CN111671734A - Bionic pH-dependent capsule shell and preparation method and application thereof - Google Patents
Bionic pH-dependent capsule shell and preparation method and application thereof Download PDFInfo
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- 239000002775 capsule Substances 0.000 title claims abstract description 141
- 230000001419 dependent effect Effects 0.000 title claims abstract description 45
- 239000011664 nicotinic acid Substances 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 239000003814 drug Substances 0.000 claims abstract description 61
- 229940079593 drug Drugs 0.000 claims abstract description 38
- 239000004925 Acrylic resin Substances 0.000 claims abstract description 25
- 229920000178 Acrylic resin Polymers 0.000 claims abstract description 24
- 108010010803 Gelatin Proteins 0.000 claims abstract description 24
- 229920000159 gelatin Polymers 0.000 claims abstract description 24
- 239000008273 gelatin Substances 0.000 claims abstract description 24
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- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 23
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 21
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000002994 raw material Substances 0.000 claims abstract description 16
- 239000003292 glue Substances 0.000 claims description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 34
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- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
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- 229920000609 methyl cellulose Polymers 0.000 description 3
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
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- 229960003943 hypromellose Drugs 0.000 description 2
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- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 229910000406 trisodium phosphate Inorganic materials 0.000 description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- OROGUZVNAFJPHA-UHFFFAOYSA-N 3-hydroxy-2,4-dimethyl-2H-thiophen-5-one Chemical compound CC1SC(=O)C(C)=C1O OROGUZVNAFJPHA-UHFFFAOYSA-N 0.000 description 1
- 241000402754 Erythranthe moschata Species 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 102100029469 WD repeat and HMG-box DNA-binding protein 1 Human genes 0.000 description 1
- 101710097421 WD repeat and HMG-box DNA-binding protein 1 Proteins 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- -1 and to date Substances 0.000 description 1
- 230000001458 anti-acid effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
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- 230000029087 digestion Effects 0.000 description 1
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- 238000009505 enteric coating Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
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- 235000013305 food Nutrition 0.000 description 1
- 238000012395 formulation development Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000013376 functional food Nutrition 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- YIXJRHPUWRPCBB-UHFFFAOYSA-N magnesium nitrate Chemical class [Mg+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O YIXJRHPUWRPCBB-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
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- 125000005397 methacrylic acid ester group Chemical group 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
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- 230000002035 prolonged effect Effects 0.000 description 1
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- 239000007858 starting material Substances 0.000 description 1
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- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
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- 238000010998 test method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
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- 229940126680 traditional chinese medicines Drugs 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4816—Wall or shell material
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4816—Wall or shell material
- A61K9/4825—Proteins, e.g. gelatin
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a bionic pH-dependent capsule shell and a preparation method and application thereof, belonging to the technical field of pharmacy and medicine bag materials. The bionic pH-dependent capsule shell comprises the following raw materials: and (2) component A: 50 percent of hydroxypropyl methylcellulose,
30-49% of L100-55 acrylic resin,
Description
Technical Field
The invention belongs to the technical field of pharmacy and medicine bag materials, relates to a capsule shell, and particularly relates to a bionic pH-dependent capsule shell and a preparation method and application thereof.
Background
The capsule shell is the most common medicine filling material for modern medicines, functional foods and the like, has unique advantages and plays a vital role in the medicine and health-care food industries. Capsules have many advantages over tablets: the development of a new capsule dosage form is simpler than the development of a new tablet, the filling of the drug is easier, no extrusion process is required and the unpleasant odor of the drug is easily masked. From the early 19 th century, Maths invented the first pharmaceutical capsule with gelatin, and to date, capsules have been the first choice for formulation development in industrial production.
The capsule has the following characteristics: the appearance is beautiful, the appearance is smooth, and the improper bitterness and odor generated by the raw materials of the medicine can be covered, so that the medicine is easy to accept by consumers. Meanwhile, the functional factor has good bioavailability, small auxiliary material dosage and high release speed in gastrointestinal tracts, and the functional substances can be disintegrated and released within ten minutes after the oral preparation is taken. However, capsules also have certain disadvantages: firstly, the medicines with high solubility and strong stimulation to the gastrointestinal tract are not recommended to be prepared into capsules, and when the medicines are dissolved in the stomach, the gastric mucosa is stimulated due to the local over-high concentration; secondly, the medicine which can change the capsule is not suitable for being prepared into the capsule, for example, the medicine which can deteriorate the capsule due to instability after being contacted with the wall material of the capsule, the medicine which influences the release speed, and the medicine which is easy to soften or become brittle due to the influence of humidity are not generally recommended to be prepared into the capsule; thirdly, capsules are not generally suitable for children; in addition, compared with other dosage forms, the capsule shell has larger mass difference and higher production cost, and is easy to deteriorate under the influence of external environmental factors such as humidity and the like.
The capsule wall material of the traditional capsule takes gelatin as the main material, the production process of the gelatin capsule shell is simple, but the problems exist, such as poor protection effect on moisture and oxygen sensitive drugs, easy esophagus adhesion, slow disintegration in the storage process, reduction of drug dissolution and the like, and the reasons for the problems are as follows: gelatin capsules are susceptible to softening by exposure to air. There have been attempts to improve the moisture resistance of gelatin by modifying gelatin by acylation with an acid anhydride such as succinic acid, maleic acid, phthalic acid, fumaric acid or the like, vulcanization with thiolactone or treatment with formaldehyde to harden the gelatin appropriately, but as a result, the disintegration time of the gelatin capsule tends to be prolonged to make it impossible to apply the gelatin capsule to production. Recently, there are some improvements on the preparation method of gelatin capsules, such as microneedle perforation, vacuum drying, and adding hydrophilic auxiliary materials into gelatin solution, but these methods have too complicated preparation process or too high friability of the prepared capsules, and are difficult to be widely applied.
Gelatin capsules also have problems during the coating process, such as brittleness of the capsule shell, difficulty in adhering the coating film to the smooth capsule shell surface, etc. At present, the aqueous coating process is gradually replacing the original coating process due to toxicity, environment, cost and other reasons, which makes the coating of gelatin capsules more difficult. HPMC (hypromellose) capsules have good stability to water and can be prepared using aqueous coating processes. However, the coating of HPMC capsules suffers from the disadvantage that the capsule shells must be filled with the drug first and then coated, rather than being coated directly as with gelatin capsule shells and then subsequently used to fill the drug.
The enteric capsule is prepared by coating enteric coating on the gelatin capsule, can release medicine in the intestinal tract in a positioning way, so that some medicines sensitive to gastric juice or medicines irritating to the stomach have better application, and the medicine can be directly positioned in the intestinal tract to release to exert curative effect after being applied to the enteric capsule, and has the characteristics of small dosage, high curative effect and low side effect, so that the enteric capsule obtains wide attention. However, due to the special properties of gelatin, the traditional coating method is difficult to achieve the desired effect, or the drug properties in the coating or the stability of the whole capsule are influenced. On the other hand, the enteric capsule adopts the traditional gelatin as the raw material, and the characteristic of slow release with different pH values cannot be realized. For example, patent document CN 106138007 a discloses a composition of enteric capsule shell, enteric capsule shell and preparation method thereof, which has excellent anti-acid property, but does not have sustained release property under different pH conditions.
The acrylic resin is a high molecular polymer prepared by copolymerizing acrylic acid, methacrylic acid and ester thereof according to a certain proportion. It has the advantages of safety, stability, inertia, no irritation, etc., and can be well formed into film, so that it has good application in capsule preparation. Such pharmaceutically acceptable acrylate polymers are collectively known by the trade name Youqite
Is a polyacrylic resin invented by Rohm company of Germany,
l100-55(EL-55) and
s100(ES) is
Two types of the drug can be widely applied in families, can be used as tablet coating materials and applied to colon targeted drug delivery, and meet different drug release requirements under different pH values by adjusting the proportion of the two types of the drug. At present, the preparation of the pH-dependent sustained-release preparation becomes a research hotspot in the field of traditional Chinese medicines.
However, most of the acrylic resins can only be prepared into pellets when used for preparing pH-dependent sustained-release Chinese medicinal preparations, and the pellets are coated with materials of different types, mixed and filled into gelatin capsules, so that the problems of the gelatin capsules are not solved, for example, in patent document CN1386498A, only one pH-dependent sustained-release Chinese medicinal pellet preparation is prepared, but not the pellets are directly prepared into capsule preparations, so that the capsules have the characteristics of pH-dependent sustained-release. For example, in journal literature, "study of musk heart-protecting pH-dependent gradient drug release pellets", songhuo, pharmaceutical science report [ J ], only relates to a method for preparing pH-dependent gradient drug release pellets, but cannot expand the pellets onto capsule shells for production, and cannot realize that the capsule shells can meet the characteristics of pH-dependent gradient drug release.
Therefore, on the basis of the current research, the development of a capsule shell for preparing pH-dependent gradient drug release, a preparation method and an application thereof are urgently needed to solve the defect that the existing medicament can only prepare gradient drug release pellets.
Disclosure of Invention
The invention aims to solve the technical problems and provides a bionic pH-dependent capsule shell and a preparation method and application thereof. The capsule shell provided by the invention can meet the characteristic that the obtained capsule shell has pH-dependent gradient drug release, can release the drug in the capsule at different positions and time according to the change of pH values of different parts of gastrointestinal tract of a digestion system in a human body to achieve a slow release effect, and has the characteristics of dissolution, disintegration and stable release and absorption, and the dissolution and disintegration of the capsule shell can be consistent with the pH value of the gastrointestinal tract.
The invention firstly provides a bionic pH-dependent capsule shell, which comprises the following components in parts by weight: and (2) component A: according to the weight percentageCalculated as 50 percent of hydroxypropyl methylcellulose,
30-49% of L100-55 acrylic resin,
1-20% of L100 acrylic resin; and (B) component: a pharmaceutical gelatin;
wherein, the weight percentages of the component A and the component B are as follows: 5-35 percent and 95-65 percent.
Preferably, the weight percentages of the raw materials of the component A in the scheme are as follows: 50 percent of hydroxypropyl methylcellulose,
40 percent of L100-55 acrylic resin,
L100 acrylic resin 10%.
Preferably, the weight percentages of the component A and the component B in the scheme are as follows: 25 percent to 75 percent.
The capsule shell in the invention is a buckled closed structure.
In the capsule shell raw material composition of the invention
L100-55 is a copolymer obtained by copolymerizing methacrylic acid and methacrylic acid ester, and is soluble in an ionic solution having a pH of 5.5 or more.
L100 is a copolymer obtained by copolymerizing methacrylic acid and methyl methacrylate at a ratio of 50:50, and is soluble at pH > 6 and insoluble in gastric juice, and can be used as an enteric material. Of the above two types
Has the solubility under different pH values and good compatibility between the two types. Another starting material of the inventionThe methyl cellulose can have good solubility in an ethanol solvent at a certain temperature, the viscosity of the methyl cellulose is reduced firstly in the heating and temperature rising process, the viscosity of the solution can be rapidly increased after the heating is continued, and the gelling temperature can be rapidly reached. The capsule shell has the characteristics of high polymer materials, when entering a human body, the capsule shell firstly passes through the stomach and then reaches the small intestine and the rectum, and the pH value of the parts changes from acidity to alkalinity, so that the high polymer materials of the capsule shell can swell along with the change of the pH value, so that a plurality of holes exist on the surface of the shell, and the holes on the surface of the shell are continuously enlarged along with the difference of the pH value, so that the capsule shell can continuously release the medicine in the shell along with the change of the size of the holes, and the slow release effect under the environment pH values of different parts of the stomach and intestine of the human body is realized.
The capsule shell provided by the invention also well solves the defect of incomplete in-vivo degradation of the methylcellulose capsule, and the medicine encapsulated by the capsule shell has high in-vivo bioavailability.
The capsule shell of the invention also has the characteristics of stable release and absorption. The principle is not like pellet slow release, but the slow release can be carried out in different pH environments of different parts of the stomach and intestine directly through the slow release characteristic of the capsule shell.
The invention also aims to provide a preparation method of the bionic pH-dependent capsule shell, which comprises the following steps:
(1) taking the following raw materials as a component A in percentage by weight: 50 percent of hydroxypropyl methylcellulose,
30-49% of L100-55 acrylic resin and
1-20% of L100 acrylic resin; firstly, dissolving hydroxypropyl methylcellulose in ethanol solutionThen adding the mixture under ultrasonic oscillation and stirring
L100-55 and
l100, heating and dissolving to obtain a prefabricated glue solution;
(2) taking medicinal gelatin as a component B, dissolving the medicinal gelatin in an ethanol solution, adding the prefabricated glue solution obtained in the step (1), and heating and mixing to obtain a glue solution; the glue solution comprises the following components in percentage by weight: 5-35% and 95-65%;
(3) and (3) standing and defoaming the glue solution obtained in the step (2), dipping the glue solution in a capsule shell mold for molding, drying and demolding to obtain the bionic pH-dependent capsule shell.
The invention adopts the raw materials and well prepares the bionic pH-dependent gradient drug release capsule shell under the preparation method. The preparation process of the invention is that the combination A is prepared into a prefabricated glue solution in advance, then the prefabricated glue solution and the gelatin in the component B are prepared into a glue solution according to a certain proportion, and finally the glue solution is formed. The components are mixed together to prepare a prefabricated glue solution, so that the formability of the high polymer material is good, not only can a subsequent pH-dependent sustained-release capsule shell be prepared, but also the problems that the gelatin shell becomes brittle and a coating film is difficult to adhere to the surface of a smooth capsule shell in the coating process of the gelatin capsule are solved. The invention well solves the problems that only the pellets can be prepared and the pH-dependent pellets can be prepared by coating the pellets with different sustained-release materials in the prior art, but the pH-dependent sustained-release capsule shell can not be prepared. The capsule shell prepared by the invention is directly loaded with the medicine, so that the characteristic that the medicine in the capsule is released at different positions and time in the gastrointestinal tract of the digestive system of a human body under different pH conditions can be directly realized, and the slow release effect of the medicine is realized. The present invention relates to the absorption and release of drugs in capsule shells, the release rate of which is determined by the position of the digestive tract reached by the capsule and its pH value. The absorption of the drug within the capsule shell is determined by the properties of the drug itself.
The capsule shell of the present invention is required to be prepared in a closed form, preferably in a snap-fit closed form, the dissolution and disintegration of which can be consistent with gastrointestinal pH.
The raw materials of the medicine filled in the capsule shell can be granules, microspheres, powder and the like. Unless otherwise specified, the pH of the drug (1g drug per 100ml water) should be in the range of 3-10.
The hygienic requirements, physicochemical indexes, moisture and appearance index attributes of the capsule meet the technical requirements under the item of capsules in the 2020 edition of pharmacopoeia.
The raw materials for preparing the capsule shell are all medicinal grade; the capsule shell should be preserved in dark, and the environmental humidity should be below RH 15%.
Further, the mass fraction of the ethanol solution in the step (1) is 60-75%.
Further, the temperature after the temperature rise in the step (1) is 65-75 ℃.
Further, the vibration frequency of the ultrasonic wave in the step (1) is 30-50 Hz, and the stirring speed is 300-500 r/min.
Further, the mass fraction of the ethanol solution in the step (2) is 40-50%.
Further, the temperature of the heating and mixing in the step (2) is 75-90 ℃.
Further, in the step (3), the drying and demolding step is performed after the film is dried at 40 ℃ for 3 hours to form the film.
In the above preferable steps of the invention, the adopted process conditions can ensure that the bionic pH-dependent capsule shell of the invention can be well prepared.
The invention also aims to provide application of the bionic pH-dependent capsule shell prepared by the method, and the bionic pH-dependent capsule shell is applied to the aspect of medicine loading or gradient release of wrapped medicines.
Compared with the prior art, the invention has the following beneficial effects:
the invention overcomes the problem that the prior art can only prepare the pH-dependent gradient release pellets, directly prepares a bionic pH-dependent gradient release capsule shell, provides a preparation method of the gradient release capsule shell, has simple preparation process, easily obtained raw materials and easily controlled production process, can release the medicament in the capsule at different positions and time according to the change of the environmental pH value of different parts of the gastrointestinal tract of the digestive system in the human body to achieve the slow release effect, and has the characteristics of stable release and absorption, and the dissolution and disintegration of the capsule shell can be consistent with the pH value of the gastrointestinal tract.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more clearly understood, the present invention is described in detail below with reference to the following embodiments, and it should be noted that the following embodiments are only for explaining and illustrating the present invention and are not intended to limit the present invention. The invention is not limited to the embodiments described above, but rather, may be modified within the scope of the invention.
Example 1
A bionic pH-dependent capsule shell is prepared by the following method:
(1) taking the following raw materials as a component A in percentage by weight: 50 percent of hydroxypropyl methylcellulose,
L100-55 acrylic resin 30% and
20% of L100 acrylic resin; firstly, dissolving hydroxypropyl methylcellulose in an ethanol solution with the mass fraction of 60%, and then adding the hydroxypropyl methylcellulose under ultrasonic oscillation and stirring
L100-55 and
l100, heating to 65 ℃ to dissolve to obtain a prefabricated glue solution; the vibration frequency of the ultrasonic wave is 30Hz, and the stirring speed is 300 r/min;
(2) taking medicinal gelatin as a component B, dissolving the medicinal gelatin in an ethanol solution, adding the prefabricated glue solution obtained in the step (1), heating to 75 ℃, and mixing to obtain a glue solution; the glue solution comprises the following components in percentage by weight: 5 percent to 95 percent;
(3) and (3) standing and defoaming the glue solution obtained in the step (2), dipping the glue solution into a capsule shell mold for molding, drying at 40 ℃ for 3 hours to form a film, and then demolding to obtain the bionic pH-dependent capsule shell.
Example 2
A bionic pH-dependent capsule shell is prepared by the following method:
(1) taking the following raw materials as a component A in percentage by weight: 50 percent of hydroxypropyl methylcellulose,
L100-55 acrylic resin 40% and
10% of L100 acrylic resin; firstly, dissolving hydroxypropyl methylcellulose in 65 percent ethanol solution by mass, and then adding the hydroxypropyl methylcellulose into the ethanol solution under ultrasonic oscillation and stirring
L100-55 and
l100, heating to 72 ℃ to dissolve to obtain a prefabricated glue solution; the vibration frequency of the ultrasonic wave is 40Hz, and the stirring speed is 400 r/min;
(2) taking medicinal gelatin as a component B, dissolving the medicinal gelatin in an ethanol solution, adding the prefabricated glue solution obtained in the step (1), heating to 82 ℃, and mixing to obtain a glue solution; the glue solution comprises the following components in percentage by weight: 25 percent to 75 percent;
(3) and (3) standing and defoaming the glue solution obtained in the step (2), dipping the glue solution into a capsule shell mold for molding, drying at 40 ℃ for 3 hours to form a film, and then demolding to obtain the bionic pH-dependent capsule shell.
Example 3
A bionic pH-dependent capsule shell is prepared by the following method:
(1) according to weight percentageTaking the following raw materials as a component A in percentage by weight: 50 percent of hydroxypropyl methylcellulose,
L100-55 acrylic resin 49% and
1% of L100 acrylic resin; firstly, dissolving hydroxypropyl methylcellulose in 75 percent of ethanol solution by mass percent, and then adding the hydroxypropyl methylcellulose into the ethanol solution under the ultrasonic oscillation and stirring
L100-55 and
l100, heating to 75 ℃ to dissolve to obtain a prefabricated glue solution; the vibration frequency of the ultrasonic wave is 50Hz, and the stirring speed is 500 r/min;
(2) taking medicinal gelatin as a component B, dissolving the medicinal gelatin in an ethanol solution, adding the prefabricated glue solution obtained in the step (1), heating to 90 ℃, and mixing to obtain a glue solution; the glue solution comprises the following components in percentage by weight: 35 percent to 65 percent;
(3) and (3) standing and defoaming the glue solution obtained in the step (2), dipping the glue solution into a capsule shell mold for molding, drying at 40 ℃ for 3 hours to form a film, and then demolding to obtain the bionic pH-dependent capsule shell.
Comparative example 1
According to the method of example 1, the medicinal gelatin component B of step (2) is removed, and the gelatin solution is directly prepared from the component A to obtain the capsule shell.
Comparative example 2
The hypromellose of component A in step (1) was prepared according to the method of example 1,
L100-55 acrylic resin and
the weight percentage of the L100 acrylic resin is adjusted to 45 percent to 50 percent: 5%, other methods are unchangedAnd preparing the capsule shell.
Comparative example 3
The capsule shell was prepared by adjusting the weight percentage of the component A and the component B in example 1 to 40% to 60% without changing other methods.
Experimental example 1
Determination of friability of capsule shells:
50 capsule shells prepared in the above examples and comparative examples were taken, placed in a plate, placed in a desiccator containing a saturated magnesium nitrate solution, kept at a constant temperature of 25 ℃. + -. 1 ℃ for 24 hours, taken out, immediately placed one by one in a glass tube having an inner diameter of 24mm and a height of 200mm standing on a wooden plate, a cylindrical weight having a diameter of 22mm was freely dropped from the mouth of the glass tube, and the presence or absence of capsule breakage was observed.
The test results showed that the capsule shells of examples 1 to 3 of the present invention were not ruptured (0 capsule), and the number of ruptured capsules of comparative examples 1 to 3 were 1 capsule, and 0 capsule, respectively.
Experimental example 2
Determination of disintegration time of capsule shell:
6 capsules of the capsule shells of examples 1 to 3 and comparative examples 1 to 3 were taken, and examined according to the disintegration time limit examination method in the second part of the pharmacopoeia of China, 2010 edition, which is the method in capsules, and each capsule was disintegrated within 10 min.
Experimental example 3
The in vitro drug release test method comprises the following steps:
the capsule shells of examples 1-3 and comparative examples 1-3 are filled with drugs (taking indapamide as an example) to obtain the indapamide sustained-release capsules, and the in vitro cumulative release degree is determined:
indapamide sustained-release capsules are used for simulating the in-vitro release of total gastrointestinal fluids and simulating release media with different pH values in stomach, small intestine and rectum in vivo, and the release medium simulation method comprises the following steps: releasing in 250ml hydrochloric acid solution with pH 1.2 for 2 hr, and adding Na3PO4Adjusting pH to 6.8, releasing for 6h, and adding Na3PO4The pH value is adjusted to 7.8, and the release time is 16 h.
Release method test: respectively filling 6 indapamide sustained-release capsules into dialysis bags, placing the dialysis bags in a dissolution cup filled with 250ml of release medium, performing release tests at 37 ℃ and at the rotating speed of 100r/min, sampling at 2h, 4h, 6h, 8h, 10h, 12h, 14h and 24h at regular time, supplementing the release medium with the same volume, filtering the release solution, determining in a high performance liquid chromatograph, and calculating the cumulative release percentage of the medicament.
The in vitro release results are shown in table 1:
TABLE 1
From the results, the capsule shell has the characteristic of gradient slow release along with the change of pH value at different parts of a human body. The capsule shell prepared by the raw materials and the method can have a plurality of small holes on the surface of the membrane after demoulding and forming, when the capsule shell enters the gastrointestinal tract of a human body, the capsule shell firstly passes through the stomach and then reaches the small intestine and the rectum, and because the pH values of the parts are changed from acidity to alkalinity, the capsule shell high polymer material can be swelled along with the change of the pH value, so that the holes on the surface of the shell are continuously enlarged, and the capsule shell can realize the continuous release of the medicine in the shell along with the change of the sizes of the holes, thereby realizing the slow release effect on different parts of the gastrointestinal tract of the human body.
Experimental example 4
The stability evaluation of the capsule shell obtained by the invention refers to the stability study of the XIXC pharmaceutical preparation in the second part of Chinese pharmacopoeia, 2010 edition, for an accelerated experiment.
The specific method comprises dividing the capsule into three batches, respectively packaging under sealed condition and non-sealed condition, and standing at 40 + -2 deg.C and relative humidity of 75% + -5% for 3 months. Samples were taken at the end of 1, 2, 3 months during the test period and drug dissolution behavior was examined. The result shows that the water absorption of the capsule shell under the non-sealed package is stronger and the stability is difficult to maintain. Therefore, the capsule shell is hermetically preserved with RH 15% or less.
Claims (10)
1. A bionic pH-dependent capsule shell is characterized in that the raw materials of the capsule shell comprise the following components:
and (2) component A: 50 percent of hydroxypropyl methylcellulose,
30-49% of L100-55 acrylic resin,
1-20% of L100 acrylic resin; and (B) component: a pharmaceutical gelatin;
wherein, the weight percentages of the component A and the component B are as follows: 5-35 percent and 95-65 percent.
2. The biomimetic pH-dependent capsule shell according to claim 1, wherein the weight percentage of each raw material in the component A is as follows: 50 percent of hydroxypropyl methylcellulose,
40 percent of L100-55 acrylic resin,
L100 acrylic resin 10%.
3. The biomimetic pH-dependent capsule shell according to claim 1, wherein the weight percentages of component a and component B are: 25 percent to 75 percent.
4. The biomimetic pH dependent capsule shell of claim 1, wherein the capsule shell is a snap-fit closure structure.
5. A process for the preparation of a biomimetic pH dependent capsule shell according to any of claims 1-4, comprising the steps of:
(1) taking a component A: 50 percent of hydroxypropyl methylcellulose,
30-49% of L100-55 acrylic resin and
1-20% of L100 acrylic resin; firstly, dissolving hydroxypropyl methylcellulose in ethanol solution, and then adding the hydroxypropyl methylcellulose under ultrasonic oscillation stirring
L100-55 and
l100, heating and dissolving to obtain a prefabricated glue solution;
(2) dissolving the medicinal gelatin of the component B in an ethanol solution, adding the prefabricated glue solution obtained in the step (1), and heating and mixing to obtain a glue solution; the glue solution comprises the following components in percentage by weight: 5-35% and 95-65%;
(3) and (3) standing and defoaming the glue solution obtained in the step (2), dipping the glue solution in a capsule shell mold for molding, drying and demolding to obtain the bionic pH-dependent capsule shell.
6. The preparation method of the bionic pH-dependent capsule shell as claimed in claim 5, wherein the ethanol solution in the step (1) has a mass fraction of 60-75%, and the temperature after the temperature rise is 65-75 ℃.
7. The preparation method of the bionic pH-dependent capsule shell according to claim 5, wherein the ultrasonic wave in the step (1) has a vibration frequency of 30-50 Hz and a stirring speed of 300-500 r/min.
8. The preparation method of the bionic pH-dependent capsule shell as claimed in claim 5, wherein the ethanol solution in the step (2) is 40-50% by mass, and the temperature for heating and mixing is 75-90 ℃.
9. The method for preparing a biomimetic pH dependent capsule shell according to claim 5, wherein the step of drying and demolding in step (3) is to perform demolding after drying at 40 ℃ for 3 hours to form a film.
10. Use of a biomimetic pH-dependent capsule shell according to any of claims 1-4 or prepared by a method according to any of claims 5-9 for drug loading or for gradient release of a coated drug.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4591475A (en) * | 1982-03-26 | 1986-05-27 | Warner-Lambert Company | Method for molding capsules |
| CN101461792A (en) * | 2008-12-30 | 2009-06-24 | 吴国庆 | Gelatine enteric capsule shell material |
| CN102038709A (en) * | 2010-12-24 | 2011-05-04 | 重庆时珍阁普生药业有限公司 | Enteric-coated capsule prepared from leeches as raw material |
-
2020
- 2020-06-23 CN CN202010577411.2A patent/CN111671734A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4591475A (en) * | 1982-03-26 | 1986-05-27 | Warner-Lambert Company | Method for molding capsules |
| CN101461792A (en) * | 2008-12-30 | 2009-06-24 | 吴国庆 | Gelatine enteric capsule shell material |
| CN102038709A (en) * | 2010-12-24 | 2011-05-04 | 重庆时珍阁普生药业有限公司 | Enteric-coated capsule prepared from leeches as raw material |
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