CN112137983B - Benzonatate soft capsule and preparation method thereof - Google Patents
Benzonatate soft capsule and preparation method thereof Download PDFInfo
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- CN112137983B CN112137983B CN201910567244.0A CN201910567244A CN112137983B CN 112137983 B CN112137983 B CN 112137983B CN 201910567244 A CN201910567244 A CN 201910567244A CN 112137983 B CN112137983 B CN 112137983B
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
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- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
- A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
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- A61K9/4816—Wall or shell material
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Abstract
The invention provides a benzonatate soft capsule and a preparation method thereof, wherein the content of the soft capsule is benzonatate, and the capsule shell comprises the following components in parts by weight: 10 parts of gelatin, 3.2-3.8 parts of glycerol, 9.5-10.5 parts of water and impurity butyraldehyde, wherein the total amount of the impurity butyraldehyde is not more than 0.05% (500ppm) within 36 months of shading and room temperature placement. The benzonatate soft capsule has stable quality and long validity period of 36 months; the preservative and the pigment are not contained, so that the clinical medication is safe; has biological equivalence with original developer (TESSALON); the preparation process is simple and easy to produce.
Description
Technical Field
The invention relates to a soft capsule and a preparation method thereof, in particular to a benzonatate soft capsule and a preparation method thereof, belonging to the technical field of pharmaceutical preparations.
Background
The benzonatate belongs to a peripheral antitussive, is chemically named as 4-butylaminobenzoic acid nonapolyethylene glycol monomethylether ester, is a faint yellow viscous liquid, can keep the physical characteristics of the benzonatate by adopting a soft capsule dosage form, can well protect contents by using a rubber sheet, ensures the chemical stability of the benzonatate, and solves the adverse effect caused by the local anesthesia action of the oral cavity.
Benzonatate soft capsules (benzonate) were developed by feverer and were approved by the U.S. food and drug administration for sale on the market at 2/10 th of 1958 under the trade name tesselon, and were sold as soft capsules in the specifications of 100mg and 200 mg.
By inquiring the specifications of the original medicines, the content of the soft capsule in the prescription is only benzonatate, and other auxiliary materials are not added. The soft capsule shell mainly comprises gelatin, glycerin, water, methyl paraben, propyl paraben and D & C Yellow 10. Wherein, the methylparaben and the propylparaben are preservatives, the D & C Yellow10 is pigment, and the long-term overdose is harmful to human bodies.
Chinese patent CN201710605901.7 discloses a benzonatate liposome soft capsule and a preparation method thereof, which comprises the following components in parts by weight: 10 to 20 percent of benzonatate, 15 to 25 percent of beta-cyclodextrin, 40 to 70 percent of soybean lecithin, 0.5 to 2 percent of gelatin, 0.1 to 1 percent of glycerin and 20 to 25 percent of cholesterol by weight, and the preparation method comprises the following steps: (1) taking beta-cyclodextrin, adding distilled water, grinding uniformly, adding benzonatate, fully grinding, and drying to obtain a benzonatate inclusion compound; (2) taking the inclusion compound of the benzonatate, soybean phospholipid or soybean phospholipid, cholesterol and an appropriate amount of ethanol, fully and uniformly mixing, stirring and dissolving the mixture under warm conditions (30-35 ℃), and cooling the mixture to obtain the benzonatate liposome; (3) adding a proper amount of water into gelatin to swell the gelatin, heating glycerol and a proper amount of water in a gelatin boiling pot to 70-80 ℃, uniformly mixing, adding the swelled gelatin, stirring, and melting to obtain a capsule shell; (4) the benzonatate liposome and the capsule shell are pressed into soft capsules by a soft capsule machine. The prescription of the product is not consistent with the original product, the curative effect of the product is possibly different from the original product, the preparation process is complex, and the cost is high.
Disclosure of Invention
The invention aims to provide a benzonatate soft capsule which does not contain preservatives and pigments, has simple preparation process and stable quality and has the same curative effect as the original ground product and a preparation method thereof.
The invention adopts the following technical scheme:
the benzonatate soft capsule consists of a soft capsule content and a capsule shell, wherein the soft capsule content is benzonatate, and the capsule shell consists of the following components in parts by weight: 10 parts of gelatin, 3.2-3.8 parts of glycerol and 9.5-10.5 parts of water.
The benzonatate soft capsule also comprises impurity butyraldehyde, and the total amount of the impurity butyraldehyde is not more than 0.5 percent, preferably not more than 0.15 percent, more preferably not more than 0.1 percent, and more preferably not more than 0.05 percent (500ppm) after shading and standing at room temperature for 36 months.
The invention optimizes the proportion of capsule shell of the soft capsule and the preparation process, the prepared soft capsule of benzonatate is placed in 36 months under the light-shielding and room temperature, the total amount of impurity butyraldehyde is not more than 500ppm, and the quality of the medicine is ensured.
Furthermore, the content of the benzonatate in the benzonatate soft capsule is 50-400mg, preferably 100-200mg, preferably 100mg, 150mg and 200 mg.
In some embodiments of the present invention, a benzonatate soft capsule is composed of a soft capsule content and a capsule shell, wherein the soft capsule content is benzonatate 100mg, and the capsule shell is composed of the following components by weight: 10 parts of gelatin, 3.5-3.7 parts of glycerol and 10 parts of water.
Further, in some embodiments of the present invention, a benzonatate soft capsule is composed of a soft capsule content and a capsule shell, wherein the soft capsule content is benzonatate 100mg, and the capsule shell is composed of the following components by weight: 10 parts of gelatin, 3.6 parts of glycerol and 10 parts of water.
In other embodiments of the present invention, a benzonatate soft capsule comprises a soft capsule content and a capsule shell, wherein the soft capsule content is benzonatate 200mg, and the capsule shell comprises the following components by weight: 10 parts of gelatin, 3.5-3.7 parts of glycerol and 10 parts of water.
Further, in some embodiments of the present invention, a benzonatate soft capsule is composed of a soft capsule content and a capsule shell, wherein the soft capsule content is benzonatate 200mg, and the capsule shell is composed of the following components by weight: 10 parts of gelatin, 3.6 parts of glycerol and 10 parts of water.
The benzonatate soft capsule also comprises impurities, wherein the impurities comprise butyraldehyde, and the total amount of the impurities is not more than 0.1 percent, more preferably not more than 0.05 percent, and the impurities are shaded and placed at room temperature for 36 months.
In another aspect of the invention, the preparation method of the benzonatate soft capsule is provided.
The benzonatate soft capsule is characterized in that the preparation method comprises the following steps:
(1) preparing a liquid medicine: placing the weighed benzonatate raw material in a heat-preserving container, and keeping the temperature of the raw material at 35 +/-2 ℃;
(2) preparing glue solution: opening a sol tank, sucking weighed glycerol and purified water into the sol tank, sucking gelatin into the sol tank when the temperature is raised to 75 +/-2 ℃, stirring for 2-7 minutes, then opening a vacuum pump, keeping the vacuum degree at-0.7 to-1.0 bar, and extracting water until the weight ratio of the extracted water to the gelatin in the sol tank is 0.15-0.25: 1, turning off the vacuum pump and stopping stirring;
(3) pressing: pressing by rotary molding method, pumping the glue solution into a glue solution box, controlling the temperature of the glue solution box to be 60.0 + -2.0 deg.C, and pumping the medicinal liquid into a hopper; starting a pill pressing machine, enabling glue solution to flow through a cooled roller to form adhesive tapes with a certain thickness, enabling the liquid medicine in a hopper to pass through a spraying body when two bright adhesive tapes pass through the middle of a pair of corresponding rotating cylindrical dies, injecting quantitative liquid medicine into semi-closed capsules on a stamping die, pressing the two adhesive tapes by a rolling die along the relative rotation of the dies, and cutting off the two adhesive tapes along the outline of a die cavity to form a completely sealed soft capsule;
(4) primary drying: the primary drying is drying in a rotating cage, the rotating speed is controlled to be 6-8rpm, and the drying time is 2-4 hours;
(5) secondary drying: the primary drying is tunnel drying, the temperature is controlled to be 20-24 ℃, and the drying time is 45-55 hours;
(6) and (5) performing mechanical inspection, visual inspection and packaging to obtain the benzonatate soft capsule.
In the above preparation method, in the step (2), the ratio of the weight of the extracted water to the weight of the gelatin in the sol tank is preferably 0.18 to 0.22: 1, more preferably the ratio of the weight of the extracted moisture to the weight of the gelatin in the sol tank is 0.20: 1.
in the preparation method, in the step (3), the thickness of the adhesive tape is 0.025inch to 0.035 inch; preferably 0.029inch to 0.033inch, more preferably 0.031 inch.
The benzonatate prepared by the invention has the following advantages:
(1) the benzonatate soft capsule of the invention has stable quality and long effective period of 36 months. (2) The benzonatate soft capsule does not contain preservatives and pigments, and is safe in clinical medication. (3) The benzonatate soft capsule of the invention has the same in vitro dissolution curve as the original research and has bioequivalence. (4) The benzonatate soft capsule of the invention has simple preparation process and easy production.
Drawings
FIG. 1: dissolution profile of 200mg of original formulation (tessalaon) in dissolution medium (water).
FIG. 2: dissolution profile of 100mg of the original formulation (TESSALON) in dissolution medium (water).
FIG. 3: reference product 1 (from the manufacturer, THEPHARANETWORK LLC) has a dissolution profile in dissolution medium (water) of 150 mg.
Detailed Description
The invention discloses a benzonatate soft capsule and a preparation method thereof, and the benzonatate soft capsule can be realized by properly improving process parameters or prescription ratio by taking the contents of the invention as reference and combining the principle of pharmacy. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the scope of the invention. While the invention has been described in terms of preferred embodiments, it will be apparent to those skilled in the art that variations may be applied, or changes and combinations may be made, in the methods and applications described herein to achieve and use the inventive techniques without departing from the spirit, scope, and content of the invention.
The present invention is further illustrated by the following examples, which are not intended to limit the invention in any way.
Original medicine grinding: tessalaon (trade name); the specification is 100mg and 200 mg; the manufacturer is PFIZER (pfIZER); the orange peel book of the united states lists it as RLD (reference formulation). The dissolution curves are shown in FIGS. 1 and 2.
Reference product 1: the specification of the benzonatate soft capsule is as follows: 150 MG; the manufacturer is THEPHARANETWORK LLC; the orange peel book of the united states lists it as RS (standard formulation). The dissolution profile is shown in FIG. 3.
The dissolution curve measuring method comprises the following steps:
referring to the method in the FDA website dissolution method database, the dissolution conditions are as follows:
dissolution medium: purified water, 900mL
The method comprises the following steps: appendix XC second law pulp method of the second part of the book of Chinese pharmacopoeia 2015 year edition
Rotating speed: 50 revolutions per minute
Sampling points: 10min, 15min, 30min, 45 min.
Comparing the measured dissolution curve with the original drug or reference product, and calculating f 2 ，f 2 >50, the dissolution behavior is consistent with that of the original research.
Example 1: benzonatate soft capsule
The prescription composition is as follows:
the preparation method comprises the following steps:
(1) preparing a liquid medicine: placing the weighed raw material of benzonatate in a heat-preserving container, and keeping the temperature of the raw material at 35 +/-2 ℃;
(2) preparing glue solution: opening a sol tank, sucking weighed glycerol and purified water into the sol tank, sucking gelatin into the sol tank when the temperature is raised to 75 +/-2 ℃, stirring for 5 minutes, then opening a vacuum pump, keeping the vacuum degree at-0.7 to-1.0 bar, and extracting water until the weight ratio of the extracted water to the gelatin in the sol tank is 0.20: 1, turning off the vacuum pump and stopping stirring;
(3) pressing: pressing by adopting a rotary molding method, pumping the glue solution into a glue solution box by a glue solution pump, controlling the temperature of the glue solution box to be 60.0 +/-2.0 ℃, and pumping the liquid medicine into a hopper by a liquid medicine pump; starting a pill press, enabling glue solution to flow through a cooled roller to form an adhesive tape with the thickness of 0.031inch, enabling the liquid medicine in a hopper to pass through a spraying body when two adhesive tapes penetrate through the middle of a pair of cylindrical dies rotating correspondingly, injecting a certain amount of liquid medicine into a semi-closed capsule on a stamping die, pressing the two adhesive tapes by the rolling die along the relative rotation of the dies, and cutting the two adhesive tapes along the outline of a die cavity to form a completely sealed soft capsule;
(4) primary drying: the primary drying is tumble drying, the rotating speed is controlled to be 7rpm, and the drying time is 3 hours;
(5) secondary drying: the primary drying is tunnel drying, the temperature is controlled to be 20-24 ℃, and the drying time is 50 hours;
(6) and (5) performing mechanical inspection, visual inspection and packaging to obtain the benzonatate soft capsule.
And (3) measuring the dissolution curve of the benzonatate soft capsule prepared in the step (6), and comparing the dissolution curve with the dissolution curve of a reference preparation with the same specification, wherein the results are as follows:
| sample(s) | f 2 |
| Example 1 | 87 |
Example 2: benzonatate soft capsule
The prescription composition is as follows:
the preparation method comprises the following steps:
(1) preparing a liquid medicine: placing the weighed raw material of benzonatate in a heat-preserving container, and keeping the temperature of the raw material at 35 +/-2 ℃;
(2) preparing glue solution: opening a sol tank, sucking weighed glycerol and purified water into the sol tank, sucking gelatin into the sol tank when the temperature is raised to 75 +/-2 ℃, stirring for 5 minutes, then opening a vacuum pump, keeping the vacuum degree at-0.7 to-1.0 bar, and extracting water until the weight ratio of the extracted water to the gelatin in the sol tank is 0.20: 1, turning off the vacuum pump and stopping stirring;
(3) pressing: pressing by rotary molding method, pumping the glue solution into a glue solution box, controlling the temperature of the glue solution box to be 60.0 + -2.0 deg.C, and pumping the medicinal liquid into a hopper; starting a pill pressing machine, enabling glue solution to flow through a cooled roller to form an adhesive tape with the thickness of 0.031inch, enabling the liquid medicine in a hopper to pass through a spraying body when two bright adhesive tapes pass through the middle of a pair of corresponding rotating cylindrical dies, injecting a certain amount of liquid medicine into a semi-closed capsule on a stamping die, pressing the two adhesive tapes by a rolling die along the relative rotation of the dies, and cutting the two adhesive tapes along the outline of a die cavity to form a completely sealed soft capsule;
(4) primary drying: the primary drying is tumble drying, the rotating speed is controlled to be 7rpm, the drying time is 3 hours (5), and the secondary drying is carried out: the primary drying is tunnel drying, the temperature is controlled to be 20-24 ℃, and the drying time is 50 hours;
(6) and performing mechanical inspection, visual inspection and packaging to obtain the benzonatate soft capsule.
And (3) measuring the dissolution curve of the benzonatate soft capsule prepared in the step (6), and comparing the dissolution curve with the dissolution curve of the original preparation with the same specification, wherein the results are as follows:
| sample (I) | f 2 |
| Example 2 | 78 |
Example 3: benzonatate soft capsule
The prescription composition is as follows:
the preparation method comprises the following steps:
(1) preparing a liquid medicine: placing the weighed raw material of benzonatate in a heat-preserving container, and keeping the temperature of the raw material at 35 +/-2 ℃;
(2) preparing glue solution: opening a sol tank, sucking weighed glycerol and purified water into the sol tank, sucking gelatin into the sol tank when the temperature is raised to 75 +/-2 ℃, stirring for 5 minutes, then opening a vacuum pump, keeping the vacuum degree at-0.7 to-1.0 bar, and extracting water until the weight ratio of the extracted water to the gelatin in the sol tank is 0.20: 1, turning off the vacuum pump and stopping stirring;
(3) pressing: pressing by rotary molding method, pumping the glue solution into a glue solution box, controlling the temperature of the glue solution box to be 60.0 + -2.0 deg.C, and pumping the medicinal liquid into a hopper; starting a pill pressing machine, enabling glue solution to flow through a cooled roller to form an adhesive tape with the thickness of 0.031inch, enabling the liquid medicine in a hopper to pass through a spraying body when two bright adhesive tapes pass through the middle of a pair of corresponding rotating cylindrical dies, injecting a certain amount of liquid medicine into a semi-closed capsule on a stamping die, pressing the two adhesive tapes by a rolling die along the relative rotation of the dies, and cutting the two adhesive tapes along the outline of a die cavity to form a completely sealed soft capsule;
(4) primary drying: the primary drying is tumble drying, the rotating speed is controlled to be 7rpm, and the drying time is 3 hours;
(5) secondary drying: the primary drying is tunnel drying, the temperature is controlled to be 20-24 ℃, and the drying time is 50 hours;
(6) and (5) performing mechanical inspection, visual inspection and packaging to obtain the benzonatate soft capsule.
And (3) measuring the dissolution curve of the benzonatate soft capsule prepared in the step (6), and comparing the dissolution curve with the dissolution curve of a reference preparation with the same specification, wherein the results are as follows:
| sample(s) | f 2 |
| Example 3 | 75 |
Example 4: benzonatate soft capsule
The prescription composition is as follows:
the preparation method comprises the following steps:
(1) preparing a liquid medicine: placing the weighed raw material of benzonatate in a heat-preserving container, and keeping the temperature of the raw material at 35 +/-2 ℃;
(2) preparing glue solution: opening a sol tank, sucking weighed glycerol and purified water into the sol tank, sucking gelatin into the sol tank when the temperature is raised to 75 +/-2 ℃, stirring for 5 minutes, then opening a vacuum pump, keeping the vacuum degree at-0.7 to-1.0 bar, and extracting water until the weight ratio of the extracted water to the gelatin in the sol tank is 0.16: 1, turning off the vacuum pump and stopping stirring;
(3) pressing: pressing by rotary molding method, pumping the glue solution into a glue solution box, controlling the temperature of the glue solution box to be 60.0 + -2.0 deg.C, and pumping the medicinal liquid into a hopper; starting a pill pressing machine, enabling glue solution to flow through a cooled roller to form an adhesive tape with the thickness of 0.026inch, enabling liquid medicine in a hopper to pass through a spraying body when two bright adhesive tapes pass through the middle of a pair of corresponding rotating cylindrical dies, injecting quantitative liquid medicine into a semi-closed capsule on a die stamping die, pressing the two adhesive tapes by a rolling die along with the relative rotation of the dies, and cutting the two adhesive tapes along the outline of a die cavity to form a completely sealed soft capsule;
(4) primary drying: the primary drying is tumble drying, the rotating speed is controlled to be 6rpm, and the drying time is 4 hours;
(5) secondary drying: the primary drying is tunnel drying, the temperature is controlled to be 20-24 ℃, and the drying time is 46 hours;
(6) and (5) performing mechanical inspection, visual inspection and packaging to obtain the benzonatate soft capsule.
And (3) measuring the dissolution curve of the benzonatate soft capsule prepared in the step (6), and comparing the dissolution curve with the dissolution curve of a reference preparation with the same specification, wherein the results are as follows:
| sample (I) | f 2 |
| Example 4 | 56 |
Example 5: benzonatate soft capsule
The prescription composition is as follows:
the preparation method comprises the following steps:
(1) preparing a liquid medicine: placing the weighed raw material of benzonatate in a heat-preserving container, and keeping the temperature of the raw material at 35 +/-2 ℃;
(2) preparing glue solution: opening a sol tank, sucking weighed glycerol and purified water into the sol tank, sucking gelatin into the sol tank when the temperature is raised to 75 +/-2 ℃, stirring for 5 minutes, then opening a vacuum pump, keeping the vacuum degree at-0.7 to-1.0 bar, and extracting water until the weight ratio of the extracted water to the gelatin in the sol tank is 0.18: 1, turning off the vacuum pump and stopping stirring;
(3) pressing: pressing by rotary molding method, pumping the glue solution into a glue solution box, controlling the temperature of the glue solution box to be 60.0 + -2.0 deg.C, and pumping the medicinal liquid into a hopper; starting a pill pressing machine, enabling glue solution to flow through a cooled roller to form an adhesive tape with the thickness of 0.033inch, enabling the liquid medicine in a hopper to pass through a spraying body when two bright adhesive tapes pass through the middle of a pair of cylindrical dies rotating correspondingly, injecting quantitative liquid medicine into a semi-closed capsule on a die stamping die, pressing the two adhesive tapes by a rolling die along the relative rotation of the dies, and cutting along the outline of a die cavity to form a completely sealed soft capsule;
(4) primary drying: the primary drying is tumble drying, the rotating speed is controlled to be 6rpm, and the drying time is 3.5 hours;
(5) secondary drying: the primary drying is tunnel drying, the temperature is controlled to be 20-24 ℃, and the drying time is 48 hours;
(6) and performing mechanical inspection, visual inspection and packaging to obtain the benzonatate soft capsule.
And (3) measuring the dissolution curve of the benzonatate soft capsule prepared in the step (6), and comparing the dissolution curve with the dissolution curve of a reference preparation with the same specification, wherein the results are as follows:
| sample(s) | f 2 |
| Example 5 | 62 |
Example 6: benzonatate soft capsule
The prescription composition is as follows:
the preparation method comprises the following steps:
(1) preparing a liquid medicine: placing the weighed raw material of benzonatate in a heat-preserving container, and keeping the temperature of the raw material at 35 +/-2 ℃;
(2) preparing glue solution: opening a sol tank, sucking weighed glycerol and purified water into the sol tank, sucking gelatin into the sol tank when the temperature is raised to 75 +/-2 ℃, stirring for 5 minutes, then opening a vacuum pump, keeping the vacuum degree at-0.7 to-1.0 bar, and extracting water until the weight ratio of the extracted water to the gelatin in the sol tank is 0.22: 1, turning off the vacuum pump and stopping stirring;
(3) pressing: pressing by adopting a rotary molding method, pumping the glue solution into a glue solution box by a glue solution pump, controlling the temperature of the glue solution box to be 60.0 +/-2.0 ℃, and pumping the liquid medicine into a hopper by a liquid medicine pump; starting a pill pressing machine, enabling glue solution to flow through a cooled roller to form an adhesive tape with the thickness of 0.029inch, enabling the liquid medicine in a hopper to pass through a spraying body when two bright adhesive tapes pass through the middle of a pair of corresponding rotating cylindrical dies, injecting quantitative liquid medicine into a semi-closed capsule on a stamping die, pressing the two adhesive tapes by a rolling die along the relative rotation of the dies, and cutting the two adhesive tapes along the outline of a die cavity to form a completely sealed soft capsule;
(4) primary drying: the primary drying is tumble drying, the rotating speed is controlled to be 7rpm, and the drying time is 3 hours;
(5) secondary drying: the primary drying is tunnel drying, the temperature is controlled to be 20-24 ℃, and the drying time is 52 hours;
(6) and (5) performing mechanical inspection, visual inspection and packaging to obtain the benzonatate soft capsule.
And (3) measuring the dissolution curve of the benzonatate soft capsule prepared in the step (6), and comparing the dissolution curve with the dissolution curve of a reference preparation with the same specification, wherein the results are as follows:
| sample(s) | f 2 |
| Example 6 | 64 |
Example 7: benzonatate soft capsule
The prescription composition is as follows:
the preparation method comprises the following steps:
(1) preparing a liquid medicine: placing the weighed raw material of benzonatate in a heat-preserving container, and keeping the temperature of the raw material at 35 +/-2 ℃;
(2) preparing glue solution: opening a sol tank, sucking weighed glycerol and purified water into the sol tank, sucking gelatin into the sol tank when the temperature is raised to 75 +/-2 ℃, stirring for 5 minutes, then opening a vacuum pump, keeping the vacuum degree at-0.7 to-1.0 bar, and extracting water until the weight ratio of the extracted water to the gelatin in the sol tank is 0.19: 1, turning off the vacuum pump and stopping stirring;
(3) pressing: pressing by rotary molding method, pumping the glue solution into a glue solution box, controlling the temperature of the glue solution box to be 60.0 + -2.0 deg.C, and pumping the medicinal liquid into a hopper; starting a pill pressing machine, enabling glue solution to flow through a cooled roller to form a glue tape with the thickness of 0.030inch, enabling the liquid medicine in a hopper to pass through a spraying body when two plain adhesive tapes pass through the middle of a pair of cylindrical dies rotating correspondingly, injecting quantitative liquid medicine into a semi-closed capsule on a stamping die, pressing the two glue tapes by a rolling die along the relative rotation of the dies, and cutting along the outline of a die cavity to form a completely sealed soft capsule;
(4) primary drying: the primary drying is tumble drying, the rotating speed is controlled to be 7rpm, and the drying time is 3 hours;
(5) secondary drying: the primary drying is tunnel drying, the temperature is controlled to be 20-24 ℃, and the drying time is 52 hours;
(6) and (5) performing mechanical inspection, visual inspection and packaging to obtain the benzonatate soft capsule.
And (3) measuring the dissolution curve of the benzonatate soft capsule prepared in the step (6), and comparing the dissolution curve with the dissolution curve of a reference preparation with the same specification, wherein the results are as follows:
| sample (I) | f 2 |
| Example 7 | 68 |
Example 8: benzonatate soft capsule
The prescription composition is as follows:
the preparation method comprises the following steps:
(1) preparing a liquid medicine: placing the weighed benzonatate raw material in a heat-preserving container, and keeping the temperature of the raw material at 35 +/-2 ℃;
(2) preparing glue solution: opening a sol tank, sucking weighed glycerol and purified water into the sol tank, sucking gelatin into the sol tank when the temperature is raised to 75 +/-2 ℃, stirring for 5 minutes, then opening a vacuum pump, keeping the vacuum degree at-0.7 to-1.0 bar, and extracting water until the weight ratio of the extracted water to the gelatin in the sol tank is 0.25: 1, turning off the vacuum pump and stopping stirring;
(3) pressing: pressing by rotary molding method, pumping the glue solution into a glue solution box, controlling the temperature of the glue solution box to be 60.0 + -2.0 deg.C, and pumping the medicinal liquid into a hopper; starting a pill pressing machine, enabling glue solution to flow through a cooled roller to form an adhesive tape with the thickness of 0.035inch, enabling the liquid medicine in a hopper to pass through a spraying body when two bright adhesive tapes pass through the middle of a pair of corresponding rotating cylindrical dies, injecting a certain amount of liquid medicine into a semi-closed capsule on a stamping die, pressing the two adhesive tapes by a rolling die along with the relative rotation of the dies, and cutting the two adhesive tapes along the outline of a die cavity to form a completely sealed soft capsule;
(4) primary drying: the primary drying is tumble drying, the rotating speed is controlled to be 8rpm, and the drying time is 2 hours;
(5) secondary drying: the primary drying is tunnel drying, the temperature is controlled to be 20-24 ℃, and the drying time is 54 hours;
(6) and (5) performing mechanical inspection, visual inspection and packaging to obtain the benzonatate soft capsule.
And (3) measuring the dissolution curve of the benzonatate soft capsule prepared in the step (6), and comparing the dissolution curve with the dissolution curve of a reference preparation with the same specification, wherein the results are as follows:
| sample (I) | f 2 |
| Example 8 | 52 |
Example 9: benzonatate soft capsule
The prescription composition is as follows:
the preparation method comprises the following steps:
(1) preparing a liquid medicine: placing the weighed raw material of benzonatate in a heat-preserving container, and keeping the temperature of the raw material at 35 +/-2 ℃;
(2) preparing glue solution: opening a sol tank, sucking weighed glycerol and purified water into the sol tank, sucking gelatin into the sol tank when the temperature is raised to 75 +/-2 ℃, stirring for 5 minutes, then opening a vacuum pump, keeping the vacuum degree at-0.7 to-1.0 bar, and extracting water until the weight ratio of the extracted water to the gelatin in the sol tank is 0.15: 1, turning off the vacuum pump and stopping stirring;
(3) pressing: pressing by adopting a rotary molding method, pumping the glue solution into a glue solution box by a glue solution pump, controlling the temperature of the glue solution box to be 60.0 +/-2.0 ℃, and pumping the liquid medicine into a hopper by a liquid medicine pump; starting a pill pressing machine, enabling glue solution to flow through a cooled roller to form an adhesive tape with the thickness of 0.025inch, enabling the liquid medicine in a hopper to pass through a spraying body when two bright adhesive tapes pass through the middle of a pair of corresponding rotating cylindrical dies, injecting a certain amount of liquid medicine into a semi-closed capsule on a stamping die, pressing the two adhesive tapes by a rolling die along the relative rotation of the dies, and cutting the two adhesive tapes along the outline of a die cavity to form a completely sealed soft capsule;
(4) primary drying: the primary drying is tumble drying, the rotating speed is controlled to be 8rpm, and the drying time is 4 hours;
(5) secondary drying: the primary drying is tunnel drying, the temperature is controlled to be 20-24 ℃, and the drying time is 53 hours;
(6) and (5) performing mechanical inspection, visual inspection and packaging to obtain the benzonatate soft capsule.
And (3) measuring the dissolution curve of the benzonatate soft capsule prepared in the step (6), and comparing the dissolution curve with the dissolution curve of a reference preparation with the same specification, wherein the results are as follows:
| sample(s) | f 2 |
| Example 9 | 54 |
Example 10: benzonatate soft capsule
The prescription composition is as follows:
the preparation method comprises the following steps:
(1) preparing a liquid medicine: placing the weighed raw material of benzonatate in a heat-preserving container, and keeping the temperature of the raw material at 35 +/-2 ℃;
(2) preparing glue solution: opening a sol tank, sucking weighed glycerol and purified water into the sol tank, sucking gelatin into the sol tank when the temperature is raised to 75 +/-2 ℃, stirring for 5 minutes, then opening a vacuum pump, keeping the vacuum degree at-0.7 to-1.0 bar, and extracting water until the weight ratio of the extracted water to the gelatin in the sol tank is 0.20: 1, turning off the vacuum pump and stopping stirring;
(3) pressing: pressing by adopting a rotary molding method, pumping the glue solution into a glue solution box by a glue solution pump, controlling the temperature of the glue solution box to be 60.0 +/-2.0 ℃, and pumping the liquid medicine into a hopper by a liquid medicine pump; starting a pill pressing machine, enabling glue solution to flow through a cooled roller to form an adhesive tape with the thickness of 0.031inch, enabling the liquid medicine in a hopper to pass through a spraying body when two bright adhesive tapes pass through the middle of a pair of corresponding rotating cylindrical dies, injecting a certain amount of liquid medicine into a semi-closed capsule on a stamping die, pressing the two adhesive tapes by a rolling die along the relative rotation of the dies, and cutting the two adhesive tapes along the outline of a die cavity to form a completely sealed soft capsule;
(4) primary drying: the primary drying is tumble drying, the rotating speed is controlled to be 7rpm, and the drying time is 3 hours;
(5) secondary drying: the primary drying is tunnel drying, the temperature is controlled to be 20-24 ℃, and the drying time is 50 hours;
(6) and (5) performing mechanical inspection, visual inspection and packaging to obtain the benzonatate soft capsule.
And (3) measuring the dissolution curve of the benzonatate soft capsule prepared in the step (6), and comparing the dissolution curve with the dissolution curve of a reference preparation with the same specification, wherein the results are as follows:
| sample (I) | f 2 |
| Example 10 | 68 |
Comparative example 1: benzonatate soft capsule
The prescription composition is as follows:
the preparation method comprises the following steps: the steps (1), (2), (3) and (6) are the same as those in example 1
(4) Primary drying: the primary drying is tumble drying, the rotating speed is controlled to be 5rpm, and the drying time is 4 hours;
(5) secondary drying: the primary drying is tunnel drying, the temperature is controlled to be 20-24 ℃, and the drying time is 60 hours.
The prepared benzonatate soft capsule is subjected to dissolution curve measurement and is compared with the dissolution curve of a reference preparation with the same specification, and the results are as follows:
| sample (I) | f 2 |
| Comparative example 1 | 48 |
Comparative example 2: benzonatate soft capsule
The prescription composition is as follows:
the preparation method comprises the following steps: the steps (1), (2), (3) and (6) are the same as those in example 1
(4) Primary drying: the primary drying is tumble drying, the rotating speed is controlled to be 5rpm, and the drying time is 3 hours;
(5) secondary drying: the primary drying is tunnel drying, the temperature is controlled to be 20-24 ℃, and the drying time is 58 hours.
The prepared benzonatate soft capsule is subjected to dissolution curve measurement and is compared with the dissolution curve of a reference preparation with the same specification, and the results are as follows:
comparative example 3: benzonatate soft capsule
The prescription composition is as follows:
the preparation method comprises the following steps: the steps (1), (2), (3) and (6) are the same as those in example 1
(4) Primary drying: the primary drying is tumble drying, the rotating speed is controlled to be 6rpm, and the drying time is 2 hours;
(5) secondary drying: the primary drying is tunnel drying, the temperature is controlled to be 20-24 ℃, and the drying time is 42 hours.
The prepared benzonatate soft capsule is subjected to dissolution curve measurement and is compared with the dissolution curve of a reference preparation with the same specification, and the results are as follows:
| sample (I) | f 2 |
| Comparative example 3 | 49 |
Comparative example 4: benzonatate soft capsule
The prescription composition is as follows:
the preparation method comprises the following steps: the steps (1), (2), (3) and (6) are the same as those in example 1
(4) Primary drying: the primary drying is drying in a rotating cage, the rotating speed is controlled to be 5rpm, and the drying time is 1.5 hours;
(5) secondary drying: the primary drying is tunnel drying, the temperature is controlled to be 20-24 ℃, and the drying time is 40 hours.
The prepared benzonatate soft capsule is subjected to dissolution curve measurement and is compared with the dissolution curve of a reference preparation with the same specification, and the results are as follows:
| sample (I) | f 2 |
| Comparative example 4 | 43 |
Comparative example 5: benzonatate soft capsule
The prescription composition is as follows:
the preparation method comprises the following steps:
(1) preparing a liquid medicine: placing the weighed raw material of benzonatate in a heat-preserving container to keep the temperature of the raw material at 30 +/-2 ℃;
(2) preparing glue solution: opening a sol tank, sucking weighed glycerol and purified water into the sol tank, sucking gelatin into the sol tank when the temperature is raised to 75 +/-2 ℃, stirring for 5 minutes, then opening a vacuum pump, keeping the vacuum degree at-0.7 to-1.0 bar, and extracting water until the weight ratio of the extracted water to the gelatin in the sol tank is 0.20: 1, turning off the vacuum pump and stopping stirring;
(3) pressing: pressing by adopting a rotary molding method, pumping the glue solution into a glue solution box by a glue solution pump, controlling the temperature of the glue solution box to be 60.0 +/-2.0 ℃, and pumping the liquid medicine into a hopper by a liquid medicine pump; starting a pill pressing machine, enabling a glue solution to flow through a cooled roller to form an adhesive tape with the thickness of 0.040inch, enabling the liquid medicine in a hopper to pass through a spraying body when two adhesive tapes penetrate through the middle of a pair of cylindrical dies rotating correspondingly, injecting a certain amount of liquid medicine into a semi-closed capsule on a stamping die, pressing the two adhesive tapes by a rolling die along the relative rotation of the dies, and cutting the two adhesive tapes along the outline of a die cavity to form a completely sealed soft capsule;
(4) primary drying: the primary drying is tumble drying, the rotating speed is controlled to be 7rpm, and the drying time is 4.5 hours;
(5) secondary drying: the primary drying is tunnel drying, the temperature is controlled to be 20-24 ℃, and the drying time is 58 hours;
(6) and (5) performing mechanical inspection, visual inspection and packaging to obtain the benzonatate soft capsule.
The prepared benzonatate soft capsule is subjected to dissolution curve measurement and is compared with the dissolution curve of a reference preparation with the same specification, and the results are as follows:
| sample (I) | f2 |
| Comparative example 5 | 45 |
Comparative example 6: benzonatate soft capsule
The prescription composition is as follows:
the preparation method comprises the following steps:
(1) preparing a liquid medicine: placing the weighed benzonatate raw material in a heat-preserving container, and keeping the temperature of the raw material at 30 +/-2 ℃;
(2) preparing glue solution: opening a sol tank, sucking weighed glycerol and purified water into the sol tank, sucking gelatin into the sol tank when the temperature is raised to 75 +/-2 ℃, stirring for 5 minutes, then opening a vacuum pump, keeping the vacuum degree at-0.7 to-1.0 bar, and extracting water until the weight ratio of the extracted water to the gelatin in the sol tank is 0.20: 1, turning off the vacuum pump and stopping stirring;
(3) pressing: pressing by adopting a rotary molding method, pumping the glue solution into a glue solution box by a glue solution pump, controlling the temperature of the glue solution box to be 60.0 +/-2.0 ℃, and pumping the liquid medicine into a hopper by a liquid medicine pump; starting a pill pressing machine, enabling glue solution to flow through a cooled roller to form an adhesive tape with the thickness of 0.020inch, enabling the liquid medicine in a hopper to pass through a spraying body when two bright adhesive tapes pass through the middle of a pair of corresponding rotating cylindrical dies, injecting quantitative liquid medicine into a semi-closed capsule on a stamping die, pressing the two adhesive tapes by a rolling die along the relative rotation of the dies, and cutting the two adhesive tapes along the outline of a die cavity to form a completely sealed soft capsule;
(4) primary drying: the primary drying is tumble drying, the rotating speed is controlled to be 7rpm, and the drying time is 1.5 hours;
(5) secondary drying: the primary drying is tunnel drying, the temperature is controlled to be 20-24 ℃, and the drying time is 40 hours;
(6) and (5) performing mechanical inspection, visual inspection and packaging to obtain the benzonatate soft capsule.
The prepared benzonatate soft capsule is subjected to dissolution curve measurement and is compared with the dissolution curve of a reference preparation with the same specification, and the results are as follows:
| sample (I) | f 2 |
| Comparative example 6 | 41 |
Comparative example 7: benzonatate soft capsule
The prescription composition is as follows:
the preparation method comprises the following steps:
(1) preparing a liquid medicine: placing the weighed raw material of benzonatate in a heat-preserving container, and keeping the temperature of the raw material at 35 +/-2 ℃;
(2) preparing glue solution: opening a sol tank, sucking weighed glycerol and purified water into the sol tank, sucking gelatin into the sol tank when the temperature is raised to 75 +/-2 ℃, stirring for 5 minutes, then opening a vacuum pump, keeping the vacuum degree at-0.7 to-1.0 bar, and extracting water until the weight ratio of the extracted water to the gelatin in the sol tank is 0.12: 1, turning off the vacuum pump and stopping stirring;
(3) pressing: pressing by rotary molding method, pumping the glue solution into a glue solution box, controlling the temperature of the glue solution box to be 60.0 + -2.0 deg.C, and pumping the medicinal liquid into a hopper; starting a pill pressing machine, enabling glue solution to flow through a cooled roller to form an adhesive tape with the thickness of 0.020inch, enabling the liquid medicine in a hopper to pass through a spraying body when two bright adhesive tapes pass through the middle of a pair of corresponding rotating cylindrical dies, injecting quantitative liquid medicine into a semi-closed capsule on a stamping die, pressing the two adhesive tapes by a rolling die along the relative rotation of the dies, and cutting the two adhesive tapes along the outline of a die cavity to form a completely sealed soft capsule;
(4) primary drying: the primary drying is tumble drying, the rotating speed is controlled to be 7rpm, and the drying time is 5 hours;
(5) secondary drying: the primary drying is tunnel drying, the temperature is controlled to be 20-24 ℃, and the drying time is 58 hours;
(6) and performing mechanical inspection, visual inspection and packaging to obtain the benzonatate soft capsule.
The prepared benzonatate soft capsule is subjected to dissolution curve measurement and is compared with the dissolution curve of a reference preparation with the same specification, and the results are as follows:
| sample (I) | f 2 |
| Comparative example 7 | 49 |
And (3) data analysis:
1. by analyzing examples 1 to 10 and comparative examples 1 to 4: the proportion of gelatin, glycerol and water in the capsule shell influences the structure of the capsule shell of the benzonatate soft capsule, further influences the dissolution behavior of the benzonatate soft capsule, and can be seen from examples 1-10: when the ratio of gelatin: glycerol: when the weight ratio of water is 10:3.2-3.8:9.5-10.5, the f2 of the dissolution curve of the prepared benzonatate soft capsule is more than 50, is similar to the dissolution behavior of the original preparation, and has the same curative effect (bioequivalence) as the original preparation; further, when gelatin: glycerol: when the weight ratio of water is 10:3.5-3.7:9.5-10.5, the dissolution curve f2 of the prepared benzonatate soft capsule is more than 65, is more similar to the dissolution behavior of the original preparation, and has the same curative effect (bioequivalence) as the original preparation; further, when gelatin: glycerol: when the weight ratio of water is 10:3.6:10, the f2 of the dissolution curve of the prepared benzonatate soft capsule is not lower than 75, is more similar to the dissolution behavior of the original preparation, and has the same curative effect (bioequivalence) as the original preparation. As can be seen from comparative examples 1-4, when the gelatin: glycerin: when the weight ratio of water is beyond the range of 10:3.2-3.8:9.5-10.5, the dissolution curve f2 of the prepared benzonatate soft capsule is less than 50, which is inconsistent with the dissolution of the original preparation, and the curative effect of the benzonatate soft capsule is different from the original preparation.
2. The water pumping amount in the step (2), the thickness of the adhesive tape in the step (3), the drying time in the step (4) and the step (5) and the like in the preparation method influence the dissolution behavior of the benzonatate soft capsule, when the process parameters are beyond the range of the invention, the f2 of the dissolution curve of the prepared benzonatate soft capsule is less than 50 and is inconsistent with the dissolution of the original preparation, and the curative effect of the benzonatate soft capsule is different from the original preparation.
Example 11 stability test
Taking a proper amount of samples of examples 1-10 and comparative examples 1-8, and carrying out temperature control at 25 +/-2 ℃; the sample is placed for 36 months under the condition of relative humidity of 60% +/-5%, and samples are taken at the end of 3 rd, 6 th, 9 th, 12 th, 18 th, 24 th and 36 th months respectively, and the properties, dissolution rate, related substances (single impurity and total impurity) butyraldehyde and content of the sample are measured.
The internal control standard is
Appearance: is a yellow transparent oval soft capsule, and the content is a light yellow viscous liquid.
Dissolution rate: the amount of benzonatate dissolved out at 30 minutes should be not less than 80% of the indicated amount.
Related substances are as follows: the single impurity is not more than 0.2 percent, and the total impurity is not more than 0.5 percent.
Butyraldehyde: not more than 500ppm
The contents are as follows: the content of the active ingredients is 95.0 to 105.0 percent of the marked content
The microbial limit: should comply with the regulations
By analyzing examples 1 to 10 and comparative examples 1 to 7: the compatibility of the benzonatate soft capsule content and the capsule shell is influenced by the proportion of the gelatin, the glycerol and the water in the capsule shell and the specific preparation process, the stability of the benzonatate soft capsule is further influenced, and the examples 1 to 10 show that: when the gelatin: glycerin: when the weight ratio of water is 10:3.2-3.8:9.5-10.5, the benzonatate soft capsule prepared by the preparation method is heated at the temperature of 25 +/-2 ℃; standing for 36 months under the condition that the relative humidity is 60% +/-5%, wherein the content of single impurity is not more than 0.2%, the content of total impurity is not more than 0.5%, and the content of impurity butyraldehyde is not more than 100ppm, so that the prepared benzonatate soft capsule is stable; when the gelatin: glycerol: when the weight ratio of water is 10:3.5-3.7:9.5-10.5, the benzonatate soft capsule prepared by the preparation method is heated at the temperature of 25 +/-2 ℃; the prepared benzonatate soft capsule is more stable when placed for 36 months under the condition that the relative humidity is 60 +/-5 percent, the content of single impurity is not more than 0.1 percent, the total impurity is not more than 0.2 percent, and the content of impurity butyraldehyde is not more than 50 ppm; when the ratio of gelatin: glycerol: when the weight ratio of water is 10:3.6:10, the benzonatate soft capsule prepared by the preparation method is kept at the temperature of 25 +/-2 ℃; standing at relative humidity of 60% +/-5% for 36 months with single impurity not more than 0.05% and total impurity not more than 0.1%; the content of impurity butyraldehyde is not more than 20ppm, and the prepared benzonatate soft capsule is more stable.
When the gelatin: glycerol: when the weight ratio of water exceeds the range of 10:3.2-3.8:9.5-10.5 or the water pumping amount, the thickness of the adhesive tape, the drying temperature and the like in the preparation method exceed the ranges, preparing the obtained benzonatate soft capsule, and keeping the temperature at 25 +/-2 ℃; the soft capsule is placed for 36 months under the condition that the relative humidity is 60 +/-5 percent, the content of single impurity is more than 0.2 percent, the content of total impurity is more than 0.5 percent, the content of impurity butyraldehyde is more than 100ppm, and the prepared benzonatate soft capsule has poor stability.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (8)
1. The benzonatate soft capsule consists of a soft capsule content and a capsule shell, wherein the soft capsule content is benzonatate, and the capsule shell is characterized by consisting of the following components in parts by weight: 10 parts of gelatin, 3.2-3.8 parts of glycerol and 9.5-10.5 parts of water; the benzonatate soft capsule is placed for 36 months under the condition of shading and room temperature, and the total content of impurity butyraldehyde in the benzonatate soft capsule is not more than 100 ppm;
the preparation method comprises the following steps:
(1) preparing a liquid medicine: placing the weighed raw material of benzonatate in a heat-preserving container, and keeping the temperature of the raw material at 35 +/-2 ℃;
(2) preparing glue solution: opening a sol tank, sucking weighed glycerol and purified water into the sol tank, sucking gelatin into the sol tank when the temperature is raised to 75 +/-2 ℃, stirring for 2-7 minutes, then opening a vacuum pump, keeping the vacuum degree at-0.7 to-1.0 bar, and extracting water until the weight ratio of the extracted water to the gelatin in the sol tank is 0.15-0.25: 1, turning off the vacuum pump and stopping stirring;
(3) pressing: pressing by rotary molding method, pumping the glue solution into a glue solution box, controlling the temperature of the glue solution box to be 60.0 + -2.0 deg.C, and pumping the medicinal liquid into a hopper; starting a pill pressing machine, enabling glue solution to flow through a cooled roller to form adhesive tapes with the thickness of 0.025inch-0.035inch, enabling the liquid medicine in a hopper to pass through a spraying body when two adhesive tapes pass through the middle of a pair of corresponding rotating cylindrical dies, injecting quantitative liquid medicine into semi-closed capsules on a die stamping die, pressing the two adhesive tapes by a rolling die along the relative rotation of the dies, and cutting along the outline of a die cavity to form completely sealed soft capsules;
(4) primary drying: the primary drying is drying in a rotating cage, the rotating speed is controlled to be 6-8rpm, and the drying time is 2-4 hours;
(5) secondary drying: the secondary drying is tunnel drying, the temperature is controlled to be 20-24 ℃, and the drying time is 45-55 hours;
(6) and (5) performing mechanical inspection, visual inspection and packaging to obtain the benzonatate soft capsule.
2. The benzonatate soft capsule according to claim 1, wherein the content of the soft capsule is 100mg of benzonatate, and the capsule shell comprises the following components in parts by weight: 10 parts of gelatin, 3.5-3.7 parts of glycerol and 10 parts of water.
3. The benzonatate soft capsule according to claim 1, wherein the content of the soft capsule is benzonatate 200mg, and the capsule shell comprises the following components by weight: 10 parts of gelatin, 3.5-3.7 parts of glycerol and 10 parts of water.
4. The benzonatate soft capsule according to claim 3, wherein the content of the soft capsule is benzonatate 200mg, and the capsule shell comprises the following components by weight: 10 parts of gelatin, 3.6 parts of glycerol and 10 parts of water.
5. The benzonatate soft capsule of claim 1, wherein in step (2), the weight ratio of the extracted water to the gelatin in the sol-gel tank is 0.18-0.22: 1.
6. the benzonatate soft capsule of claim 1, wherein in step (2), the weight ratio of the extracted water to the gelatin in the sol-gel tank is 0.20: 1.
7. the benzonatate soft capsule of claim 1, wherein in step (3), the thickness of the adhesive tape is 0.029inch to 0.033 inch.
8. The benzonatate soft capsule of claim 1, wherein in step (3), the thickness of the adhesive tape is 0.031 inch.
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