
The process of simulating granules for oral administration is carried out by suspending (suitable for the solid pharmaceutical composition or granules of the present invention which are not completely soluble) or dissolving (suitable for granules which are completely soluble) in an appropriate amount of water in advance, and then orally administering. This test example examined and compared the amount of the drug dissolved in water when the solid pharmaceutical composition or the granule was subjected to the above-mentioned process. The specific operation is as follows:
the solid pharmaceutical compositions of examples 1 to 8 or the granules of preparation example 1 (each material is 50mg in terms of active drug) are respectively put into a centrifuge tube with the length of 15cm and the volume of 20ml, 15ml of water for injection is precisely added, the centrifuge tube is held by a hand and turned upside down 15 times at the frequency of 60 times per minute, a proper amount of the solid pharmaceutical compositions or the granules is immediately filtered by a 0.22 mu m microporous filter membrane, the concentration of berberine hydrochloride in the filtrate is determined by an HPLC method for determining the content of berberine hydrochloride capsules on page 1054 of China pharmacopoeia, 2020 edition, and the percentage of the active drug entering the solution after the test materials are processed is calculated according to the concentration (each sample is represented by the average value of 6 tests).
As a result: examples 1-5 and 8 the percentage of active agent in the solid pharmaceutical composition after the treatment is in the range of 1.1-2.7%, for example, the percentage of active agent in the solid pharmaceutical composition of example 1 after the treatment is 2.14%; the percentage of the active drug in the solution of the 5 solid pharmaceutical compositions of example 6 after the treatment is in the range of 11.2-13.8%, for example, the percentage of the active drug in the solution of the solid pharmaceutical composition obtained by the method of example 6 with reference to example 1 after the treatment is 12.31%; the percentage of the active drug in the solution of the 5 solid pharmaceutical compositions of example 7 after the treatment is within the range of 16.2-17.7%, for example, the percentage of the active drug in the solution of the solid pharmaceutical composition obtained by the method of example 7 with reference to example 1 after the treatment is 17.16%; formulation example 1 the granules obtained by using the 10 solid pharmaceutical compositions of examples 1 to 5 and 8 had the percentage of the active drug in the solution after the treatment in the range of 1.3 to 3.2%, for example, the percentage of the active drug in the solution after the treatment in the granules prepared by using the solid pharmaceutical composition of example 1 in formulation example 1 was 2.02%; formulation example 1 the granules obtained by using the 5 solid pharmaceutical compositions of example 6 had the percentage of the active drug in the solution after the treatment ranged from 10.7 to 13.6%, for example, formulation example 1 the granules prepared by using the solid pharmaceutical composition of example 6 obtained by referring to the method of example 1 had the percentage of the active drug in the solution after the treatment ranged from 12.35%; formulation example 1 the percentage of active drug in the granules obtained by using the 5 solid pharmaceutical compositions of example 7 after the above treatment to the solution was in the range of 15.9 to 18.1%, for example, the percentage of active drug in the solution after the above treatment of the granules prepared by using the solid pharmaceutical composition of example 7 obtained by referring to the method of example 1 in formulation example 1 was 16.84%.
From the above results, in the dosage process of the simulated oral granules, the active substances of the solid pharmaceutical compositions obtained in examples 1 to 5 and 8 are dissolved in water in a relatively small amount, and most of the active substances are not dissolved and still remain in the granules; however, when the organic acid is not added or the timing of the addition of the organic acid is different, a considerable amount of the drug is dissolved in water, which is disadvantageous in that the drug is expected to be dissolved and absorbed in the gastrointestinal tract.
Test example 2: the amount of the composition dissolved in simulated saliva
When the simulated granules are administered orally, the drug may stay in the mouth and mix with saliva before swallowing or swallowing along drinking water. This test example examined and compared the amount of drug dissolved in artificial saliva when a solid pharmaceutical composition or granules were subjected to the above-described procedure. The specific operation is as follows: the solid pharmaceutical compositions of examples 1 to 8 or the granules of preparation example 1 (each material is 50mg in terms of active drug) are respectively put into a centrifuge tube with the length of 15cm and the volume of 20ml, 15ml of artificial saliva is precisely added, the centrifuge tube is held by a hand and turned upside down 10 times at the frequency of 60 times per minute, a proper amount of the artificial saliva is immediately filtered by a 0.22 mu m microporous filter membrane, the concentration of berberine hydrochloride in the filtrate is determined by an HPLC method for determining the content of berberine hydrochloride capsules at 1054 page of the second part of China pharmacopoeia 2020 edition, and the percentage of the active drug entering the artificial saliva after the test material is processed is calculated according to the concentration (each sample is represented by the average value of 6 tests).
As a result: examples 1-5 and 8 the percentage of active agent in the artificial saliva after the above treatment of the solid pharmaceutical composition is in the range of 0.6-1.7%, for example, the percentage of active agent in the artificial saliva after the above treatment of the solid pharmaceutical composition of example 1 is 1.13%; the percentage of the active drug entering the artificial saliva of the 5 solid pharmaceutical compositions of example 6 after the treatment is within the range of 8.7-10.4%, for example, the percentage of the active drug entering the artificial saliva of the solid pharmaceutical composition obtained by the method of example 6 with reference to example 1 after the treatment is 9.83%; the percentage of the active drug entering the artificial saliva of the 5 solid pharmaceutical compositions of example 7 after the treatment is within the range of 12.3-14.1%, for example, the percentage of the active drug entering the artificial saliva of the solid pharmaceutical composition obtained by the method of example 7 with reference to example 1 after the treatment is 12.82%; formulation example 1 the granules obtained by using the 10 solid pharmaceutical compositions of examples 1 to 5 and 8 had the percentage of the active drug entering the artificial saliva after the treatment in the range of 0.6 to 1.5%, for example, the percentage of the active drug entering the artificial saliva after the treatment in the granules prepared by using the solid pharmaceutical composition of example 1 in formulation example 1 was 0.87%; formulation example 1 the granules obtained by using the 5 kinds of solid pharmaceutical compositions of example 6 had the percentage of the active drug entering artificial saliva after the treatment as described above ranged from 9.2% to 10.8%, for example, formulation example 1 the granules prepared by using the solid pharmaceutical composition of example 6 obtained by referring to the method of example 1 had the percentage of the active drug entering artificial saliva after the treatment as described above was 10.17%; formulation example 1 the granules obtained using the 5 solid pharmaceutical compositions of example 7 were treated as described above to give an active substance in an amount ranging from 13.1 to 14.7% in artificial saliva, for example, formulation example 1 the granules prepared using the solid pharmaceutical composition of example 7 obtained by referring to the method of example 1 were treated as described above to give an active substance in an amount of 13.27% in artificial saliva.
From the above results, it can be seen that, in the oral administration process of the simulated oral granules of the solid pharmaceutical compositions obtained in examples 1 to 5 and 8, the active substances are dissolved into the artificial saliva in a relatively small amount, and most of the active substances are not dissolved and still remain in the granules; however, when the organic acid is not added or the timing of the addition of the organic acid is different, a considerable amount of the drug is dissolved in the artificial saliva, which is disadvantageous in that the drug is expected to be dissolved and absorbed in the gastrointestinal tract.
The formula of the artificial saliva used in the test of the invention is as follows: sorbitol 22 g, potassium chloride 1.2 g, sodium chloride 0.9 g, magnesium chloride 0.05 g, calcium phosphate 0.1 g, sodium dihydrogen phosphate 0.02 g, distilled water to 1000ml, after preparation adjusted to pH =6.8 with 1M hydrochloric acid or 1M sodium hydroxide, bottled, and steam sterilized at 100 ℃ for 30 minutes.
Test example 3: determination of dissolution
The dissolution rates of all the solid pharmaceutical compositions obtained in examples 1 to 8 and all the pharmaceutical preparations obtained in preparation example 1 were measured by a dissolution rate and release rate measurement method (first method of 0931, the four ministry of pharmacopoeia of China, 2020 edition), and the pharmaceutical preparations or the solid pharmaceutical compositions were measured in the form of capsules by filling each capsule with 100mg of the active ingredient.
Dissolution conditions: 1000ml of water was used as the dissolution medium, and the rotation speed was 120 rpm, and samples were taken at 45 minutes according to the method.
The determination method comprises the following steps: taking a proper amount of the dissolution liquid, filtering, taking 2ml of the subsequent filtrate, placing the subsequent filtrate in a 25ml measuring flask, diluting with water to scale, and shaking up. Measuring absorbance at 263nm wavelength by ultraviolet-visible spectrophotometry (0401 in the four parts of the Chinese pharmacopoeia, 2020 edition), with absorption coefficient of C20H18ClNO4 & 2H2O
Figure DEST_PATH_IMAGE002
The amount of elution was calculated for 724 per pellet.
As a result: in all the test samples, the dissolution rate at 45 minutes was within the range of 89 to 95%, for example, the dissolution rate of the solid pharmaceutical composition in the form of fine particles obtained in example 1 was 93.2%, the dissolution rate of the solid pharmaceutical composition obtained in example 6 by referring to the formulation and the preparation method of example 1 was 91.7%, the dissolution rate of the solid pharmaceutical composition obtained in example 8 by referring to the formulation and the preparation method of example 1 was 93.1%, and the dissolution rate of the pharmaceutical preparation obtained in preparation example 1 by using the solid pharmaceutical composition of example 1 was 93.6%, indicating that the compositions obtained in the different methods were very satisfactory in dissolution rates when examined by the conventional dissolution rate measuring method.
Example 11: preparation of solid pharmaceutical compositions in particulate form
Prescription: ibuprofen: 50 parts by weight, ewt, L100: 100 parts by weight, ewt, L100-55: 100 parts by weight, yutecqi S100: 100 parts by weight, ewt RL 100: 100 parts by weight, citric acid: 100 parts by weight, 95% ethanol: appropriate amount (removed in the preparation process).
The preparation method comprises the following steps: (1) adding poly (meth) acrylic resin into ethanol, stirring to dissolve (solid concentration is 20%), adding active drug, and stirring to dissolve; (2) spray drying the solution obtained in the step (1) to obtain a fine granular material A; (3) adding citric acid into ethanol, stirring to dissolve to obtain citric acid solution (solid concentration is 15%), spraying citric acid solution into material A in fluidized boiling state in fluidized bed spray dryer, and continuously fluidizing and boiling to dry material after spraying to obtain fine granular material B, to obtain solid material composition.
Example 12: preparation of solid pharmaceutical compositions in particulate form
Prescription: ibuprofen: 50 parts by weight, ewt, L100: 100 parts by weight, ewt, L100-55: 110 parts by weight, yutecqi S100: 90 parts by weight, ewt RL 100: 110 parts by weight, citric acid: 90 parts by weight, 95% ethanol: appropriate amount (removed in the preparation process).
The preparation method comprises the following steps: (1) adding poly (meth) acrylic resin into ethanol, stirring to dissolve (solid concentration is 25%), adding active drug, and stirring to dissolve; (2) spray drying the solution obtained in the step (1) to obtain a fine granular material A; (3) adding citric acid into ethanol, stirring to dissolve to obtain citric acid solution (solid concentration is 13%), spraying citric acid solution into material A in fluidized boiling state in fluidized bed spray dryer, and continuously fluidizing and boiling to dry material after spraying to obtain fine granular material B, to obtain solid material composition.
Example 13: preparation of solid pharmaceutical compositions in particulate form
Prescription: ibuprofen: 50 parts by weight, ewt, L100: 100 parts by weight, ewt, L100-55: 90 parts by weight, yutecqi S100: 110 parts by weight, ewt RL 100: 90 parts by weight, citric acid: 110 parts by weight, 98% ethanol: appropriate amount (removed in the preparation process).
The preparation method comprises the following steps: (1) adding poly (meth) acrylic resin into ethanol, stirring to dissolve (solid content is 15%), adding active drug, and stirring to dissolve; (2) spray drying the solution obtained in the step (1) to obtain a fine granular material A; (3) adding citric acid into ethanol, stirring to dissolve to obtain citric acid solution (solid concentration is 17%), spraying citric acid solution into material A in fluidized boiling state in fluidized bed spray dryer, and continuously fluidizing and boiling to dry material after spraying to obtain fine granular material B, to obtain solid material composition.
Example 14: preparation of solid pharmaceutical compositions in particulate form
Prescription: ibuprofen: 50 parts by weight, ewt, L100: 100 parts by weight, ewt, L100-55: 120 parts by weight, yutecqi S100: 80 parts by weight, Esterqi RL 100: 120 parts by weight, citric acid: 120 parts by weight, 99% ethanol: appropriate amount (removed in the preparation process).
The preparation method comprises the following steps: (1) adding poly (meth) acrylic resin into ethanol, stirring to dissolve (solid concentration is 10%), adding active drug, and stirring to dissolve; (2) spray drying the solution obtained in the step (1) to obtain a fine granular material A; (3) adding citric acid into ethanol, stirring to dissolve to obtain citric acid solution (solid concentration is 20%), spraying citric acid solution into material A in fluidized boiling state in fluidized bed spray dryer, and continuously fluidizing and boiling to dry material after spraying to obtain fine granular material B, to obtain solid material composition.
Example 15: preparation of solid pharmaceutical compositions in particulate form
Prescription: ibuprofen: 50 parts by weight, ewt, L100: 100 parts by weight, ewt, L100-55: 80 parts by weight, yutecqi S100: 120 parts by weight, ewt RL 100: 80 parts by weight, citric acid: 80 parts by weight, 90% ethanol: appropriate amount (removed in the preparation process).
The preparation method comprises the following steps: (1) adding poly (meth) acrylic resin into ethanol, stirring to dissolve (solid concentration is 30%), adding active drug, and stirring to dissolve; (2) spray drying the solution obtained in the step (1) to obtain a fine granular material A; (3) adding citric acid into ethanol, stirring to dissolve to obtain citric acid solution (solid concentration is 10%), spraying citric acid solution into material A in fluidized boiling state in fluidized bed spray dryer, and continuously fluidizing and boiling to dry material after spraying to obtain fine granular material B, to obtain solid material composition.
Example 16: preparation of solid pharmaceutical compositions in particulate form
Referring to the formulation and preparation method of examples 11-15, respectively, except that citric acid was dissolved in the poly (meth) acrylic resin solution of step (1) (concentration based on poly (meth) acrylic resin) to obtain 5 kinds of material A as solid pharmaceutical compositions.
Example 17: preparation of solid pharmaceutical compositions in particulate form
Referring to the formulation and preparation method of examples 11-15, respectively, except that citric acid was not added and the operation of step (3) was not performed, 5 materials A were obtained as solid pharmaceutical compositions.
Example 18: preparation of solid pharmaceutical compositions in particulate form
Referring to the formulation and preparation method of examples 11-15 respectively, except that citric acid was replaced by an equal amount of tartaric acid, 5 materials a were obtained as solid pharmaceutical compositions.
Formulation example 11: preparation of pharmaceutical preparations in the form of granules
Prescription: the solid pharmaceutical compositions of examples 11-18: 50 parts by weight of active drug, glucose: 800 parts by weight, sucrose: 500 parts by weight, hydroxypropyl methylcellulose: 60 parts by weight, sucralose: 40 parts by weight of essence (orange): 2 parts by weight.
The preparation method comprises the following steps: (a) weighing a half amount of hydroxypropyl methyl cellulose to prepare a 5% aqueous solution, and then adding sucralose to stir and dissolve to obtain an adhesive solution; (b) weighing the solid pharmaceutical composition, glucose, sucrose powder (pre-crushed) and the rest hydroxypropyl methylcellulose in the embodiments 11 to 18, quickly mixing, and then adding a binder solution to perform wet granulation; drying and granulating; (c) weighing essence, sieving with 60 mesh sieve, and mixing with the above dry granules; (d) packaging with aluminum plastic composite film bags containing 50mg active drug.
The content of ibuprofen in the solid pharmaceutical compositions of examples 11 to 18 or the granules of preparation example 11 was measured by the HPLC method for measuring the content of ibuprofen capsules on page 212 of the second part of the "chinese pharmacopoeia" 2020 edition, and the results were in agreement with the theoretical dosage of each sample preparation.
Test example 11: the amount of the composition dissolved in water
The process of simulating granules for oral administration is carried out by suspending (suitable for the solid pharmaceutical composition or granules of the present invention which are not completely soluble) or dissolving (suitable for granules which are completely soluble) in an appropriate amount of water in advance, and then orally administering. This test example examined and compared the amount of the drug dissolved in water when the solid pharmaceutical composition or the granule was subjected to the above-mentioned process. The specific operation is as follows:
the solid pharmaceutical compositions of examples 11 to 18 or the granules of preparation example 11 (each material is 50mg in terms of active drug) are respectively put into a centrifuge tube with the length of 15cm and the volume of 20ml, 15ml of water for injection is precisely added, the centrifuge tube is held by a hand and turned up and down 15 times at the frequency of 60 times per minute, a proper amount of the solid pharmaceutical compositions or granules is immediately filtered by a 0.22 mu m microporous filter membrane, the concentration of ibuprofen in the filtrate is measured by an HPLC method for measuring the content of ibuprofen capsules on page 212 of the second part of the 2020 edition Chinese pharmacopoeia, and the percentage of the active drug entering the solution after the test material is processed is calculated according to the weight (each sample is represented by the average value of 6 tests).
As a result: examples 11-15 and 18 the percentage of active agent in the solid pharmaceutical composition after the treatment is in the range of 1.3-2.5%, for example, the percentage of active agent in the solid pharmaceutical composition of example 11 after the treatment is 1.72%; the percentage of the active drug in the solution of the 5 solid pharmaceutical compositions of example 16 after the treatment is in the range of 13.4 to 15.2%, for example, the percentage of the active drug in the solution of the solid pharmaceutical composition obtained by the method of example 16 with reference to example 11 after the treatment is 14.53%; the percentage of the active drug in the solution of the 5 solid pharmaceutical compositions of example 17 after the treatment is in the range of 15.4 to 17.3%, for example, the percentage of the active drug in the solution of the solid pharmaceutical composition obtained in example 17 with reference to the method of example 11 after the treatment is 16.63%; formulation example 11 the granules obtained using the 10 solid pharmaceutical compositions of examples 11 to 15 and 18 had the percentage of the active drug in the solution after the treatment ranged from 1.1 to 2.9%, for example, formulation example 11 the granules prepared using the solid pharmaceutical composition of example 11 had the percentage of the active drug in the solution after the treatment ranged from 2.16%; formulation example 11 the granules obtained using the 5 solid pharmaceutical compositions of example 16 were treated as described above to give active agents in the range of 11.4 to 13.3% in solution, for example, formulation example 11 the granules prepared using the solid pharmaceutical composition of example 16 with reference to the method of example 11 were treated as described above to give active agents in the range of 12.18% in solution; formulation example 11 the granules obtained using the 5 solid pharmaceutical compositions of example 17 were treated as described above to give active agents in the range of 15.2 to 17.7% in solution, for example, formulation example 11 the granules prepared using the solid pharmaceutical composition of example 17 with reference to the method of example 11 were treated as described above to give active agents in the range of 16.31% in solution.
From the above results, in the dosage process of the simulated oral granules, the active substances of the solid pharmaceutical compositions obtained in examples 11 to 15 and 18 are dissolved in water in a relatively small amount, and most of the active substances are not dissolved and still remain in the granules; however, when the organic acid is not added or the timing of the addition of the organic acid is different, a considerable amount of the drug is dissolved in water, which is disadvantageous in that the drug is expected to be dissolved and absorbed in the gastrointestinal tract.
Test example 12: the amount of the composition dissolved in simulated saliva
When the simulated granules are administered orally, the drug may stay in the mouth and mix with saliva before swallowing or swallowing along drinking water. This test example examined and compared the amount of drug dissolved in artificial saliva when a solid pharmaceutical composition or granules were subjected to the above-described procedure. The specific operation is as follows: the solid pharmaceutical compositions of examples 11 to 18 or the granules of preparation example 11 (each material is 50mg in terms of active drug) are respectively put into a centrifuge tube with the length of 15cm and the volume of 20ml, 15ml of artificial saliva is precisely added, the centrifuge tube is held by a hand and turned upside down 10 times at the frequency of 60 times per minute, a proper amount of the artificial saliva is immediately taken and filtered by a 0.22 mu m microporous membrane, the concentration of ibuprofen in filtrate is measured by an HPLC method for measuring the content of ibuprofen capsules on page 212 of the second part of the 2020 edition Chinese pharmacopoeia, and the percentage of the active drug entering the artificial saliva after the test material is processed is calculated according to the concentration (each sample is represented by the average value of 6 tests).
As a result: examples 11-15 and 18 the percentage of active agent in artificial saliva after the above treatment of the solid pharmaceutical composition is in the range of 0.8-1.5%, for example, the percentage of active agent in artificial saliva after the above treatment of the solid pharmaceutical composition of example 11 is 1.24%; the percentage of the active drug in the artificial saliva of the 5 solid pharmaceutical compositions of example 16 after the treatment is in the range of 9.4-11.2%, for example, the percentage of the active drug in the artificial saliva of the solid pharmaceutical composition obtained by the method of example 16 with reference to example 11 after the treatment is 10.47%; the percentage of the active drug in the artificial saliva of the 5 solid pharmaceutical compositions of example 17 after the treatment is in the range of 11.2-14.5%, for example, the percentage of the active drug in the artificial saliva of the solid pharmaceutical composition obtained by the method of example 17 with reference to example 11 after the treatment is 13.26%; formulation example 11 the granules obtained using the 10 solid pharmaceutical compositions of examples 11 to 15 and 18 had the percentage of active drug entering artificial saliva after the treatment described above ranged from 0.6 to 1.2%, for example, formulation example 11 the granules prepared using the solid pharmaceutical composition of example 11 had the percentage of active drug entering artificial saliva after the treatment described above ranged from 0.93%; formulation example 11 using the 5 solid pharmaceutical compositions of example 16, the percentage of active agent in artificial saliva obtained by the above treatment was in the range of 8.8 to 11.2%, for example formulation example 11 using the solid pharmaceutical composition of example 16 obtained by reference to example 11, the percentage of active agent in artificial saliva obtained by the above treatment was 9.83%; formulation example 11 the granules obtained using the 5 solid pharmaceutical compositions of example 17 were treated as described above to give an active substance in an amount of 13.1 to 14.7% by weight of the artificial saliva, for example, formulation example 11 the granules prepared using the solid pharmaceutical composition of example 17 with reference to the method of example 11 were treated as described above to give an active substance in an amount of 13.27% by weight of the artificial saliva.
From the above results, it can be seen that in the oral administration process of the simulated oral granules of the solid pharmaceutical compositions obtained in examples 11 to 15 and example 18, the active substance is dissolved into the artificial saliva in a relatively small amount, and most of the active substance is not dissolved and still remains in the granules; however, when the organic acid is not added or the timing of the addition of the organic acid is different, a considerable amount of the drug is dissolved in the artificial saliva, which is disadvantageous in that the drug is expected to be dissolved and absorbed in the gastrointestinal tract.
The formula of the artificial saliva used in the test of the invention is as follows: sorbitol 22 g, potassium chloride 1.2 g, sodium chloride 0.9 g, magnesium chloride 0.05 g, calcium phosphate 0.1 g, sodium dihydrogen phosphate 0.02 g, distilled water to 1000ml, after preparation adjusted to pH =6.8 with 1M hydrochloric acid or 1M sodium hydroxide, bottled, and steam sterilized at 100 ℃ for 30 minutes.
Test example 13: determination of dissolution
The dissolution rates of all the solid pharmaceutical compositions obtained in examples 11 to 18 and all the pharmaceutical preparations obtained in preparation example 11 were measured by a dissolution rate and release rate measurement method (first method of 0931, the four ministry of pharmacopoeia of China, 2020 edition), and these pharmaceutical preparations or solid pharmaceutical compositions were measured in the form of capsules by filling each capsule with 100mg of the active ingredient.
Dissolution conditions: 900ml of phosphate buffer (pH7.2) was used as the dissolution medium, and the rotation speed was 100 rpm, and samples were taken over 30 minutes by the same method.
Test solution: taking 10ml of dissolution liquid, filtering, precisely taking a proper amount of subsequent filtrate, and quantitatively diluting with dissolution medium to prepare a solution containing about 0.1mg ibuprofen in each 1 ml.
Control solution: taking ibuprofen reference substance, precisely weighing, adding appropriate amount of methanol for dissolving, and quantitatively diluting with dissolution medium to obtain solution containing about 0.1mg per 1 ml.
Chromatographic conditions and system applicability requirements: see 2020 edition "Chinese pharmacopoeia" second part 212 ibuprofen capsule content determination item.
The determination method comprises the following steps: the dissolution amount of each capsule is calculated under the content determination item of ibuprofen capsule on the second part 212 page of China pharmacopoeia of 2020 edition.
As a result: the dissolution amounts of all the test samples were in the range of 91 to 96%, for example, the dissolution amount of the solid pharmaceutical composition in the form of fine particles obtained in example 11 was 94.4%, the dissolution amount of the solid pharmaceutical composition obtained in example 16 by referring to the formulation and the preparation method of example 11 was 93.1%, the dissolution amount of the solid pharmaceutical composition obtained in example 18 by referring to the formulation and the preparation method of example 11 was 93.8%, and the dissolution amount of the pharmaceutical preparation obtained in preparation example 11 by using the solid pharmaceutical composition of example 11 was 92.7%, indicating that the compositions obtained in the different methods were very satisfactory in dissolution rates when examined by the conventional dissolution rate measuring method.
Example 21: preparation of solid pharmaceutical compositions in particulate form
Prescription: azithromycin: 50 parts by weight, ewt, L100: 100 parts by weight, ewt, L100-55: 100 parts by weight, yutecqi S100: 100 parts by weight, ewt RL 100: 100 parts by weight, citric acid: 100 parts by weight, 95% ethanol: appropriate amount (removed in the preparation process).
The preparation method comprises the following steps: (1) adding poly (meth) acrylic resin into ethanol, stirring to dissolve (solid concentration is 20%), adding active drug, and stirring to dissolve; (2) spray drying the solution obtained in the step (1) to obtain a fine granular material A; (3) adding citric acid into ethanol, stirring to dissolve to obtain citric acid solution (solid concentration is 15%), spraying citric acid solution into material A in fluidized boiling state in fluidized bed spray dryer, and continuously fluidizing and boiling to dry material after spraying to obtain fine granular material B, to obtain solid material composition.
Example 22: preparation of solid pharmaceutical compositions in particulate form
Prescription: azithromycin: 50 parts by weight, ewt, L100: 100 parts by weight, ewt, L100-55: 110 parts by weight, yutecqi S100: 90 parts by weight, ewt RL 100: 110 parts by weight, citric acid: 90 parts by weight, 95% ethanol: appropriate amount (removed in the preparation process).
The preparation method comprises the following steps: (1) adding poly (meth) acrylic resin into ethanol, stirring to dissolve (solid concentration is 25%), adding active drug, and stirring to dissolve; (2) spray drying the solution obtained in the step (1) to obtain a fine granular material A; (3) adding citric acid into ethanol, stirring to dissolve to obtain citric acid solution (solid concentration is 13%), spraying citric acid solution into material A in fluidized boiling state in fluidized bed spray dryer, and continuously fluidizing and boiling to dry material after spraying to obtain fine granular material B, to obtain solid material composition.
Example 23: preparation of solid pharmaceutical compositions in particulate form
Prescription: azithromycin: 50 parts by weight, ewt, L100: 100 parts by weight, ewt, L100-55: 90 parts by weight, yutecqi S100: 110 parts by weight, ewt RL 100: 90 parts by weight, citric acid: 110 parts by weight, 98% ethanol: appropriate amount (removed in the preparation process).
The preparation method comprises the following steps: (1) adding poly (meth) acrylic resin into ethanol, stirring to dissolve (solid content is 15%), adding active drug, and stirring to dissolve; (2) spray drying the solution obtained in the step (1) to obtain a fine granular material A; (3) adding citric acid into ethanol, stirring to dissolve to obtain citric acid solution (solid concentration is 17%), spraying citric acid solution into material A in fluidized boiling state in fluidized bed spray dryer, and continuously fluidizing and boiling to dry material after spraying to obtain fine granular material B, to obtain solid material composition.
Example 24: preparation of solid pharmaceutical compositions in particulate form
Prescription: azithromycin: 50 parts by weight, ewt, L100: 100 parts by weight, ewt, L100-55: 120 parts by weight, yutecqi S100: 80 parts by weight, Esterqi RL 100: 120 parts by weight, citric acid: 120 parts by weight, 99% ethanol: appropriate amount (removed in the preparation process).
The preparation method comprises the following steps: (1) adding poly (meth) acrylic resin into ethanol, stirring to dissolve (solid concentration is 10%), adding active drug, and stirring to dissolve; (2) spray drying the solution obtained in the step (1) to obtain a fine granular material A; (3) adding citric acid into ethanol, stirring to dissolve to obtain citric acid solution (solid concentration is 20%), spraying citric acid solution into material A in fluidized boiling state in fluidized bed spray dryer, and continuously fluidizing and boiling to dry material after spraying to obtain fine granular material B, to obtain solid material composition.
Example 25: preparation of solid pharmaceutical compositions in particulate form
Prescription: azithromycin: 50 parts by weight, ewt, L100: 100 parts by weight, ewt, L100-55: 80 parts by weight, yutecqi S100: 120 parts by weight, ewt RL 100: 80 parts by weight, citric acid: 80 parts by weight, 90% ethanol: appropriate amount (removed in the preparation process).
The preparation method comprises the following steps: (1) adding poly (meth) acrylic resin into ethanol, stirring to dissolve (solid concentration is 30%), adding active drug, and stirring to dissolve; (2) spray drying the solution obtained in the step (1) to obtain a fine granular material A; (3) adding citric acid into ethanol, stirring to dissolve to obtain citric acid solution (solid concentration is 10%), spraying citric acid solution into material A in fluidized boiling state in fluidized bed spray dryer, and continuously fluidizing and boiling to dry material after spraying to obtain fine granular material B, to obtain solid material composition.
Example 26: preparation of solid pharmaceutical compositions in particulate form
Referring to the formulation and preparation method of examples 21-25, respectively, except that citric acid was dissolved in the poly (meth) acrylic resin solution of step (1) (concentration based on poly (meth) acrylic resin) to obtain 5 kinds of material A as solid pharmaceutical compositions.
Example 27: preparation of solid pharmaceutical compositions in particulate form
Referring to the formulation and preparation method of examples 21-25, respectively, except that citric acid was not added and the operation of step (3) was not performed, 5 kinds of material A were obtained as solid pharmaceutical compositions.
Example 28: preparation of solid pharmaceutical compositions in particulate form
Referring to the formulation and preparation method of examples 21-25 respectively, except that citric acid was replaced by equal amount of tartaric acid, 5 materials a were obtained as solid pharmaceutical compositions.
Preparation example 21: preparation of pharmaceutical preparations in the form of granules
Prescription: the solid pharmaceutical compositions of examples 21-28: 50 parts by weight of active drug, glucose: 800 parts by weight, sucrose: 500 parts by weight, hydroxypropyl methylcellulose: 60 parts by weight, sucralose: 40 parts by weight of essence (orange): 2 parts by weight.
The preparation method comprises the following steps: (a) weighing a half amount of hydroxypropyl methyl cellulose to prepare a 5% aqueous solution, and then adding sucralose to stir and dissolve to obtain an adhesive solution; (b) weighing the solid pharmaceutical composition of example 21-28, glucose, sucrose powder (pre-crushed) and the rest hydroxypropyl methylcellulose, quickly mixing, and then adding a binder solution to perform wet granulation; drying and granulating; (c) weighing essence, sieving with 60 mesh sieve, and mixing with the above dry granules; (d) packaging with aluminum plastic composite film bags containing 50mg active drug.
The content of azithromycin in each solid pharmaceutical composition of examples 21 to 28 or each granule of formulation example 21 was measured by the HPLC method for measuring the content of azithromycin capsules on page 693 of the "chinese pharmacopoeia" second part, 2020 edition, and the results were in agreement with the theoretical dosage of each sample preparation.
Test example 21: the amount of the composition dissolved in water
The process of simulating granules for oral administration is carried out by suspending (suitable for the solid pharmaceutical composition or granules of the present invention which are not completely soluble) or dissolving (suitable for granules which are completely soluble) in an appropriate amount of water in advance, and then orally administering. This test example examined and compared the amount of the drug dissolved in water when the solid pharmaceutical composition or the granule was subjected to the above-mentioned process. The specific operation is as follows: the solid pharmaceutical compositions of examples 21 to 28 or the granules of formulation 21 (each material is 50mg in terms of active drug) were placed in a centrifuge tube 15cm long and 20ml in volume, 15ml of water for injection was precisely added, the centrifuge tube was held by a hand and turned upside down 15 times at a frequency of 60 times per minute, an appropriate amount of the solid pharmaceutical compositions or granules was immediately filtered through a 0.22 μm microporous membrane, the concentration of azithromycin in the filtrate was measured by an HPLC method for measuring the content of azithromycin capsules on page 693 of the second part of the chinese pharmacopoeia, 2020 edition, and the percentage of active drug in the solution after the treatment of the test material was calculated on the basis of the above (each sample was represented by the average value of 6 tests).
As a result: examples 21-25 and 28 the percentage of active agent in the solid pharmaceutical composition after the treatment is in the range of 0.8-2.0%, for example, the percentage of active agent in the solid pharmaceutical composition of example 21 after the treatment is 1.42%; the percentage of the active drug in the solution of the 5 solid pharmaceutical compositions of example 26 after the treatment is within the range of 9.3 to 11.7%, for example, the percentage of the active drug in the solution of the solid pharmaceutical composition obtained in example 26 with reference to the method of example 21 after the treatment is 10.24%; the percentage of the active drug in the solution of the 5 solid pharmaceutical compositions of example 27 after the treatment is in the range of 11.6-13.8%, for example, the percentage of the active drug in the solution of the solid pharmaceutical composition obtained by the method of example 27 with reference to example 21 is 12.17%; formulation example 21 using the 10 solid pharmaceutical compositions of examples 21 to 25 and example 28, the percentage of the active drug in the solution after the treatment was in the range of 1.1 to 1.9%, for example, formulation example 21 using the solid pharmaceutical composition of example 21, the percentage of the active drug in the solution after the treatment was 1.52%; formulation example 21 using the 5 solid pharmaceutical compositions of example 26, the percentage of the active agent in the solution after the treatment was within the range of 10.7 to 13.1%, for example, formulation example 21 using the solid pharmaceutical composition of example 26 obtained by referring to the method of example 21, the percentage of the active agent in the solution after the treatment was 11.26%; formulation example 21 the percentage of active drug in the solution of granules obtained using the 5 solid pharmaceutical compositions of example 27 after the above treatment was in the range of 11.3 to 14.5%, for example, the percentage of active drug in the solution of granules obtained using the solid pharmaceutical composition of example 27 obtained by referring to the method of example 21 in formulation example 21 after the above treatment was 13.24%.
From the above results, in the dosage process of the simulated oral granules, the active substances of the solid pharmaceutical compositions obtained in examples 21-25 and example 28 are dissolved in water in a relatively small amount, and most of the active substances are not dissolved and still remain in the granules; however, when the organic acid is not added or the timing of the addition of the organic acid is different, a considerable amount of the drug is dissolved in water, which is disadvantageous in that the drug is expected to be dissolved and absorbed in the gastrointestinal tract.
Test example 22: the amount of the composition dissolved in simulated saliva
When the simulated granules are administered orally, the drug may stay in the mouth and mix with saliva before swallowing or swallowing along drinking water. This test example examined and compared the amount of drug dissolved in artificial saliva when a solid pharmaceutical composition or granules were subjected to the above-described procedure. The specific operation is as follows: the solid pharmaceutical compositions of examples 21 to 28 or the granules of formulation 21 (each material is 50mg in terms of active drug) were placed in a centrifuge tube 15cm long and 20ml in volume, 15ml of artificial saliva was added precisely, the tube was turned upside down 10 times by holding with a hand at a frequency of 60 times per minute, an appropriate amount of the solution was immediately filtered through a 0.22 μm microporous membrane, the concentration of azithromycin in the filtrate was measured by an HPLC method for measuring the content of azithromycin in page 693 of the second part of the chinese pharmacopoeia, 2020 edition, and the percentage of active drug entering artificial saliva after the above treatment of the test material was calculated based on this (each sample is represented by the average value of 6 tests).
As a result: examples 21-25 and 28 the percentage of active agent in artificial saliva after the above treatment of the solid pharmaceutical composition is in the range of 0.9-2.2%, for example 1.74% of the active agent in artificial saliva after the above treatment of the solid pharmaceutical composition of example 21; the percentage of the active drug in the artificial saliva of the 5 solid pharmaceutical compositions of example 26 after the treatment is in the range of 11.2-14.0%, for example, the percentage of the active drug in the artificial saliva of the solid pharmaceutical composition obtained by the method of example 26 with reference to example 21 after the treatment is 12.84%; the percentage of the active drug in the artificial saliva of the 5 solid pharmaceutical compositions of example 27 after the treatment is in the range of 12.4-14.1%, for example, the percentage of the active drug in the artificial saliva of the solid pharmaceutical composition obtained by the method of example 27 with reference to example 21 is 13.42%; preparation example 21 granules prepared by using the 10 solid pharmaceutical compositions of examples 21 to 25 and example 28 had the percentage of the active drug entering artificial saliva after the treatment in the range of 0.7 to 1.4%, for example, the percentage of the active drug entering artificial saliva after the treatment in the granules prepared by using the solid pharmaceutical composition of example 21 of preparation example 21 was 1.14%; formulation example 21 using the 5 solid pharmaceutical compositions of example 26, the percentage of active drug in artificial saliva after the treatment was in the range of 7.9 to 10.4%, for example, formulation example 21 using the solid pharmaceutical composition of example 26 with reference to example 21, the percentage of active drug in artificial saliva after the treatment was 8.72%; formulation example 21 the granules obtained using the 5 solid pharmaceutical compositions of example 27 were treated as described above to give active agents in an amount ranging from 12.4 to 14.2% of artificial saliva, for example, formulation example 21 the granules prepared using the solid pharmaceutical composition of example 27 with reference to the method of example 21 were treated as described above to give active agents in an amount of 13.16% of artificial saliva.
From the above results, it can be seen that in the oral administration process of the simulated oral granules of the solid pharmaceutical compositions obtained in examples 21 to 25 and example 28, the active substance is dissolved into the artificial saliva in a relatively small amount, and most of the active substance is not dissolved and still remains in the granules; however, when the organic acid is not added or the timing of the addition of the organic acid is different, a considerable amount of the drug is dissolved in the artificial saliva, which is disadvantageous in that the drug is expected to be dissolved and absorbed in the gastrointestinal tract.
The formula of the artificial saliva used in the test of the invention is as follows: sorbitol 22 g, potassium chloride 1.2 g, sodium chloride 0.9 g, magnesium chloride 0.05 g, calcium phosphate 0.1 g, sodium dihydrogen phosphate 0.02 g, distilled water to 1000ml, after preparation adjusted to pH =6.8 with 1M hydrochloric acid or 1M sodium hydroxide, bottled, and steam sterilized at 100 ℃ for 30 minutes.
Test example 23: determination of dissolution
The dissolution rates of all the solid pharmaceutical compositions obtained in examples 21 to 28 and all the pharmaceutical preparations obtained in preparation example 21 were measured by a dissolution rate and release rate measurement method (second method 0931, the four ministry of pharmacopoeia of China, 2020 edition), and these pharmaceutical preparations or solid pharmaceutical compositions were measured in the form of capsules by filling each capsule with an amount of 125mg of the active ingredient.
Dissolution conditions: 500ml of phosphate buffer (pH6.0) (6000 ml of 0.1mol/L disodium hydrogenphosphate solution, about 40ml of hydrochloric acid was added, and the pH was adjusted to 6.0. + -. 0.05) was used as a dissolution medium, and the sample was taken at 45 minutes per 100 rpm according to the method.
Test solution: taking a proper amount of the dissolved liquid, filtering and taking a subsequent filtrate.
Control solution: taking a proper amount of azithromycin reference substance, precisely weighing, adding a proper amount of ethanol (about 1ml of ethanol is added for every 2 mg) to dissolve, and quantitatively diluting with a dissolution medium to prepare a solution containing about 0.25mg of azithromycin in every 1 ml.
The system applicability solution, chromatographic conditions and system applicability requirements are found in the content determination item.
The determination method comprises the following steps: see the content determination item.
System applicability solution: and taking a proper amount of an azithromycin system applicability reference substance, adding acetonitrile to dissolve and dilute the azithromycin system applicability reference substance to prepare a solution containing 10mg of azithromycin per 1 ml.
Chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filling agent; phosphate buffer solution (0.05 mol/L dipotassium hydrogen phosphate solution is taken, the pH value is adjusted to 8.2 by 20 percent phosphoric acid solution) -ethyl wax (45:55) is taken as a mobile phase; the detection wavelength is 210 nm; the injection volume was 50. mu.l.
System applicability requirements: system applicability the solution chromatogram should be consistent with the standard chromatogram.
The determination method comprises the following steps: precisely measuring the test solution and the reference solution, respectively injecting into a liquid chromatograph, and recording the chromatogram. Calculating the dissolution amount of each grain by peak area according to an external standard method.
As a result: the dissolution amounts of all the test samples were in the range of 88 to 93%, for example, the dissolution amount of the solid pharmaceutical composition in the form of fine particles obtained in example 21 was 91.6%, the dissolution amount of the solid pharmaceutical composition obtained in example 26 with reference to the formulation and the preparation method of example 21 was 89.4%, the dissolution amount of the solid pharmaceutical composition obtained in example 28 with reference to the formulation and the preparation method of example 21 was 92.4%, and the dissolution amount of the pharmaceutical preparation obtained in preparation example 21 using the solid pharmaceutical composition of example 21 was 90.4%, indicating that the compositions obtained in the different methods were very satisfactory in dissolution rates when examined by the conventional dissolution rate measurement method.
Example 31: preparation of solid pharmaceutical compositions in particulate form
Prescription: atorvastatin calcium: 50 parts by weight, ewt, L100: 100 parts by weight, ewt, L100-55: 100 parts by weight, yutecqi S100: 100 parts by weight, ewt RL 100: 100 parts by weight, citric acid: 100 parts by weight, 95% ethanol: appropriate amount (removed in the preparation process).
The preparation method comprises the following steps: (1) adding poly (meth) acrylic resin into ethanol, stirring to dissolve (solid concentration is 20%), adding active drug, and stirring to dissolve; (2) spray drying the solution obtained in the step (1) to obtain a fine granular material A; (3) adding citric acid into ethanol, stirring to dissolve to obtain citric acid solution (solid concentration is 15%), spraying citric acid solution into material A in fluidized boiling state in fluidized bed spray dryer, and continuously fluidizing and boiling to dry material after spraying to obtain fine granular material B, to obtain solid material composition.
Example 32: preparation of solid pharmaceutical compositions in particulate form
Prescription: atorvastatin calcium: 50 parts by weight, ewt, L100: 100 parts by weight, ewt, L100-55: 110 parts by weight, yutecqi S100: 90 parts by weight, ewt RL 100: 110 parts by weight, citric acid: 90 parts by weight, 95% ethanol: appropriate amount (removed in the preparation process).
The preparation method comprises the following steps: (1) adding poly (meth) acrylic resin into ethanol, stirring to dissolve (solid concentration is 25%), adding active drug, and stirring to dissolve; (2) spray drying the solution obtained in the step (1) to obtain a fine granular material A; (3) adding citric acid into ethanol, stirring to dissolve to obtain citric acid solution (solid concentration is 13%), spraying citric acid solution into material A in fluidized boiling state in fluidized bed spray dryer, and continuously fluidizing and boiling to dry material after spraying to obtain fine granular material B, to obtain solid material composition.
Example 33: preparation of solid pharmaceutical compositions in particulate form
Prescription: atorvastatin calcium: 50 parts by weight, ewt, L100: 100 parts by weight, ewt, L100-55: 90 parts by weight, yutecqi S100: 110 parts by weight, ewt RL 100: 90 parts by weight, citric acid: 110 parts by weight, 98% ethanol: appropriate amount (removed in the preparation process).
The preparation method comprises the following steps: (1) adding poly (meth) acrylic resin into ethanol, stirring to dissolve (solid content is 15%), adding active drug, and stirring to dissolve; (2) spray drying the solution obtained in the step (1) to obtain a fine granular material A; (3) adding citric acid into ethanol, stirring to dissolve to obtain citric acid solution (solid concentration is 17%), spraying citric acid solution into material A in fluidized boiling state in fluidized bed spray dryer, and continuously fluidizing and boiling to dry material after spraying to obtain fine granular material B, to obtain solid material composition.
Example 34: preparation of solid pharmaceutical compositions in particulate form
Prescription: atorvastatin calcium: 50 parts by weight, ewt, L100: 100 parts by weight, ewt, L100-55: 120 parts by weight, yutecqi S100: 80 parts by weight, Esterqi RL 100: 120 parts by weight, citric acid: 120 parts by weight, 99% ethanol: appropriate amount (removed in the preparation process).
The preparation method comprises the following steps: (1) adding poly (meth) acrylic resin into ethanol, stirring to dissolve (solid concentration is 10%), adding active drug, and stirring to dissolve; (2) spray drying the solution obtained in the step (1) to obtain a fine granular material A; (3) adding citric acid into ethanol, stirring to dissolve to obtain citric acid solution (solid concentration is 20%), spraying citric acid solution into material A in fluidized boiling state in fluidized bed spray dryer, and continuously fluidizing and boiling to dry material after spraying to obtain fine granular material B, to obtain solid material composition.
Example 35: preparation of solid pharmaceutical compositions in particulate form
Prescription: atorvastatin calcium: 50 parts by weight, ewt, L100: 100 parts by weight, ewt, L100-55: 80 parts by weight, yutecqi S100: 120 parts by weight, ewt RL 100: 80 parts by weight, citric acid: 80 parts by weight, 90% ethanol: appropriate amount (removed in the preparation process).
The preparation method comprises the following steps: (1) adding poly (meth) acrylic resin into ethanol, stirring to dissolve (solid concentration is 30%), adding active drug, and stirring to dissolve; (2) spray drying the solution obtained in the step (1) to obtain a fine granular material A; (3) adding citric acid into ethanol, stirring to dissolve to obtain citric acid solution (solid concentration is 10%), spraying citric acid solution into material A in fluidized boiling state in fluidized bed spray dryer, and continuously fluidizing and boiling to dry material after spraying to obtain fine granular material B, to obtain solid material composition.
Example 36: preparation of solid pharmaceutical compositions in particulate form
Referring to the formulation and preparation method of examples 31-35, respectively, except that citric acid was dissolved in the poly (meth) acrylic resin solution of step (1) (concentration based on poly (meth) acrylic resin) to obtain 5 kinds of material A as solid pharmaceutical compositions.
Example 37: preparation of solid pharmaceutical compositions in particulate form
Referring to the formulation and preparation method of examples 31-35 respectively, except that citric acid was not added and the operation of step (3) was not performed, 5 materials A were obtained as solid pharmaceutical compositions.
Example 38: preparation of solid pharmaceutical compositions in particulate form
Referring to the formulation and preparation method of examples 31-35 respectively, except that citric acid was replaced by equal amount of tartaric acid, 5 materials a were obtained as solid pharmaceutical compositions.
Formulation example 31: preparation of pharmaceutical preparations in the form of granules
Prescription: the solid pharmaceutical compositions of examples 31-38: 50 parts by weight of active drug, glucose: 800 parts by weight, sucrose: 500 parts by weight, hydroxypropyl methylcellulose: 60 parts by weight, sucralose: 40 parts by weight of essence (orange): 2 parts by weight.
The preparation method comprises the following steps: (a) weighing a half amount of hydroxypropyl methyl cellulose to prepare a 5% aqueous solution, and then adding sucralose to stir and dissolve to obtain an adhesive solution; (b) weighing the solid pharmaceutical composition, glucose, sucrose powder (pre-crushed) and the rest hydroxypropyl methylcellulose in the embodiments 31 to 38, quickly mixing, and then adding a binder solution for wet granulation; drying and granulating; (c) weighing essence, sieving with 60 mesh sieve, and mixing with the above dry granules; (d) packaging with aluminum plastic composite film bags containing 10mg active drug.
The content of atorvastatin calcium in each of the solid pharmaceutical compositions of examples 31 to 38 or each of the granules of formulation example 31 was measured using the following [ content measurement a ] method, and the results were in agreement with the theoretical charge for each sample preparation:
[ MEASUREMENT A ] taking a proper amount of a sample, precisely weighing, grinding, precisely weighing a proper amount (about 10mg of atorvastatin calcium), placing the sample in a 50ml measuring flask, adding a proper amount of ethanol, fully shaking to dissolve the atorvastatin calcium, adding ethanol to dilute to a scale, shaking up, filtering, precisely weighing 2ml of a subsequent filtrate, placing the subsequent filtrate in a 25ml measuring flask, adding ethanol to dilute to the scale, shaking up to obtain a sample solution; taking a proper amount of an atorvastatin calcium reference substance, precisely weighing, and adding ethanol to prepare a solution containing 16ug of atorvastatin calcium per 1ml, wherein the solution is used as a reference substance solution; measuring absorbance at wavelength of 246nm by spectrophotometry, and calculating.
Test example 31: the amount of the composition dissolved in water
The process of simulating granules for oral administration is carried out by suspending (suitable for the solid pharmaceutical composition or granules of the present invention which are not completely soluble) or dissolving (suitable for granules which are completely soluble) in an appropriate amount of water in advance, and then orally administering. This test example examined and compared the amount of the drug dissolved in water when the solid pharmaceutical composition or the granule was subjected to the above-mentioned process. The specific operation is as follows: the solid pharmaceutical compositions of examples 31 to 38 or the granules of preparation example 31 (each material is 10mg in terms of active drug) were placed in a centrifuge tube 15cm long and 20ml in volume, 15ml of water for injection was precisely added, the centrifuge tube was held by a hand and turned over 15 times at a frequency of 60 times per minute, an appropriate amount of the mixture was immediately filtered through a 0.22 μm microporous membrane, and the concentration of atorvastatin calcium in the filtrate was determined by a [ content determination a ] method, whereby the percentage of active drug in the solution after the treatment of the test material was calculated (each sample is represented by the average of 6 tests).
As a result: examples 31-35 and 38 the percentage of active agent in the solid pharmaceutical composition after the treatment is in the range of 0.9-1.8%, for example, the percentage of active agent in the solid pharmaceutical composition of example 31 after the treatment is 1.27%; the percentage of the active drug in the solution of the 5 solid pharmaceutical compositions of example 36 after the treatment is within the range of 10.3 to 12.8%, for example, the percentage of the active drug in the solution of the solid pharmaceutical composition obtained by the method of example 36 with reference to example 31 is 11.37%; the percentage of the active drug in the solution of the 5 solid pharmaceutical compositions of example 37 after the treatment is within the range of 12.3-15.2%, for example, the percentage of the active drug in the solution of the solid pharmaceutical composition obtained by the method of example 37 with reference to example 31 is 13.42%; formulation example 31 the granules obtained by using the 10 solid pharmaceutical compositions of examples 31 to 35 and example 38, the percentage of the active drug in the solution after the treatment is in the range of 1.1 to 1.7%, for example, the percentage of the active drug in the solution after the treatment is 1.33% in the granules prepared by using the solid pharmaceutical composition of example 31 in formulation example 31; formulation example 31 the granules obtained by using the 5 solid pharmaceutical compositions of example 36, the percentage of the active drug in the solution after the treatment is in the range of 11.5 to 13.9%, for example, the percentage of the active drug in the solution after the treatment is 12.31% in the granules prepared by using the solid pharmaceutical composition of example 36 obtained by referring to the method of example 31 in formulation example 31; formulation example 31 the granules obtained using the 5 solid pharmaceutical compositions of example 37 were treated as described above to give a percentage of active drug in solution ranging from 13.1 to 15.6%, for example formulation example 31 the granules prepared using the solid pharmaceutical composition of example 37 with reference to the method of example 31 were treated as described above to give a percentage of active drug in solution of 13.73%.
From the above results, in the dosage process of the simulated oral granules, the active substances of the solid pharmaceutical compositions obtained in examples 31 to 35 and 38 are dissolved in water in a relatively small amount, and most of the active substances are not dissolved and still remain in the granules; however, when the organic acid is not added or the timing of the addition of the organic acid is different, a considerable amount of the drug is dissolved in water, which is disadvantageous in that the drug is expected to be dissolved and absorbed in the gastrointestinal tract.
Test example 32: the amount of the composition dissolved in simulated saliva
When the simulated granules are administered orally, the drug may stay in the mouth and mix with saliva before swallowing or swallowing along drinking water. This test example examined and compared the amount of drug dissolved in artificial saliva when a solid pharmaceutical composition or granules were subjected to the above-described procedure. The specific operation is as follows: the solid pharmaceutical compositions of examples 31 to 38 or the granules of preparation example 31 (each material is 10mg in terms of active drug) were placed in a centrifuge tube 15cm long and 20ml in volume, 15ml of artificial saliva was precisely added, the centrifuge tube was held by a hand and turned upside down 10 times at a frequency of 60 times per minute, an appropriate amount of the saliva was immediately filtered through a 0.22 μm microporous membrane, the concentration of atorvastatin calcium in the filtrate was measured by using a [ content measurement a ] method, and the percentage of active drug in the artificial saliva after the test material was treated as described above was calculated based on the above (each sample was represented by the average of 6 tests).
As a result: examples 31-35 and 38 the percentage of active agent in artificial saliva after the above treatment of the solid pharmaceutical composition is in the range of 0.9-1.7%, for example 1.46% of active agent in artificial saliva after the above treatment of the solid pharmaceutical composition of example 31; the percentage of the active drug in the artificial saliva of the 5 solid pharmaceutical compositions of example 36 after the treatment is within the range of 10.3-13.1%, for example, the percentage of the active drug in the artificial saliva of the solid pharmaceutical composition obtained by the method of example 36 with reference to example 31 after the treatment is 11.32%; the percentage of the active drug in the artificial saliva of the 5 solid pharmaceutical compositions of example 37 after the treatment is in the range of 11.7-14.0%, for example, the percentage of the active drug in the artificial saliva of the solid pharmaceutical composition obtained by the method of example 37 with reference to example 31 is 12.17%; formulation example 31 the granules obtained by using the 10 solid pharmaceutical compositions of examples 31 to 35 and example 38, wherein the percentage of the active drug entering the artificial saliva after the treatment is in the range of 0.8 to 1.9%, for example, the percentage of the active drug entering the artificial saliva after the treatment is 1.47% in the granules prepared by using the solid pharmaceutical composition of example 31 of formulation example 31; formulation example 31 the granules obtained by using the 5 solid pharmaceutical compositions of example 36, wherein the percentage of the active drug entering artificial saliva after the treatment is in the range of 9.8-13.2%, for example, the percentage of the active drug entering artificial saliva after the treatment is 11.64% for the granules prepared by using the solid pharmaceutical composition of example 36 obtained by referring to the method of example 31 in formulation example 31; formulation example 31 the granules obtained using the 5 solid pharmaceutical compositions of example 37 were treated as described above to give active agents in artificial saliva in a percentage of 12.7 to 15.9%, for example formulation example 31 the granules prepared using the solid pharmaceutical composition of example 37 with reference to the method of example 31 were treated as described above to give active agents in artificial saliva in a percentage of 15.33%.
From the above results, it can be seen that in the oral administration process of the simulated oral granules of the solid pharmaceutical compositions obtained in examples 31 to 35 and 38, the active substance is dissolved into the artificial saliva in a relatively small amount, and most of the active substance is not dissolved and still remains in the granules; however, when the organic acid is not added or the timing of the addition of the organic acid is different, a considerable amount of the drug is dissolved in the artificial saliva, which is disadvantageous in that the drug is expected to be dissolved and absorbed in the gastrointestinal tract.
The formula of the artificial saliva used in the test of the invention is as follows: sorbitol 22 g, potassium chloride 1.2 g, sodium chloride 0.9 g, magnesium chloride 0.05 g, calcium phosphate 0.1 g, sodium dihydrogen phosphate 0.02 g, distilled water to 1000ml, after preparation adjusted to pH =6.8 with 1M hydrochloric acid or 1M sodium hydroxide, bottled, and steam sterilized at 100 ℃ for 30 minutes.
Test example 33: determination of dissolution
In this test example, the dissolution rates of all the solid pharmaceutical compositions obtained in examples 31 to 38 and all the pharmaceutical preparations obtained in preparation example 31 were measured, and these pharmaceutical preparations or solid pharmaceutical compositions were packaged in empty capsules in an amount of 10mg of the active ingredient per capsule, and measured in the form of capsules. The dissolution rate determination method is as follows:
taking a sample, according to a dissolution determination method of XC second method in appendix II of 2000 edition of Chinese pharmacopoeia, taking 900ml of water as a solvent, rotating at 50 r/min, operating according to the method, taking a proper amount of solution after 45 minutes, filtering, and taking a subsequent filtrate as a sample solution; taking a proper amount of an atorvastatin calcium reference substance (about equivalent to 25mg of atorvastatin calcium), precisely weighing, placing in a 25ml measuring flask, adding methanol for dissolving and diluting to a scale, shaking up, precisely measuring 1ml, placing in a 100ml measuring flask, adding water for diluting to a scale, shaking up, and taking as a reference substance solution; and taking the two solutions, respectively measuring the absorbance at 241nm wavelength by a spectrophotometry, and calculating the elution amount.
As a result: the dissolution amounts of all the test samples were in the range of 91 to 96%, for example, the dissolution amount of the solid pharmaceutical composition in the form of fine particles obtained in example 31 was 94.7%, the dissolution amount of the solid pharmaceutical composition obtained in example 36 with reference to the formulation and the preparation method of example 31 was 93.8%, the dissolution amount of the solid pharmaceutical composition obtained in example 38 with reference to the formulation and the preparation method of example 31 was 95.1%, and the dissolution amount of the pharmaceutical preparation obtained in preparation example 31 using the solid pharmaceutical composition of example 31 was 92.2%, indicating that the compositions obtained in the different methods were very satisfactory in dissolution rates when examined by the conventional dissolution rate measuring method.
Example 41: preparation of solid pharmaceutical compositions in particulate form
Referring to the procedure of example 1, except that the active agent therein was replaced with an equal weight of one of the following drugs, 24 compositions were obtained: loratadine, finasteride, tacrolimus, alfacalcidol, sodium ritathiophosphate, clopidogrel, ozagrel, donepezil, huperzine a, memantine, famotidine, topiramate, escitalopram, nimodipine, amlodipine, dipyridamole, simvastatin, pravastatin, sildenafil, celecoxib, itraconazole, posaconazole, nateglinide, repaglinide.
Example 42: preparation of solid pharmaceutical compositions in particulate form
Referring to the formulation and preparation of example 41, except that citric acid was replaced with an equal amount of tartaric acid, 24 compositions were obtained.
Example 43: preparation of solid pharmaceutical compositions in particulate form
Referring to the formulation and preparation of example 41, except that citric acid was dissolved in the poly (meth) acrylic resin solution of step (1) (concentration based on poly (meth) acrylic resin), 24 compositions were obtained.
Example 44: preparation of solid pharmaceutical compositions in particulate form
Referring to the formulation and preparation of example 41 except that citric acid was not added and the procedure of step (3) was not carried out, 5 kinds of material A were obtained as solid pharmaceutical compositions to obtain 24 compositions.
Test example 41: the amount of the composition dissolved in water
The compositions of examples 41 to 44 (each material is 50mg in terms of active drug) were placed in a centrifuge tube 15cm long and 20ml in volume, 15ml of water for injection was precisely added, the tube was held by a hand at a frequency of 60 times per minute and turned up and down 15 times, an appropriate amount of the solution was immediately filtered through a 0.22 μm microporous membrane, the concentration of the active drug in the filtrate was measured by a known method for measuring the content of each active drug (the conventional method for measuring the drug is easily available to those skilled in the art), and the percentage of the active drug in the solution after the above treatment of the test material was calculated (each sample was represented by the average value of 6 tests).
As a result: the percentage of the active drug in the solution of the composition of examples 41-42 after the treatment is in the range of 0.3-3.3%, for example, the percentage of the active drug in the solution of the composition of example 41 after the treatment is 1.36%; the percentage of the active agent in the solution of the composition of example 43 after the treatment is in the range of 9.6 to 17.4%, for example, the percentage of the active agent in the solution of the composition of example 43 after the treatment is 14.63%; example 44 the percentage of the active agent in the solution of the composition after the treatment is in the range of 13.5 to 19.2%, for example, the percentage of the active agent in the solution of the composition of example 43 loratadine after the treatment is 14.72%; from the above results, in the dosage process of the simulated oral granules, the active substances of the compositions of examples 41 to 42 are dissolved in water in a relatively small amount, and most of the active substances are not dissolved and still remain in the granules; however, when the organic acid is not added or the timing of the addition of the organic acid is different, a considerable amount of the drug is dissolved in water, which is disadvantageous in that the drug is expected to be dissolved and absorbed in the gastrointestinal tract.
Test example 42: the amount of the composition dissolved in simulated saliva
The compositions (each material is 50mg of active drug) in the examples 41-44 are respectively put into a centrifuge tube with the length of 15cm and the volume of 20ml, 15ml of artificial saliva is precisely added, the centrifuge tube is held by a hand and overturned up and down for 10 times at the frequency of 60 times per minute, an appropriate amount of the artificial saliva is immediately taken and filtered by a 0.22 mu m microporous filter membrane, the concentration of the active drug in the filtrate is determined by using a known method for determining the content of each active drug (the conventional drug determination method is easily obtained by a person skilled in the art), and the percentage of the active drug entering the artificial saliva of the test material after the treatment is calculated according to the concentration (each sample is represented by the average value of 6 tests).
As a result: the percentage of the active drug in the artificial saliva of the composition of examples 41-42, after the treatment, is in the range of 0.3-2.8%, for example, the percentage of the active drug in the artificial saliva of the composition of example 41, after the treatment, is 1.64%; the percentage of the active drug in the artificial saliva of the composition of example 43 after the treatment is in the range of 9.4-15.6%, for example, the percentage of the active drug in the artificial saliva of the composition of example 43 after the treatment is 12.35%; the percentage of the active drug in the artificial saliva of the composition of example 44 after the treatment is in the range of 11.5 to 18.4%, for example, the percentage of the active drug in the artificial saliva of the composition of example 44 after the treatment is 14.33%; from the above results, it can be seen that the compositions of examples 41-42 showed a relatively small amount of active substance dissolved into artificial saliva during oral administration of the simulated oral granules, and a majority of the active substance was not dissolved and remained in the granules; however, when the organic acid is not added or the timing of the addition of the organic acid is different, a considerable amount of the drug is dissolved in the artificial saliva, which is disadvantageous in that the drug is expected to be dissolved and absorbed in the gastrointestinal tract.
The formula of the artificial saliva used in the test of the invention is as follows: sorbitol 22 g, potassium chloride 1.2 g, sodium chloride 0.9 g, magnesium chloride 0.05 g, calcium phosphate 0.1 g, sodium dihydrogen phosphate 0.02 g, distilled water to 1000ml, after preparation adjusted to pH =6.8 with 1M hydrochloric acid or 1M sodium hydroxide, bottled, and steam sterilized at 100 ℃ for 30 minutes.
Test example 3: determination of dissolution
The dissolution rates of all the compositions obtained in examples 41 to 42 were measured by dissolution rate and release rate measurement methods (first method of 0931, the four ministry of pharmacopoeia of China, 2020 edition), and the compositions were measured in the form of capsules by dispensing 100mg of the active ingredient per capsule.
Dissolution conditions: taking 1000ml of water as a dissolution medium, operating at a rotating speed of 120 revolutions per minute according to a method, and sampling after 90 minutes;
the determination method comprises the following steps: taking a proper amount of the dissolution liquid, filtering, taking 2ml of the subsequent filtrate, placing the subsequent filtrate in a 25ml measuring flask, diluting with water to scale, and shaking up; the concentration of the active drug in the solution is measured and the amount eluted per granule is calculated using known methods for determining the content of each active drug (such conventional methods for determining the content of drugs are readily available to those skilled in the art).
As a result: the dissolution rate of all the tested samples within the range of 77-99% in 45 minutes, for example, the dissolution rate of the loratadine composition in example 41 is 91.4%, which shows that the dissolution rates of the different active pharmaceutical compositions obtained by the method of the present invention are very satisfactory when the compositions are examined by the conventional dissolution rate determination method.
Generally, some of the above compositions dissolve in relatively small amounts when handled for a short period of time, such as when subjected to a suspension dosage or when subjected to an oral procedure, but exhibit relatively good dissolution rates in normal gastrointestinal conditions.
Although embodiments of the present disclosure have been described using specific terms, devices, and methods, such description is for illustrative purposes only. The words used are words of description rather than limitation. It is to be understood that variations and modifications may be effected by one of ordinary skill in the art without departing from the spirit and scope of the disclosure as set forth in the appended claims. Additionally, it should be understood that aspects of the various embodiments may be interchanged both in whole or in part. The spirit and scope of the appended claims should not be limited to the description of the preferred versions contained therein.

Claims (10)

1. A solid pharmaceutical composition in the form of a granulate comprising: 50 parts of active drug, 200-600 parts of poly (methyl) acrylic resin and 50-150 parts of organic acid.
2. A solid pharmaceutical composition according to claim 1, the active drug being selected from the group consisting of: ibuprofen, azithromycin, atorvastatin calcium, loratadine, finasteride, tacrolimus, alfacalcidol, sodium ritathionylphosphonate, clopidogrel, ozagrel, donepezil, huperzine A, memantine, famotidine, topiramate, escitalopram, nimodipine, amlodipine, dipyridamole, simvastatin, pravastatin, sildenafil, celecoxib, itraconazole, posaconazole, nateglinide, repaglinide.
3. The solid pharmaceutical composition according to claim 1, wherein the organic acid is selected from citric acid, tartaric acid.
4. The solid pharmaceutical composition according to claim 1, wherein the poly (meth) acrylic resin is Eudragit.
5. The solid pharmaceutical composition according to claim 1, wherein the ewing is selected from the group consisting of ewing L100, ewing L100-55, ewing S100, ewing RL100, ewing E100, ewing RL PO, ewing RS100, ewing RS PO and combinations thereof.
6. The solid pharmaceutical composition according to claim 1, which is prepared as follows:
(1) adding poly (methyl) acrylic resin into 90-99% ethanol, stirring for dissolving, then adding active drug, and stirring for dissolving;
(2) spray drying the solution obtained in the step (1) to obtain a fine granular material A;
(3) adding organic acid into 90-99% ethanol, stirring to dissolve to obtain an organic acid solution, spraying the organic acid solution into the material A in a fluidized boiling state in a fluidized bed spray dryer, and continuously fluidizing and boiling to dry the material after spraying to obtain a fine granular material B, thus obtaining the solid material composition.
7. The solid pharmaceutical composition according to claim 6, wherein the concentration of the poly (meth) acrylic resin in ethanol in step (1) is 10 to 30%.
8. The solid pharmaceutical composition according to claim 6, wherein the concentration of the organic acid in ethanol in step (3) is 10 to 20%.
9. A process for preparing a solid pharmaceutical composition according to any one of claims 1 to 8, comprising the steps of:
(1) adding poly (methyl) acrylic resin into 90-99% ethanol, stirring for dissolving, then adding active drug, and stirring for dissolving;
(2) spray drying the solution obtained in the step (1) to obtain a fine granular material A;
(3) adding organic acid into 90-99% ethanol, stirring to dissolve to obtain an organic acid solution, spraying the organic acid solution into the material A in a fluidized boiling state in a fluidized bed spray dryer, and continuously fluidizing and boiling to dry the material after spraying to obtain a fine granular material B, thus obtaining the solid material composition.
10. A pharmaceutical formulation in the form of granules, comprising: a solid pharmaceutical composition according to any one of claims 1 to 8, a filler, a flavoring agent, an adhesive.
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