CN106822907B - Two-phase release preparation containing racecadotril and preparation method thereof - Google Patents
Two-phase release preparation containing racecadotril and preparation method thereof Download PDFInfo
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- CN106822907B CN106822907B CN201611240544.0A CN201611240544A CN106822907B CN 106822907 B CN106822907 B CN 106822907B CN 201611240544 A CN201611240544 A CN 201611240544A CN 106822907 B CN106822907 B CN 106822907B
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/265—Esters, e.g. nitroglycerine, selenocyanates of carbonic, thiocarbonic, or thiocarboxylic acids, e.g. thioacetic acid, xanthogenic acid, trithiocarbonic acid
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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- 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
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Abstract
The invention relates to the field of medicines, in particular to a racecadotril biphasic release preparation and a preparation method thereof. The preparation comprises medicine-containing particles with different release performances and the like, and the dosage of the components is as follows by mass percentage: 10-90% of slow-release medicine-containing particles, 10-90% of quick-release medicine-containing particles, 0.1-0.5% of lubricant and 0.1-1.0% of flavoring agent. The two-phase release preparation not only effectively covers the bitter taste of racecadotril, but also can ensure effective blood concentration, has simple preparation process and good reproducibility, and is suitable for industrial production.
Description
Technical Field
The invention relates to a racecadotril preparation, in particular to a dual-phase release preparation containing racecadotril and a preparation method thereof.
Technical Field
Diarrhea has been a gastrointestinal disease of great concern, with a high incidence, particularly in infants and the elderly. Compared with other antidiarrheal drugs, Racecadotril (Racecadotril) is an antidiarrheal drug with a new action mechanism, can selectively and reversibly inhibit enkephalinase, prolongs the physiological activity of endogenous enkephalin in the digestive tract, so as to inhibit excessive secretion of water and electrolytes to play the role of resisting diarrhea, has higher specificity antisecretory effect, is suitable for symptomatic treatment of various diarrhea, is easy to absorb, takes effect quickly, has small adverse reaction and high safety, and is particularly suitable for infant patients. Therefore, racecadotril is the most ideal anti-diarrhea drug at present and has great market potential.
Racecadotril is a compound existing in a racemic form, namely (+/-) N- (2-acetylmercaptomethyl-1-oxo-3-phenylpropyl) glycine benzyl ester (chemical structural formula is shown as the following). The drug was developed by Bioproject in france and first marketed in 1993 under the name Tiorfan in france for the treatment of acute diarrhea in adults.
The product is absorbed rapidly by oral administration, and is converted into active metabolite (+/-) -N- (1-oxygen-2-mercaptomethyl-3-phenylpropyl) glycine rapidly after entering into human body, the strength of inhibiting effect on enkephalinase is related to the dosage, and the clinically significant inhibiting effect on enkephalinase activity is achieved within 30 minutes; at the same time, the biological half-life period t of the medicine1/2About 3 hours, the metabolic elimination rate is relatively fast. Therefore, according to the in vivo metabolism characteristics of the medicament and better exertion of the clinical curative effect of the medicament, the medicament preparation is required to have the characteristic of quick medicament release at the early stage, can quickly release a certain amount of medicament in a short time and quickly achieve the effect; then slowly releases the drug, and maintains the drug concentration in the effective treatment range, namely, the drug release characteristics of two phases of early quick release and later slow release are required.
Meanwhile, racecadotril is a lipophilic compound which is almost insoluble in water and extremely bitter in taste, so that the pharmaceutical preparation has the suitable release characteristic and needs to effectively cover the bad taste, and the problems that the drugs are difficult to effectively release and the like are often encountered when the taste is covered by adopting the conventional coating and other technical methods.
Some patent reports are reported on the pharmaceutical preparation, but the pharmaceutical preparation mainly focuses on the dosage forms such as tablets and capsules. U.S. Pat. No. 6919093B 2 first discloses the use of a coating material Eudragit
The aqueous dispersion is granulated, and the bitter taste of racecadotril is covered by high-dose apricot essence and the like, but the method has high requirements on equipment, and the effects of covering the taste and effectively releasing the racecadotril are difficult to achieve simultaneously due to the fact that the method simultaneously covers the bitter taste of racecadotril
The complex composition of the emulsifier and the apricot flavor essence in the aqueous dispersion easily causes the problems of standard exceeding of impurities of finished products and the like; CN 102166197A discloses microencapsulation treatment of racecadotril with sodium alginate and other materials by a spraying method so as to achieve the taste masking effect, but the method has complex process and higher cost. Therefore, the preparation can meet the requirements of taste masking and effective drug release, is suitable for industrialized process prescription, and has important practical significance for developing racecadotril preparations.
Disclosure of Invention
Considering the dosage form selection of racecadotril in the aspect of medicine taking of paediatric patients and simultaneously considering the bitter taste and the characteristic requirements of medicine release of the racecadotril, the invention provides a biphase medicine release preparation taking racecadotril as a main medicine, aiming at not only effectively masking the taste, but also ensuring the effective blood concentration, and the invention adopts the technical scheme that:
a racecadotril-containing biphasic release preparation for treating diarrhea of pediatric patients comprises racecadotril which is composed of quick-release drug-containing particles and racecadotril slow-release drug-containing particles, and the preparation is an oral solid preparation.
The dual-phase release preparation containing racecadotril for treating diarrhea of pediatric patients further comprises a flavoring agent and a lubricant.
A dual-phase release preparation containing racecadotril for treating diarrhea of pediatric patients is an oral solid preparation consisting of quick-release drug-containing granules, slow-release drug-containing granules, flavoring agent and lubricant.
The quick-release drug-containing particles are racecadotril quick-release drug-containing particles; the slow-release drug-containing particles are racecadotril slow-release drug-containing particles.
The preparation method is characterized in that a conventional wet granulation technology is adopted, two common auxiliary materials of ethyl cellulose and hydroxypropyl methylcellulose are selected as adhesives, sustained-release drug-containing granules are prepared by utilizing the sustained-release characteristic of the ethyl cellulose, quick-release drug-containing granules are prepared by utilizing certain hydrophilicity of the hydroxypropyl methylcellulose, and then the two drug-containing granules with different drug release rates are mixed with proper lubricants, flavoring agents and the like according to a certain proportion to prepare the drug preparation with the double-phase drug release.
Wherein the content of the first and second substances,
the sustained-release drug-containing granules are prepared by uniformly mixing racecadotril, a filling agent and a sustained-release material, preparing a soft material by a wet method, and then carrying out extrusion granulation, wherein the particle size of the obtained dry granules is controlled to be 0.42-0.71 mm. Wherein, the racecadotril accounts for 1.0 to 5.0 percent of the mass percent of the sustained-release granules, and the preferred mass percent is 3.0 percent; the mass percentage of the slow release material in the slow release particles is 0.5-10.0, preferably 2.5%; the filler can be one or more of sucrose, lactose, mannitol, sorbitol, microcrystalline cellulose, dextrin, and starch, preferably sucrose; the slow release material can be one or more of ethyl cellulose, acrylic resin, gelatin, sodium alginate, methyl cellulose, polyethylene glycol, and polyvinyl alcohol, preferably ethyl cellulose.
The quick-release drug-containing granules are prepared by uniformly mixing racecadotril, a filler and a quick-release material, preparing a soft material by a wet method, and preparing the quick-release granules by an extrusion preparation method, wherein the particle size of the obtained dry granules is controlled to be 0.42-0.71 mm. Wherein, the racecadotril accounts for 1.0 to 5.0 percent of the mass of the quick release particles, and the preferential mass is 3.0 percent; the mass percentage of the quick-release material in the quick-release particles is 0.5-10.0, preferably 1.5%; the filler can be one or more of sucrose, lactose, mannitol, sorbitol, microcrystalline cellulose, dextrin, and starch, preferably sucrose; the quick-release material can be one or more of hypromellose, hydroxypropyl cellulose, and polyvidone, preferably hypromellose.
The effective dose of racecadotril in the racecadotril biphasic release preparation is 5-50mg, preferably 30 mg; the mass ratio of the contained slow-release drug-containing particles to the quick-release drug-containing particles is 9:1 to 1:9, preferably 1-3:1, and most preferably 6: 4.
Then, the drug-containing granules are mixed with appropriate lubricants and flavoring agents, and packaged. Wherein the lubricant accounts for 0.1-2.0%, preferably 0.2% of the prescription amount; the flavoring agent accounts for 0.1-1.0%, preferably 0.3% of the prescription amount. The lubricant can be one or more selected from silicon dioxide, magnesium stearate and sodium stearyl fumarate, preferably silicon dioxide. The flavoring agent is selected from standard fruit essence such as peach essence, orange essence, etc.
Compared with the prior art, the invention has the advantages that:
(1) the hydroxypropyl methylcellulose with certain hydrophilicity is used for promoting the contact of the medicament and a dissolving medium so as to improve the medicament dissolution rate, achieve the quick-release medicament release effect, and also have the taste masking effect to a certain extent through granulation; the medicine is slowly released by utilizing the skeleton slow release effect of the water-insoluble ethyl cellulose, and meanwhile, the bitter taste of racecadotril is effectively covered by utilizing the wrapping treatment; the two modes are combined, so that the two-phase drug release is realized, and the bad taste of the racecadotril is effectively covered.
(2) The preparation method has the advantages of simple preparation process, good reproducibility and low requirement on equipment, can be completed by adopting the conventional wet granulation technology, and is suitable for industrialized production.
Drawings
FIG. 1 is an in vitro dissolution profile of the sustained release, immediate release and finished biphasic release formulations of example 2.
Detailed Description
The present invention is further illustrated by, but not limited to, the following examples.
Example 1:
prescription
(1) Prescription composition of medicine-containing granules
The preparation process of the medicine-containing granules comprises the following steps: pulverizing the medicine and sucrose to a certain particle size range, and mixing the medicine, sucrose, ethyl cellulose or hydroxypropyl methylcellulose in a wet granulating machine for 5 min; adding purified water to prepare a soft material; then placing the soft material on a 40-mesh screen of a swing type granulator for granulation; drying the formed granules in a vacuum drying oven at 50 +/-5 ℃ until the moisture content is less than 1%, and then granulating by using a 40-mesh sieve to obtain the finished product.
(2) Composition of racecadotril biphasic drug delivery preparation
The sustained-release drug-containing particles and the quick-release drug-containing particles, peach-flavor essence and fumed silica are placed in a mixer according to the proportion until the mixture is uniform, and each bag is subpackaged to obtain a final preparation product containing 3.0g and a main drug containing 30mg, namely the dual-phase release preparation containing racecadotril.
Example 2:
prescription
(1) Prescription composition of medicine-containing granules
The preparation process of the medicine-containing granules comprises the following steps: pulverizing the medicine and sucrose to a certain particle size range, and mixing the medicine, sucrose, ethyl cellulose or hydroxypropyl methylcellulose in a wet granulating machine for 5 min; adding purified water to prepare a soft material; then placing the soft material on a 40-mesh screen of a swing type granulator for granulation; drying the formed granules in a vacuum drying oven at 50 +/-5 ℃ until the moisture content is less than 1%, and then granulating by using a 40-mesh sieve to obtain the finished product.
(2) Composition of racecadotril biphasic drug delivery preparation
The sustained-release drug-containing particles and the quick-release drug-containing particles, peach-flavor essence and fumed silica are placed in a mixer according to the proportion until the mixture is uniform, and each bag is subpackaged to obtain a final preparation product containing 3.0g and a main drug containing 30mg, namely the dual-phase release preparation containing racecadotril.
Example 3:
prescription
(1) Prescription composition of medicine-containing granules
The preparation process of the medicine-containing granules comprises the following steps: pulverizing the medicine and sucrose to a certain particle size range, and mixing the medicine, sucrose, ethyl cellulose or hydroxypropyl methylcellulose in a wet granulating machine for 5 min; adding purified water to prepare a soft material; then placing the soft material on a 40-mesh screen of a swing type granulator for granulation; drying the formed granules in a vacuum drying oven at 50 +/-5 ℃ until the moisture content is less than 1%, and then granulating by using a 40-mesh sieve to obtain the finished product.
(2) Composition of racecadotril biphasic drug delivery preparation
The sustained-release drug-containing particles and the quick-release drug-containing particles, peach-flavor essence and fumed silica are placed in a mixer according to the proportion until the mixture is uniform, and each bag is subpackaged to obtain a final preparation product containing 3.0g and a main drug containing 30mg, namely the dual-phase release preparation containing racecadotril.
Example 4:
the results of the taste test of the different drug release granules and the finished product preparations obtained in examples 1-3 are shown in the following table.
Note: preferably 85-100, good 70-85, medium 55-70, and difference < 55.
As can be seen from the above table, in examples 1 to 3, after the racecadotril is granulated by using the water-insoluble ethyl cellulose as the sustained-release material, the bitter taste of the racecadotril can be effectively masked, and the taste masking effect is better as the proportion of the ethyl cellulose in the granulating prescription is increased; in the embodiments 1-3, hydrophilic hypromellose is used as a bonding agent to granulate the racecadotril, and a certain taste masking effect is also shown, but the material cannot well control the drug release and has a bitter characteristic, and the taste masking effect is more obvious along with the increase of the dosage proportion of the hypromellose. In examples 1-3, after mixing the drug-containing particles with different drug release rates according to a certain proportion,
under the action of flavoring agents and the like, the finished preparation has no bitter taste and bitter residue, good taste and easy acceptance by children. ()
Example 5:
the sustained-release drug-containing granules, the quick-release drug-containing granules, and the finished biphasic release preparation of example 2 were subjected to in vitro dissolution measurement, respectively. In vitro dissolution test conditions: medium 0.5% Sodium Dodecyl Sulfate (SDS); the rotating speed is 50 rpm; the temperature was 37.0 ℃. The dissolution results are shown in FIG. 1. As can be seen from the figure, the dissolution rate of the racecadotril sustained-release drug-containing granules in example 2 is only about 11% in 5min, and the granules are slowly released along with time, the dissolution end point of 120min is about 76%, and the sustained-release characteristic is provided; the 5min dissolution rate of the racecadotril quick-release medicine-containing granules is about 86 percent, the medicine release is rapid, and the medicine release end point is reached about 15min, which is close to complete release. After mixing the drug-containing granules with two different drug release characteristics according to a certain proportion, the initial dissolution rate of the finished preparation is about 40 percent, and then the drug-containing granules are gradually and slowly released along with time, thereby showing the obvious biphase drug release characteristics and obtaining the excellent dissolution effect.
In light of the present disclosure, those skilled in the art can utilize the present invention to its fullest extent. The preferred embodiments described above are therefore to be considered in all respects as illustrative and not restrictive.
Claims (17)
1. A racecadotril biphasic release preparation is characterized in that the racecadotril biphasic release preparation comprises racecadotril quick-release drug-containing granules and racecadotril sustained-release drug-containing granules, and the preparation is an oral solid preparation; the quick-release drug-containing particles are composed of racecadotril, a filler and a quick-release material, and the quick-release material of the quick-release drug-containing particles is hypromellose; the slow-release drug-containing granules consist of racecadotril, a filling agent and a slow-release material, wherein the slow-release material of the slow-release drug-containing granules is ethyl cellulose; the quick-release medicine-containing granules comprise the following components in percentage by mass: 1.0-5.0% of racecadotril and 0.5-10.0% of quick-release material; the sustained-release drug-containing granules comprise the following components in percentage by mass: 1.0-5.0% of racecadotril and 0.5-10.0% of slow-release material; the mass ratio of the slow-release drug-containing particles to the quick-release drug-containing particles is 1-3: 1.
2. The racecadotril biphasic release formulation of claim 1, characterized in that the formulation is an oral solid formulation consisting of immediate release drug-containing granules, sustained release drug-containing granules, flavoring agent, and lubricant.
3. A racecadotril biphasic release formulation according to claim 1 or 2, characterized in that: the filler of the quick-release medicine-containing granules is one or more of sucrose, lactose, mannitol, sorbitol, microcrystalline cellulose, dextrin and starch.
4. A racecadotril biphasic release formulation according to claim 3, characterized in that: the filler of the quick-release medicine-containing particles is sucrose.
5. A racecadotril biphasic release formulation according to claim 1 or 2, characterized in that: the filler of the sustained-release drug-containing granules is one or more of sucrose, lactose, mannitol, sorbitol, microcrystalline cellulose, dextrin and starch.
6. The racecadotril biphasic release formulation of claim 5, wherein: the filler of the sustained-release drug-containing particles is sucrose.
7. The racecadotril biphasic release formulation according to claim 2, characterized in that the flavoring agent is a standard fruit flavor.
8. A racecadotril biphasic release formulation according to claim 2, characterized in that the lubricant is one or more of silicon dioxide, magnesium stearate, sodium stearyl fumarate.
9. The racecadotril biphasic release formulation according to claim 8, characterized in that the lubricant is silicon dioxide.
10. A racecadotril biphasic release formulation according to claim 1 or 2, characterized in that the effective dose of racecadotril per racecadotril biphasic release formulation is between 5 and 50 mg.
11. A racecadotril biphasic release formulation according to claim 10, wherein the effective dose of racecadotril is 30mg per racecadotril biphasic release formulation.
12. The racecadotril biphasic release formulation of claim 1, characterized in that the mass ratio of the sustained-release drug-containing particles to the immediate-release drug-containing particles is 6: 4.
13. The racecadotril biphasic release formulation of claim 1, characterized in that the immediate release drug-containing granules comprise the following components in percentage by mass: 3.0 percent of racecadotril and 1.5 percent of quick-release material.
14. The racecadotril biphasic release preparation according to claim 1, characterized in that the sustained-release drug-containing granules comprise the following components in percentage by mass: 3.0 percent of racecadotril and 2.5 percent of slow release material.
15. A racecadotril biphasic release formulation according to claim 7, characterised in that the flavouring agent is present in an amount of 0.1-1.0% by mass of the total biphasic formulation.
16. The racecadotril biphasic release formulation of claim 8, wherein the lubricant comprises 0.1-2.0% by weight of the total biphasic formulation.
17. A process for the preparation of a racecadotril biphasic release formulation according to any one of claims 1-16, characterised in that it comprises the following steps: uniformly mixing racecadotril, filler, quick-release material or sustained-release material, making soft material by wet method, and preparing quick-release drug-containing granule or sustained-release drug-containing granule by extrusion granulation, wherein the particle diameter of the drug-containing granule is controlled at 0.42-0.71 mm.
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| CN108740677A (en) * | 2018-06-22 | 2018-11-06 | 化州化橘红药材发展有限公司 | A kind of Exocarpium Citri Grandis slow-release solid beverage and preparation method thereof |
| GB2586201B (en) * | 2019-05-14 | 2023-05-24 | Orbit Pharmaceuticals | A stable powder formulation of racecadotril |
| CN112220757B (en) * | 2020-10-16 | 2022-05-27 | 重庆市义力医药科技有限公司 | Nicotine particle composition, preparation method and preparation device thereof |
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| FR2900823B1 (en) * | 2006-05-15 | 2009-02-13 | Bioprojet Soc Civ Ile | NEW FORM OF ADMINISTRATION OF RACECADOTRIL. |
| CN102091051B (en) * | 2009-12-14 | 2013-01-23 | 北京科信必成医药科技发展有限公司 | Allopurinol dual-release preparation and preparation method thereof |
| CN104224724A (en) * | 2013-06-08 | 2014-12-24 | 北京韩美药品有限公司 | Racecadotril granules and preparation technology thereof |
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| Title |
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| "Compressed mini-tablets as a biphasic delivery system";Carla M. Lopes et al.;《International Journal of Pharmaceutics》;20060606;第323卷;第93-100页 * |
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