CN112472677A - Renin-resistant preparation and preparation method thereof - Google Patents
Renin-resistant preparation and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
Abstract
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a renin-resistant preparation and a preparation method thereof. The renin namine preparation comprises a mixture formed by a first coating and a second coating, wherein the first coating consists of a first core and a first coating film coated on the surface of the first core, and the second coating consists of a second core and a second coating film coated on the surface of the second core; the first core-spun yarn is a mixture of phenylephrine or pharmaceutically acceptable salt thereof and a first medicinal active agent and/or a first auxiliary material, and the second core-spun yarn is a mixture of chlorpheniramine maleate and/or brompheniramine maleate and a second medicinal active agent and/or a second auxiliary material. In the renin namine preparation, the first core and the second core are not contacted with each other, so that the phenylephrine and the chlorpheniramine maleate and/or the brompheniramine maleate are completely isolated, and the obtained renin namine preparation has higher product stability, safety and effectiveness.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a renin-resistant preparation and a preparation method thereof.
Background
Common cold is a common disease, and the current clinical treatment for common cold mainly comprises symptomatic treatment. Because a plurality of symptoms are generated during cold, the compound preparation can simultaneously aim at the symptoms of the cold and has the advantage of comprehensive control. The ingredients of the common cold-resistant medicine at present mainly comprise chlorpheniramine maleate/brompheniramine maleate and phenylephrine. Chlorphenamine maleate and brompheniramine maleate are antihistamine drugs and can relieve symptoms such as watery nasal discharge, nasal obstruction, sneeze and the like. Phenylephrine is a potent alpha receptor agonist, has selective vasoconstriction effects, can relieve congestion and swelling of nasopharyngeal mucosa, relieve nasal obstruction, rhinorrhea and other symptoms, has the advantages of safety, high efficiency, small side effect, no control component and the like, gradually replaces ephedrine drugs, and becomes a mainstream anti-cold drug component.
However, phenylephrine hydrochloride is easy to react with maleic acid in chlorpheniramine maleate and brompheniramine maleate, mainly secondary amine groups of phenylephrine hydrochloride and maleate groups of chlorpheniramine maleate or brompheniramine maleate are subjected to addition reaction to generate addition reaction impurities, and the content of phenylephrine hydrochloride is obviously reduced. The reaction is very easy to carry out when high temperature and high humidity exist at the same time, and great risks are brought to the safety and the effectiveness of clinical medication. E.g. marketed in the United states
Allergy&The Congestinon Relief simultaneously contains three effective components of ibuprofen, phenylephrine hydrochloride and chlorphenamine maleate, and the effective period is only 18 months due to mutual reaction between the phenylephrine hydrochloride and the chlorphenamine maleate.
In order to overcome the compatibility problem of phenylephrine hydrochloride, chlorphenamine maleate and brompheniramine maleate in a compound preparation, some related research results appear at present:
the disclosed method for stabilizing phenylephrine can improve the stability of phenylephrine in solid formulations by mixing phenylephrine into an acid-containing drug layering solution and adjusting the pH to 4.5-6.0.
According to the composition for improving the stability of the compound ibuprofen preparation and the preparation method thereof, ibuprofen, phenylephrine hydrochloride, chlorphenamine maleate and a proper amount of auxiliary materials are prepared into a melt, so that the stability of phenylephrine hydrochloride is improved.
For another example, disclosed is a liposome solid preparation of the compound paracetamol and renin pharmaceutical composition, which is prepared by preparing acetaminophen, anhydrous caffeine, phenylephrine hydrochloride, chlorphenamine maleate and vitamin B1 into liposome, so as to improve the stability of the composition.
Although the prior art can reduce the mutual contact of phenylephrine hydrochloride and chlorpheniramine maleate or bromopheniramine maleate to a certain degree, and can improve the stability of phenylephrine hydrochloride, the mutual contact of phenylephrine hydrochloride, chlorpheniramine maleate and bromopheniramine maleate in a compound preparation cannot be completely isolated, so that the mutual reaction between Active Pharmaceutical Ingredients (API) cannot be completely prevented, and the safety and effectiveness risks still exist in clinical application.
Disclosure of Invention
The invention aims to provide a renin namine preparation and a preparation method thereof, and aims to solve the technical problem that phenylephrine and chlorpheniramine maleate or brompheniramine maleate generate addition reaction to generate impurities in the existing compound preparation.
In order to achieve the above object, according to one aspect of the present invention, there is provided a renin inhibitor preparation comprising a mixture of a first coating consisting of a first core and a first coating film coated on the surface of said first core and a second coating consisting of a second core and a second coating film coated on the surface of said second core; the first core-spun yarn is a mixture of phenylephrine or pharmaceutically acceptable salt thereof and a first medicinal active agent and/or a first auxiliary material, and the second core-spun yarn is a mixture of chlorpheniramine maleate and/or brompheniramine maleate and a second medicinal active agent and/or a second auxiliary material.
The renin namine preparation provided by the invention comprises a first coating and a second coating, wherein a first core-spun of the first coating is a mixture of phenylephrine or a pharmaceutically acceptable salt thereof and a first pharmaceutical active agent and/or a first auxiliary material, a second core-spun of the second coating is a mixture of chlorphenamine maleate and/or brompheniramine maleate and a second pharmaceutical active agent and/or a second auxiliary material, and the first core-spun and the second core-spun are not contacted with each other, so that the phenylephrine and the chlorphenamine maleate and/or brompheniramine maleate are completely isolated, secondary amine groups on the phenylephrine are prevented from reacting with maleate, the obtained renin namide preparation has higher product stability, and the safety and effectiveness of clinical medication are improved. In addition, the first core and the second core of the renin namine preparation provided by the invention are also added with a medicinal active agent and/or an auxiliary material, so that the preparation has various advantages of coping with various cold symptoms, high release speed of medicinal active ingredients, higher stability and the like. The renin-chlorphenamine preparation provided by the invention belongs to a quick dissolution type preparation, wherein the dissolution rate of all active ingredients in the renin-chlorphenamine preparation is more than 85 percent within 15 minutes, and the active ingredients can be quickly absorbed in vivo, so that the aim of quickly controlling cold symptoms can be fulfilled.
In another aspect of the present invention, a method for preparing a renin namine preparation is provided, which comprises the following steps:
providing a first core, a first coating material, a second core and a second coating material, wherein the first core is a mixture of phenylephrine or a pharmaceutically acceptable salt thereof and a first pharmaceutically active agent and/or a first adjuvant, and the second core is a mixture of chlorpheniramine maleate and/or brompheniramine maleate and a second pharmaceutically active agent and/or a second adjuvant;
coating the first coating core with the first coating material to obtain a first coating;
coating the second coating core by using the second coating material to obtain a second coating;
and mixing the first coating and the second coating to obtain the renin namine preparation.
According to the preparation method provided by the invention, a first coating is obtained by coating a mixture of phenylephrine or a pharmaceutically acceptable salt thereof and a first pharmaceutical active agent and/or a first auxiliary material, and a second coating is obtained by coating a mixture of chlorpheniramine maleate and/or brompheniramine maleate and a second pharmaceutical active agent and/or a second auxiliary material, so that the phenylephrine and the chlorpheniramine maleate and/or brompheniramine maleate are completely isolated, secondary amine groups on the phenylephrine are prevented from reacting with maleate, the obtained renin chlorpheniramine preparation has higher product stability, and the safety and the effectiveness of clinical medication of the phenylephrine are improved.
Detailed Description
In order to make the objects, technical solutions and technical effects of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are clearly and completely described, and the embodiments described below are a part of the embodiments of the present invention, but not all of the embodiments. All other embodiments obtained by a person of ordinary skill in the art without any inventive step in connection with the embodiments of the present invention shall fall within the scope of protection of the present invention. Those whose specific conditions are not specified in the examples are carried out according to conventional conditions or conditions recommended by the manufacturer; the reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
In the description of the present invention, the term "and/or" describing an association relationship of associated objects means that there may be three relationships, for example, a and/or B, may mean: a is present alone, A and B are present simultaneously, and B is present alone. Wherein A and B can be singular or plural. The character "/" generally indicates that the former and latter associated objects are in an "or" relationship.
In the description of the present invention, "at least one" means one or more, "a plurality" means two or more. "at least one of the following" or similar expressions refer to any combination of these items, including any combination of the singular or plural items. For example, "at least one (a), b, or c", or "at least one (a), b, and c", may each represent: a. b, c, a-b (i.e. a and b), a-c, b-c, or a-b-c, wherein a, b, and c can be single or multiple respectively.
It should be understood that the weight of the related components mentioned in the embodiments of the present invention may not only refer to the specific content of each component, but also represent the proportional relationship of the weight among the components, and therefore, it is within the scope of the disclosure that the content of the related components is scaled up or down according to the embodiments of the present invention. Specifically, the weight described in the embodiments of the present invention may be a unit of weight known in the chemical field such as μ g, mg, g, kg, etc.
In addition, unless the context clearly uses otherwise, an expression of a word in the singular is to be understood as including the plural of the word. The terms "comprises" or "comprising" are intended to specify the presence of stated features, quantities, steps, operations, elements, portions, or combinations thereof, but are not intended to preclude the presence or addition of one or more other features, quantities, steps, operations, elements, portions, or combinations thereof.
The embodiment of the invention provides a renin-resistant preparation, which comprises a mixture formed by a first coating and a second coating, wherein the first coating consists of a first core and a first coating film coated on the surface of the first core, and the second coating consists of a second core and a second coating film coated on the surface of the second core; the first core-spun yarn is a mixture of phenylephrine or pharmaceutically acceptable salt thereof and a first medicinal active agent and/or a first auxiliary material, and the second core-spun yarn is a mixture of chlorpheniramine maleate and/or brompheniramine maleate and a second medicinal active agent and/or a second auxiliary material.
The renin namine preparation provided by the embodiment of the invention comprises a first coating and a second coating, wherein a first core-spun of the first coating is a mixture of phenylephrine or a pharmaceutically acceptable salt thereof and a first pharmaceutical active agent and/or a first auxiliary material, a second core-spun of the second coating is a mixture of chlorpheniramine maleate and/or brompheniramine maleate and a second pharmaceutical active agent and/or a second auxiliary material, and the first core-spun and the second core-spun are not contacted with each other, so that the thorough isolation of phenylephrine and chlorpheniramine maleate and/or brompheniramine maleate is realized, secondary amine groups on phenylephrine are prevented from reacting with maleate, the obtained renin namine preparation has higher product stability, and the safety and effectiveness of clinical medication are improved. In addition, the first core and the second core of the renin namine preparation provided by the embodiment of the invention are also added with a medicinal active agent and/or an auxiliary material, so that the obtained preparation has various advantages of coping with various cold symptoms, high release speed of effective ingredients of the medicament, higher stability and the like. The renin chlorphenamine preparation provided by the embodiment of the invention belongs to a quick dissolution type preparation, wherein the dissolution rate of all active ingredients in the renin chlorphenamine preparation is more than 85 percent within 15 minutes, and the active ingredients can be quickly absorbed in vivo, so that the aim of quickly controlling cold symptoms can be fulfilled.
In some embodiments, the first core and/or the second core is a microchip. The micro-tablets have the advantages of common tablets and micro-pills, and have unique advantages: small diameter, smooth and beautiful surface, good dose reproducibility, uniform dispersion, low porosity, easy swallowing, etc.; the micro-tablets can be directly used and can be filled into capsules with smaller volume, thereby improving the compliance of patients in taking medicine. More importantly, when the first core-spun and/or the second core-spun are micro-tablets, because the diameter of the micro-tablets is smaller, in the subsequent coating treatment process, the coating can be carried out by adopting a fluidized bed, and a high-efficiency micropore coating machine can also be adopted for coating, so that the adhesion problem easily generated by the coating of the micro-pills or the coating of the powder can be avoided, and the high-efficiency, continuous and large-scale production is facilitated.
In some embodiments, when the first core and/or the second core is a micro-slab, the diameter of the micro-slab is 1mm to 2 mm. Specifically, typical, but not limiting, microchip diameters are 1mm, 1.1mm, 1.2mm, 1.3mm, 1.4mm, 1.5mm, 1.6mm, 1.7mm, 1.8mm, 1.9mm, 2 mm. The micro-tablets with the size can not easily generate adhesion during coating due to small particle size, solve the problem of administration compliance of patients with dysphagia, and are particularly suitable for children and old people. Can be swallowed separately or filled into capsules according to different requirements.
In some embodiments, as an important component in the first core-spun, the weight of phenylephrine or a pharmaceutically acceptable salt thereof comprises 0.5% -4% of the weight of the renin phenazine formulation. In some embodiments, the pharmaceutically acceptable salt of phenylephrine is phenylephrine hydrochloride.
In addition to phenylephrine or a pharmaceutically acceptable salt thereof as a vasoconstrictor, a first pharmaceutically active agent and/or a first excipient is added to the first core pack. In some embodiments, the first pharmaceutically active agent includes, but is not limited to, at least one of an antipyretic analgesic, a central stimulant, an expectorant, such that the resulting pharmaceutical formulation may simultaneously address multiple cold symptoms with a fully controlled effect. In some embodiments, the antipyretic analgesic is acetaminophen; the central stimulant is caffeine; the expectorant is bromhexine hydrochloride. The first auxiliary material comprises at least one of a filling agent, a bonding agent, a disintegrating agent, a flow aid and a lubricating agent, so as to improve the stability of the obtained renin namine preparation, or achieve the effects of solubilization, dissolution assistance, sustained and controlled release and the like, and improve the quality and safety performance of the medicine. In some embodiments, the filler is selected from at least one of microcrystalline cellulose, corn starch; the adhesive is at least one selected from pregelatinized starch and polyvidone; the disintegrant is at least one selected from crospovidone, croscarmellose sodium and carboxymethyl starch sodium; the glidant is colloidal silicon dioxide; the lubricant is magnesium stearate.
The first coating consists of a first core and a first coating film coated on the surface of the first core. In some embodiments, the weight of the first coating film comprises 2% to 5% of the weight of the first core. If the ratio of the weight of the first coating film to the weight of the first core-spun is too low, namely the weight gain of the coating is too low, the mutual contact between the active pharmaceutical ingredients cannot be completely isolated; if the weight gain of the coating is too high, the production time tends to be prolonged.
In some embodiments, the material forming the first coating film is selected from at least one of polyvinyl alcohol, hypromellose. Of course, it should be understood that, in order to improve the production efficiency, a fully formulated film coating system using polyvinyl alcohol as a film forming material, such as Opadry II (Opadry II), Opadry AMB, and Opadry AMB II, may be used, and the fully formulated film coating system may be added with auxiliary materials such as plasticizer and pigment for convenient use. Or a full-formula film coating system taking hydroxypropyl methylcellulose as a film forming material, such as Opadry (Opadry), can be adopted, and auxiliary materials such as a plasticizer, a pigment and the like can be added into the full-formula film coating system at the same time, so that the film coating system is convenient to use.
In some embodiments, as an important component in the second core-spun, the weight of chlorpheniramine maleate and/or bromopheniramine maleate comprises 0.5% to 4% of the weight of the renin phenamine formulation.
In addition to chlorpheniramine maleate and/or brompheniramine maleate serving as an antihistamine, a second medicinal active agent and/or a second auxiliary material are/is added into the second core-spun. In some embodiments, the second pharmaceutically active agent includes, but is not limited to, at least one of an antipyretic analgesic, a central stimulant, an expectorant, such that the resulting pharmaceutical formulation may simultaneously address multiple cold symptoms with a fully controlled effect. In some embodiments, the antipyretic analgesic is acetaminophen; the central stimulant is caffeine; the expectorant is bromhexine hydrochloride. The second auxiliary material comprises at least one of a filling agent, a bonding agent, a disintegrating agent, a flow aid and a lubricating agent, so as to improve the stability of the obtained renin namine preparation, or achieve the effects of solubilization, dissolution assistance, sustained and controlled release and the like, and improve the quality and safety performance of the medicine. In some embodiments, the filler is selected from at least one of microcrystalline cellulose, corn starch; the adhesive is at least one selected from pregelatinized starch and polyvidone; the disintegrant is at least one selected from crospovidone, croscarmellose sodium and carboxymethyl starch sodium; the glidant is colloidal silicon dioxide; the lubricant is magnesium stearate.
The second coating consists of a second core and a second coating film coated on the surface of the second core. In some embodiments, the weight of the second coating film is 2% to 5% of the weight of the second core. If the ratio of the weight of the second coating film to the weight of the second core-spun yarn is too low, namely the weight gain of the coating is too low, the mutual contact between the active pharmaceutical ingredients cannot be completely isolated; if the weight gain of the coating is too high, the production time tends to be prolonged.
In the embodiment of the present invention, the specific selection and content of the first pharmaceutically active agent and the second pharmaceutically active agent may be the same or different; the specific selection and content of the first auxiliary material and the second auxiliary material can be the same or different.
In some embodiments, the material forming the second coating film is selected from at least one of polyvinyl alcohol, hypromellose. Of course, it should be understood that, in order to improve the production efficiency, a fully formulated film coating system using polyvinyl alcohol as a film forming material, such as Opadry II (Opadry II), Opadry AMB, and Opadry AMB II, may be used, and the fully formulated film coating system may be added with auxiliary materials such as plasticizer and pigment for convenient use. Or a full-formula film coating system taking hydroxypropyl methylcellulose as a film forming material, such as Opadry (Opadry), can be adopted, and auxiliary materials such as a plasticizer, a pigment and the like can be added into the full-formula film coating system at the same time, so that the film coating system is convenient to use.
In some embodiments, the total weight of the antipyretic analgesic in the first coating and the second coating is 60% to 80% of the weight of the renin resistant formulation.
In some embodiments, the total weight of the central stimulant in the first coating and the second coating is 3% to 10% of the weight of the renin resistant formulation.
In some embodiments, the total weight of the expectorant in the first coating and the second coating is 1% to 4% of the weight of the renin resistant formulation.
In some embodiments, the total weight of the bulking agent in the first coating and the second coating is 5-10% of the weight of the renin-resistant formulation.
In some embodiments, the total weight of the binder in the first coating and the second coating is 5-10% of the weight of the renin-resistant formulation.
In some embodiments, the total weight of the disintegrant in the first coating and the second coating is 2% to 5% of the weight of the renin resistant formulation.
In some embodiments, the total weight of the glidant in the first and second coatings is 0.5% to 1.5% of the weight of the renin-resistant formulation.
In some embodiments, the total weight of the lubricant in the first coating and the second coating is 0.5% to 1.5% by weight of the renin phenamine formulation.
In a preferred embodiment, phenylephrine hydrochloride, acetaminophen, caffeine, bromhexine hydrochloride, pregelatinized starch, povidone, corn starch, crospovidone, microcrystalline cellulose are added to a fluidized bed, fluidized mixed, and granulation is initiated. After the granulation is finished, the mixture is transferred to a granulator for granulation, and then is mixed with the croscarmellose sodium, the colloidal silicon dioxide and the magnesium stearate in a mixing cylinder, the mixture is pressed into micro-tablets with the diameter of 1mm in a rotary tablet machine, and the micro-tablets are coated in a high-efficiency micropore coating by adopting Opadry. On the other hand, brompheniramine maleate, acetaminophen, caffeine, bromhexine hydrochloride, pregelatinized starch, povidone, corn starch, crospovidone, microcrystalline cellulose are added to a fluidized bed, fluidized and mixed, and then granulation is started. After the granulation is finished, the mixture is transferred to a granulator for granulation, and then is mixed with the croscarmellose sodium, the colloidal silicon dioxide and the magnesium stearate in a mixing cylinder, the mixture is pressed into micro-tablets with the diameter of 1mm in a rotary tablet machine, and the micro-tablets are coated in a high-efficiency microporous coating by using Opadry. And finally, filling the two micro tablets into the gelatin hollow capsule by a full-automatic capsule filling machine. Of course, it should be understood that the raw and auxiliary materials need to be sieved before the granulation and mixing processes. Because the diameter of the micro-tablets is smaller and is between that of the micro-pills and the common tablets, the problem of adhesion easily caused by the micro-pills or powder coating can be avoided, and the medicine taking compliance of patients can be improved.
The renin namine preparation provided by the embodiment of the invention is suitable for being prepared into various dosage forms, preferably capsules, and has the advantages of good stability, high safety and good patient compliance.
The renin namine preparation provided by the embodiment of the invention can be prepared by the following preparation method.
The embodiment of the invention provides a preparation method of a renin namine preparation, which comprises the following steps:
s1, providing a first core, a first coating material, a second core and a second coating material, wherein the first core is a mixture of phenylephrine or a pharmaceutically acceptable salt thereof and a first pharmaceutical active agent and/or a first auxiliary material, and the second core is a mixture of chlorpheniramine maleate and/or brompheniramine maleate and a second pharmaceutical active agent and/or a second auxiliary material;
s2, coating the first coating core by using a first coating material to obtain a first coating;
s3, coating the second core by using a second coating material to obtain a second coating;
s4, mixing the first coating and the second coating to obtain the renin namine preparation.
According to the preparation method provided by the embodiment of the invention, a first coating is obtained by coating a mixture of phenylephrine or a pharmaceutically acceptable salt thereof and a first pharmaceutical active agent and/or a first auxiliary material, and a second coating is obtained by coating a mixture of chlorpheniramine maleate and/or brompheniramine maleate and a second pharmaceutical active agent and/or a second auxiliary material, so that the phenylephrine and the chlorpheniramine maleate and/or brompheniramine maleate are completely isolated, secondary amine groups on the phenylephrine are prevented from reacting with maleate, the obtained renin-chlorpheniramine preparation has higher product stability, and the safety and the effectiveness of the phenylephrine in clinical medication are improved.
It should be noted that, although the preparation processes of the first coating and the second coating are described in a specific order in S2 and S3, this does not represent a limitation on the preparation order of the first coating and the second coating, and the steps described in S2 and S3 may be performed in any order or simultaneously according to the actual preparation requirements.
Specifically, in S1, the specific selection, weight, etc. of each component in the first core-spun and the second core-spun are as described above, and are not described herein again. The first coating material is a material coated on the surface of the first core to form a first coating film, and in some embodiments, the first coating material is at least one selected from polyvinyl alcohol and hypromellose. The second coating material is a material coated on the surface of the second core to form a second coating film, and in some embodiments, the second coating material is at least one selected from polyvinyl alcohol and hypromellose.
It can be understood that the first auxiliary material in the first core-spun and the second auxiliary material in the second core-spun are preferably sieved before use, so as to improve the mixing uniformity of the first auxiliary material and other components in the first core-spun and the second core-spun, and be beneficial to improving the stability and dissolution rate of the obtained renin sensitivity preparation.
At S2, the first core is coated with the first coating material to obtain a first coating. In some embodiments, the first core-spun is a micro-tablet, and the preparation method is a granulation and tabletting method, which specifically comprises: the mixture of phenylephrine or pharmaceutically acceptable salt thereof and a first pharmaceutical active agent and/or a first auxiliary material is prepared into particles, and then the particles are subjected to compression treatment to obtain the micro-tablets.
Further, when the first core package is added with the first pharmaceutically active agent and the first auxiliary material, the phenylephrine or the pharmaceutically acceptable salt thereof, the first pharmaceutically active agent and a part of the first auxiliary material (at least one of the filling agent, the adhesive and the disintegrant) are prepared into granules, and then the granules are mixed with the other part of the first auxiliary material (at least one of the disintegrant, the glidant and the lubricant) and then are subjected to compression treatment. The granulation method is conventional in the art and includes, but is not limited to, spray granulation, extrusion screen granulation, high speed agitation granulation, fluid bed granulation, and the like. In some embodiments, when spray granulation is adopted, the air inlet temperature is 50-60 deg.C, the atomization pressure is 1.0-3.0bar, and the air inlet amount is 100m3/h-100m3H, the spraying speed is 0.1kg/min to 0.3 kg/min; the pressing treatment is to press with a round die with a diameter of 1mm under conditions of a main pressure of 10kN-40kN, a pre-pressing speed of 1kN-10kN and a tabletting speed of 20rpm-60rpm, and the diameter of the obtained micro-tablet is 1mm-2mm。
Further, when the first core-spun is a micro-tablet, the diameter of the micro-tablet is small, so that the coating treatment can be carried out by adopting a fluidized bed or a high-efficiency micropore coating machine.
At S3, the second core is coated with a second coating material to obtain a second coating. In some embodiments, the second core-spun is a micro-tablet, and the preparation method is a granulation and tabletting method, which specifically comprises: the mixture of chlorpheniramine maleate and/or brompheniramine maleate and a second medicinal active agent and/or a second auxiliary material is prepared into granules, and then the granules are subjected to compression treatment to obtain the micro-tablets.
Further, when the second core-spun is added with the second pharmaceutically active agent and the second auxiliary material, the chlorpheniramine maleate and/or the brompheniramine maleate, the second pharmaceutically active agent and a part of the second auxiliary material (at least one of the filling agent, the adhesive and the disintegrant) are prepared into granules, and then the granules are mixed with the other part of the second auxiliary material (at least one of the disintegrant, the glidant and the lubricant) and then are subjected to compression treatment. The granulation method is conventional in the art and includes, but is not limited to, spray granulation, extrusion screen granulation, high speed agitation granulation, fluid bed granulation, and the like. In some embodiments, when spray granulation is adopted, the air inlet temperature is 50-60 deg.C, the atomization pressure is 1.0-3.0bar, and the air inlet amount is 100m3/h-100m3H, the spraying speed is 0.1kg/min to 0.3 kg/min; the pressing treatment is to use a circular die with the diameter of 1mm to press under the conditions of main pressure of 10kN-40kN, pre-pressing of 1kN-10kN and tablet pressing speed of 20rpm-60rpm, and the diameter of the obtained micro-tablet is 1mm-2 mm.
Further, when the second core-spun is a micro-tablet, the diameter of the micro-tablet is small, so that the coating treatment can be carried out by adopting a fluidized bed or a high-efficiency micropore coating machine.
In S4, the first coating and the second coating are mixed to obtain the renin inhibitor. The renin namine preparation prepared by the embodiment of the invention can also be prepared into proper dosage forms according to actual requirements, and is preferably prepared into capsules. The method for preparing the corresponding dosage form is the conventional method in the field. In some embodiments, the process for making capsules comprises: and filling the renin namine preparation obtained in the step S4 into a hollow capsule to obtain the renin namine capsule.
In order to make the above implementation details and operations of the present invention clearly understood by those skilled in the art and to make the progress of the renin phenamine preparation and the process for the preparation thereof apparent in the examples of the present invention, the above technical solutions are exemplified by a plurality of examples below.
Example 1
This embodiment provides a renin-resistant preparation (capsule) and a method for preparing the same, comprising the following steps:
(11) coating phenylephrine hydrochloride:
(111) material pretreatment: respectively sieving 0.5kg of phenylephrine hydrochloride, 14kg of acetaminophen, 1.5kg of caffeine, 0.4kg of bromhexine hydrochloride, 1.4kg of pregelatinized starch, 0.5kg of povidone, 0.7kg of corn starch, 0.25kg of crospovidone and 0.5kg of microcrystalline cellulose with a 40-60-mesh sieve;
(112) fluidization and mixing: the air inlet temperature is 50-60 ℃, and the air inlet quantity is 100-300m3Sucking the sieved material into a fluidized bed under the condition of h, and fluidizing and mixing for 5 minutes to obtain a material in a fluidized state;
(113) spray granulation: the inlet air temperature is 50-60 ℃, the atomization pressure is 1.0-3.0bar, and the inlet air volume is 100-300m3Uniformly spraying 5kg of purified water on the fluidized material obtained in the step (112) at a spraying speed of 0.1-0.3kg/min to prepare wet particles;
(114) and (3) drying: the inlet air temperature is 50-60 ℃, the atomization pressure is 1.0-3.0bar, and the inlet air volume is 100-300m3Drying the wet granules under the condition of h until the moisture is 0.5-1.5%;
(115) and (3) cooling: after the drying is finished, the air inlet temperature is 20-25 ℃, the atomization pressure is 1.0-3.0bar, and the air inlet quantity is 100-3Cooling the dried granules to room temperature under the condition of h;
(116) straightening: discharging and finishing the particles cooled to room temperature;
(117) mixing: mixing the granules with 0.2kg of croscarmellose sodium, 0.12kg of colloidal silicon dioxide and 0.15kg of magnesium stearate to obtain a material;
(118) tabletting: pressing the material obtained in the step (117) into micro-tablets with the diameter of 1mm by adopting a circular die with the diameter of 1mm, the main pressure of 10-40kN, the pre-pressing of 1-10kN and the tabletting speed of 20-60 rpm;
(119) coating: coating the micro-tablets obtained in step (118) in a high-efficiency micro-pore coating machine by using Opadry as a coating material to obtain a first coating.
(12) Coating with brompheniramine maleate:
(121) material pretreatment: respectively sieving 0.5kg of brompheniramine maleate, 14kg of acetaminophen, 1.5kg of caffeine, 0.4kg of bromhexine hydrochloride, 1.4kg of pregelatinized starch, 0.5kg of povidone, 0.7kg of corn starch, 0.25kg of crospovidone and 0.5kg of microcrystalline cellulose with a 40-60-mesh sieve;
(122) fluidization and mixing: the air inlet temperature is 50-60 ℃, and the air inlet quantity is 100-300m3Sucking the sieved material into a fluidized bed under the condition of h, and fluidizing and mixing for 5 minutes to obtain a material in a fluidized state;
(123) spray granulation: the inlet air temperature is 50-60 ℃, the atomization pressure is 1.0-3.0bar, and the inlet air volume is 100-300m3Uniformly spraying 5kg of purified water on the fluidized material obtained in the step (122) at a spraying speed of 0.1-0.3kg/min to prepare wet particles;
(124) and (3) drying: after the granulation is finished, the air inlet temperature is 50-60 ℃, the atomization pressure is 1.0-3.0bar, and the air inlet quantity is 100-3Drying the wet granules under the condition of h until the moisture is 0.5-1.5%;
(125) and (3) cooling: after the drying is finished, the air inlet temperature is 20-25 ℃, the atomization pressure is 1.0-3.0bar, and the air inlet quantity is 100-3Cooling the dried granules to room temperature under the condition of h;
(126) straightening: discharging and finishing the particles cooled to room temperature;
(127) mixing: mixing the granules with 0.2kg of croscarmellose sodium, 0.12kg of colloidal silicon dioxide and 0.15kg of magnesium stearate to obtain a material;
(128) tabletting: pressing the material obtained in the step (127) into micro-tablets with the diameter of 1mm by adopting a circular die with the diameter of 1mm, the main pressure of 10-40kN, the pre-pressing of 1-10kN and the tabletting speed of 20-60 rpm;
(129) coating: coating the micro-tablets obtained in step (128) in a high-efficiency micro-pore coating machine using Opadry as a coating material to obtain a second coating.
(13) And filling the first coating and the second coating into the hollow capsule by adopting a GKF 2600 capsule filling machine to obtain the renin namine capsule.
In the obtained renin capsules, 10 ten thousand of the renin capsules comprise the following components in percentage by weight:
example 2
This embodiment provides a renin-resistant preparation (capsule) and a method for preparing the same, comprising the following steps:
(21) coating phenylephrine hydrochloride:
(211) material pretreatment: respectively sieving 0.5kg of phenylephrine hydrochloride, 12.5kg of acetaminophen, 1.5kg of caffeine, 0.4kg of bromhexine hydrochloride, 1.25kg of pregelatinized starch, 0.7kg of povidone, 0.7kg of corn starch, 0.25kg of croscarmellose sodium and 0.5kg of microcrystalline cellulose by a 40-60-mesh sieve;
(212) fluidization and mixing: the air inlet temperature is 50-60 ℃, and the air inlet quantity is 100-300m3Sucking the sieved material into a fluidized bed under the condition of h, and fluidizing and mixing for 5 minutes to obtain a material in a fluidized state;
(213) spray granulation: the inlet air temperature is 50-60 ℃, the atomization pressure is 1.0-3.0bar, and the inlet air volume is 100-300m3Uniformly spraying 4.5kg of purified water on the fluidized material obtained in the step (212) at a spraying speed of 0.1-0.3kg/min to prepare wet particles;
(214) and (3) drying: after the granulation is finished, the air inlet temperature is 50-60 ℃, the atomization pressure is 1.0-3.0bar, and the air inlet quantity is 100-3Drying the wet granules under the condition of h until the moisture is 0.5-1.5%;
(215) and (3) cooling: after the drying is finished, the air inlet temperature is 20-25 ℃, the atomization pressure is 1.0-3.0bar, and the air inlet quantity is 100-3Cooling the dried granules to room temperature under the condition of h;
(216) straightening: discharging and finishing the particles cooled to room temperature;
(217) mixing: mixing the granules with 0.25kg of carboxymethyl starch sodium, 0.15kg of colloidal silicon dioxide and 0.15kg of magnesium stearate to obtain a material;
(218) tabletting: pressing the material obtained in the step (217) into micro-tablets with the diameter of 1mm by adopting a circular die with the diameter of 1mm, the main pressure of 10-40kN, the pre-pressing of 1-10kN and the tabletting speed of 20-60 rpm;
(219) coating: coating the micro-tablets obtained in step (218) in a high efficiency micro-pore coating machine using Opadry II as the coating material to obtain a first coating.
(22) Coating with brompheniramine maleate:
(221) material pretreatment: respectively sieving 0.5kg of brompheniramine maleate, 12.5kg of acetaminophen, 1.5kg of caffeine, 0.4kg of bromhexine hydrochloride, 1.25kg of pregelatinized starch, 0.7kg of povidone, 0.7kg of corn starch, 0.25kg of croscarmellose sodium and 0.5kg of microcrystalline cellulose by a 40-60-mesh sieve;
(222) fluidization and mixing: the air inlet temperature is 50-60 ℃, and the air inlet quantity is 100-300m3Sucking the sieved material into a fluidized bed under the condition of h, and fluidizing and mixing for 5 minutes to obtain a material in a fluidized state;
(223) spray granulation: the inlet air temperature is 50-60 ℃, the atomization pressure is 1.0-3.0bar, and the inlet air volume is 100-300m3H, spraying 4.5kg of purified water uniformly onto the stream obtained in step (222) at a spraying speed of 0.1-0.3kg/minPreparing wet granules on the materials in the state of melting;
(224) and (3) drying: after the granulation is finished, the air inlet temperature is 50-60 ℃, the atomization pressure is 1.0-3.0bar, and the air inlet quantity is 100-3Drying the wet granules under the condition of h until the moisture is 0.5-1.5%;
(225) and (3) cooling: after the drying is finished, the air inlet temperature is 20-25 ℃, the atomization pressure is 1.0-3.0bar, and the air inlet quantity is 100-3Cooling the dried granules to room temperature under the condition of h;
(226) straightening: discharging and finishing the particles cooled to room temperature;
(227) mixing: mixing the granules with 0.25kg of carboxymethyl starch sodium, 0.15kg of colloidal silicon dioxide and 0.15kg of magnesium stearate to obtain a material;
(228) tabletting: pressing the material obtained in the step (227) into micro-tablets with the diameter of 1mm by adopting a circular die with the diameter of 1mm, the main pressure of 10-40kN, the pre-pressing of 1-10kN and the tabletting speed of 20-60 rpm;
(229) coating: and (3) coating the micro-tablets obtained in the step (228) in a high-efficiency micropore coating machine by adopting Opadry II as a coating material to obtain a second coating.
(23) And (3) filling the first coating and the second coating into the hollow capsule by adopting a GKF 2600 capsule filling machine to obtain the renin namine capsule.
In the obtained renin capsules, 10 ten thousand of the renin capsules comprise the following components in percentage by weight:
example 3
This embodiment provides a renin-resistant preparation (capsule) and a method for preparing the same, comprising the following steps:
(31) coating phenylephrine hydrochloride:
(311) material pretreatment: sieving 1.0kg of phenylephrine hydrochloride, 10.0kg of acetaminophen, 1.0kg of pregelatinized starch, 0.25kg of crospovidone, and 1.0kg of microcrystalline cellulose with 40-60 mesh sieve respectively;
(312) fluidization and mixing: the air inlet temperature is 50-60 ℃, and the air inlet quantity is 100-300m3Sucking the sieved material into a fluidized bed under the condition of h, and fluidizing and mixing for 5 minutes to obtain a material in a fluidized state;
(313) spray granulation: the inlet air temperature is 50-60 ℃, the atomization pressure is 1.0-3.0bar, and the inlet air volume is 100-300m3Uniformly spraying 3kg of purified water onto the fluidized material obtained in step (312) at a spraying speed of 0.1-0.3kg/min to prepare wet granules;
(314) and (3) drying: after the granulation is finished, the air inlet temperature is 50-60 ℃, the atomization pressure is 1.0-3.0bar, and the air inlet quantity is 100-3Drying the wet granules under the condition of h until the moisture is 0.5-1.5%;
(315) and (3) cooling: after the drying is finished, the air inlet temperature is 20-25 ℃, the atomization pressure is 1.0-3.0bar, and the air inlet quantity is 100-3Cooling the dried granules to room temperature under the condition of h;
(316) straightening: discharging and finishing the particles cooled to room temperature;
(317) mixing: mixing the granules with 0.25kg of croscarmellose sodium, 0.15kg of colloidal silicon dioxide and 0.15kg of magnesium stearate to obtain a material;
(318) tabletting: pressing the material obtained in the step (317) into micro-tablets with the diameter of 2mm by adopting a circular die with the diameter of 2mm, the main pressure of 10-40kN, the pre-pressing of 1-10kN and the tabletting speed of 20-60 rpm;
(319) coating: coating the minitablets obtained in step (318) in a fluidized bed using Opadry as coating material to obtain a first coating.
(32) Chlorpheniramine maleate coating:
(321) material pretreatment: respectively sieving 0.4kg chlorphenamine maleate, 10.0kg acetaminophen, 1.0kg pregelatinized starch, 0.25kg crospovidone and 1.0kg microcrystalline cellulose with 40-60 mesh sieve;
(322) fluidization and mixing: the air inlet temperature is 50-60 ℃, and the air inlet quantity is 100-300m3At the condition of/h, sucking the sieved materials into a fluidized bed, and fluidizing and mixing 5After minutes, obtaining the material in a fluidized state;
(323) spray granulation: the inlet air temperature is 50-60 ℃, the atomization pressure is 1.0-3.0bar, and the inlet air volume is 100-300m3Uniformly spraying 3kg of purified water onto the fluidized material obtained in step (322) at a spraying speed of 0.1-0.3kg/min to prepare wet granules;
(324) and (3) drying: after the granulation is finished, the air inlet temperature is 50-60 ℃, the atomization pressure is 1.0-3.0bar, and the air inlet quantity is 100-3Drying the wet granules under the condition of h until the moisture is 0.5-1.5%;
(325) and (3) cooling: after the drying is finished, the air inlet temperature is 20-25 ℃, the atomization pressure is 1.0-3.0bar, and the air inlet quantity is 100-3Cooling the dried granules to room temperature under the condition of h;
(326) straightening: discharging and finishing the particles cooled to room temperature;
(327) mixing: mixing the granules with 0.25kg of croscarmellose sodium, 0.15kg of colloidal silicon dioxide and 0.15kg of magnesium stearate to obtain a material;
(328) tabletting: pressing the material obtained in the step (327) into micro-tablets with the diameter of 2mm by adopting a circular die with the diameter of 2mm, the main pressure of 10-40kN, the pre-pressing of 1-10kN and the tablet pressing speed of 20-60 rpm;
(329) coating: coating the microplatelets from step (328) in a fluidized bed using Opadry as the coating material to provide a second coating.
(33) And filling the first coating and the second coating into the hollow capsule by adopting a GKF 2600 capsule filling machine to obtain the renin namine capsule.
In the obtained renin capsules, 10 ten thousand granules of renin capsules comprise the following components in percentage by weight:
example 4
This embodiment provides a renin-resistant preparation (capsule) and a method for preparing the same, comprising the following steps:
(41) coating phenylephrine hydrochloride:
(411) material pretreatment: sieving 0.5kg of phenylephrine hydrochloride, 15.0kg of acetaminophen, 0.75kg of caffeine, 0.4kg of bromhexine hydrochloride, 1.5kg of pregelatinized starch, 0.75kg of corn starch, 0.25kg of carboxymethyl starch sodium and 1.0kg of microcrystalline cellulose with a 40-60 mesh sieve respectively;
(412) fluidization and mixing: the air inlet temperature is 50-60 ℃, and the air inlet quantity is 100-300m3Sucking the sieved material into a fluidized bed under the condition of h, and fluidizing and mixing for 5 minutes to obtain a material in a fluidized state;
(413) spray granulation: the inlet air temperature is 50-60 ℃, the atomization pressure is 1.0-3.0bar, and the inlet air volume is 100-300m3Uniformly spraying 5kg of purified water onto the fluidized material obtained in step (412) at a spraying speed of 0.1-0.3kg/min to prepare wet granules;
(414) and (3) drying: after the granulation is finished, the air inlet temperature is 50-60 ℃, the atomization pressure is 1.0-3.0bar, and the air inlet quantity is 100-3Drying the wet granules under the condition of h until the moisture is 0.5-1.5%;
(415) and (3) cooling: after the drying is finished, the air inlet temperature is 20-25 ℃, the atomization pressure is 1.0-3.0bar, and the air inlet quantity is 100-3Cooling the dried granules to room temperature under the condition of h;
(416) straightening: discharging and finishing the particles cooled to room temperature;
(417) mixing: mixing the granules with 0.5kg of carboxymethyl starch sodium, 0.15kg of colloidal silicon dioxide and 0.15kg of magnesium stearate to obtain a material;
(418) tabletting: pressing the material obtained in the step (417) into micro-tablets with the diameter of 2mm by adopting a circular die with the diameter of 2mm, the main pressure of 10-40kN, the pre-pressing of 1-10kN and the tabletting speed of 20-60 rpm;
(419) coating: the microplatelets from step (418) were coated in a fluidized bed using Opadry II as the coating material to obtain a first coating.
(42) Chlorpheniramine maleate coating:
(421) material pretreatment: respectively sieving 0.5kg of chlorpheniramine maleate, 15.0kg of acetaminophen, 0.75kg of caffeine, 0.4kg of bromhexine hydrochloride, 1.5kg of pregelatinized starch, 0.75kg of corn starch, 0.25kg of carboxymethyl starch sodium and 1.0kg of microcrystalline cellulose with a 40-60-mesh sieve;
(422) fluidization and mixing: the air inlet temperature is 50-60 ℃, and the air inlet quantity is 100-300m3Sucking the sieved material into a fluidized bed under the condition of h, and fluidizing and mixing for 5 minutes to obtain a material in a fluidized state;
(423) spray granulation: the inlet air temperature is 50-60 ℃, the atomization pressure is 1.0-3.0bar, and the inlet air volume is 100-300m3Uniformly spraying 5kg of purified water on the fluidized material obtained in the step (422) at a spraying speed of 0.1-0.3kg/min to prepare wet particles;
(424) and (3) drying: after the granulation is finished, the air inlet temperature is 50-60 ℃, the atomization pressure is 1.0-3.0bar, and the air inlet quantity is 100-3Drying the wet granules under the condition of h until the moisture is 0.5-1.5%;
(425) and (3) cooling: after the drying is finished, the air inlet temperature is 20-25 ℃, the atomization pressure is 1.0-3.0bar, and the air inlet quantity is 100-3Cooling the dried granules to room temperature under the condition of h;
(426) straightening: discharging and finishing the particles cooled to room temperature;
(427) mixing: mixing the granules with 0.5kg of carboxymethyl starch sodium, 0.15kg of colloidal silicon dioxide and 0.15kg of magnesium stearate to obtain a material;
(428) tabletting: pressing the material obtained in the step (427) into micro-tablets with the diameter of 2mm by adopting a circular die with the diameter of 2mm, the main pressure of 10-40kN, the pre-pressing of 1-10kN and the tabletting speed of 20-60 rpm;
(429) coating: coating the microplatelets from step (428) in a fluidized bed using Opadry II as the coating material to provide a second coating.
(43) And (3) filling the phenylephrine hydrochloride micro-tablets and the chlorphenamine maleate micro-tablets into hollow capsules by adopting a GKF 2600 capsule filling machine to obtain the renin-chlorphenamine capsules.
In the obtained renin capsules, 10 ten thousand granules of renin capsules comprise the following components in percentage by weight:
comparative example 1
This comparative example provides a renin namine preparation (capsule) and a process for producing the same, which comprises the steps substantially the same as those of example 4, except that neither the micro-tablets obtained in step (418) nor the micro-tablets obtained in step (428) were subjected to a coating treatment, and then the micro-tablets obtained in step (418) and the micro-tablets obtained in step (428) were filled into empty capsules to obtain a renin namine capsule.
In the obtained renin capsules, 10 ten thousand granules of renin capsules comprise the following components in percentage by weight:
comparative example 2
The comparative example provides a renin-phenamine double-layer tablet and a preparation method thereof, and the steps are as follows:
(51) preparation of granules containing phenylephrine hydrochloride
(511) Material pretreatment: 1.0kg of phenylephrine hydrochloride, 10kg of acetaminophen, 1.0kg of pregelatinized starch, 0.25kg of povidone, 0.25kg of croscarmellose sodium and 1.0kg of microcrystalline cellulose are respectively sieved by a 40-60 mesh sieve.
(512) Fluidization and mixing: the air inlet temperature is 50-60 ℃, and the air inlet quantity is 100-300m3And (h) sucking the sieved materials into a fluidized bed, and fluidizing and mixing for 5 minutes.
(513) Spray granulation: the inlet air temperature is 50-60 ℃, the atomization pressure is 1.0-3.0bar, and the inlet air volume is 100-300m3And h, uniformly spraying 3kg of purified water on the fluidized material obtained in the step (512) at a spraying speed of 0.1-0.3kg/min to prepare wet granules.
(514) And (3) drying: after the granulation is finished, the air inlet temperature is 50-60 ℃, and the atomization pressure is 1.0-3.0bar, air intake of 100-3The wet granulate is dried at the time of the first hour until the moisture content is 1.0 to 1.5%.
(515) And (3) cooling: after the drying is finished, the air inlet temperature is 20-25 ℃, the atomization pressure is 1.0-3.0bar, and the air inlet quantity is 100-3The dried granules were cooled to room temperature under the conditions of/h.
(516) Straightening: discharging and finishing the granules cooled to room temperature.
(517) Mixing: the granulated granules were mixed well with 0.25kg of carboxymethyl starch sodium, 0.1kg of colloidal silicon dioxide, and 0.2kg of magnesium stearate.
(52) Preparation of granules containing chlorpheniramine maleate
(521) Material pretreatment: 0.4kg of brompheniramine maleate, 10kg of acetaminophen, 1.0kg of pregelatinized starch, 0.25kg of povidone, 0.25kg of croscarmellose sodium and 1.0kg of microcrystalline cellulose are respectively sieved by a 40-60 mesh sieve.
(522) Fluidization and mixing: the air inlet temperature is 50-60 ℃, and the air inlet quantity is 100-300m3And (h) sucking the sieved materials into a fluidized bed, and fluidizing and mixing for 5 minutes.
(523) Spray granulation: the inlet air temperature is 50-60 ℃, the atomization pressure is 1.0-3.0bar, and the inlet air volume is 100-300m3And h, uniformly spraying 3kg of purified water on the fluidized material obtained in the step (522) at a spraying speed of 0.1-0.3kg/min to prepare wet granules.
(524) And (3) drying: after the granulation is finished, the air inlet temperature is 50-60 ℃, the atomization pressure is 1.0-3.0bar, and the air inlet quantity is 100-3The wet granulate is dried at the time of the first hour until the moisture content is 1.0 to 1.5%.
(525) And (3) cooling: after the drying is finished, the air inlet temperature is 20-25 ℃, the atomization pressure is 1.0-3.0bar, and the air inlet quantity is 100-3The dried granules were cooled to room temperature under the conditions of/h.
(526) Straightening: discharging and finishing the granules cooled to room temperature.
(527) Mixing: the granulated granules were mixed well with 0.25kg of carboxymethyl starch sodium, 0.1kg of colloidal silicon dioxide, and 0.2kg of magnesium stearate.
(53) Laminated double-layer sheet
And pressing the granules containing the phenylephrine hydrochloride and the granules containing the brompheniramine maleate into double-layer tablets in a rotary tablet press, wherein the main pressure is 10-40kN, the prepressing is 1-10kN, and the tabletting speed is 20-60rpm, so as to obtain the renin-chlorphenamine double-layer tablets.
In the obtained renin-resistant tablets, the components and contents in every 10 ten thousand renin-resistant tablets are as follows:
experimental example 1 stability examination
The renin-phenamine preparations obtained in examples 1-4 and comparative examples 1-2 are packaged by aluminum/PVC/PVDC aluminum plastic blister and are marketed in the United states
Allergy&The Congestion Relief was placed at 30 ℃/65% RH and 25 ℃/60% RH, and samples were periodically taken for stability evaluation using as an index the adduct of phenylephrine hydrochloride produced by the reaction with maleic acid, the results of which are shown in Table 1.
TABLE 1 addition product of phenylephrine hydrochloride and maleic acid results
The results in Table 1 show that the adduct impurity of phenylephrine hydrochloride reacted with maleic acid in the renin-phenamine formulations obtained in examples 1-4 can be controlled to extremely low levels, significantly lower than the uncoated formulation obtained in comparative example 1, the two-layer tablet of comparative example 2, and those marketed in the United states
Allergy&Congestinon Relief shows that the renin inhibitor provided by the invention is prepared by mixing phenylephrine hydrochloride or pharmaceutically acceptable salt thereof with a first pharmaceutical active agent and/or a first auxiliary materialThe preparation method comprises the following steps of preparing a microchip by forming a coating film on the surface of the microchip to obtain a first coating, preparing the microchip by mixing chlorpheniramine maleate or brompheniramine maleate with a second pharmaceutical active agent and/or a second auxiliary material, and forming the coating film on the surface of the microchip to obtain a second coating, so that mutual contact between phenylephrine hydrochloride and chlorpheniramine maleate or brompheniramine maleate is completely isolated, further reaction between phenylephrine hydrochloride and maleic acid is prevented, and the quality of a product is more stable and controllable.
Experimental example 2 dissolution examination
The results of examining the dissolution of the renin phenamine preparations obtained in examples 1 to 4 and comparative examples 1 to 2 are shown in Table 2.
Table 2 dissolution measurement results of renin-phenamine preparations obtained in examples 1 to 4 and comparative examples 1 to 2
The results in table 2 show that all the active ingredients of the renin formulations obtained in examples 1 to 4 are dissolved out more than 85% within 15 minutes, and are fast dissolving formulations which can be rapidly absorbed in vivo, thereby achieving the therapeutic purpose of rapidly controlling cold symptoms.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. A renin namine preparation, which is characterized by comprising a mixture formed by a first coating and a second coating, wherein the first coating consists of a first core and a first coating film coated on the surface of the first core, and the second coating consists of a second core and a second coating film coated on the surface of the second core; the first core-spun yarn is a mixture of phenylephrine or pharmaceutically acceptable salt thereof and a first medicinal active agent and/or a first auxiliary material, and the second core-spun yarn is a mixture of chlorpheniramine maleate and/or brompheniramine maleate and a second medicinal active agent and/or a second auxiliary material.
2. The renin-phenamine formulation of claim 1, wherein the first core and/or the second core is a microchip.
3. The renin-phenamine formulation of claim 2, wherein the diameter of the micro-tablets is from 1mm to 2 mm.
4. The renin namine formulation according to claim 1, wherein the weight of phenylephrine or a pharmaceutically acceptable salt thereof is from 0.5% to 4% of the weight of the renin namine formulation; and/or
The weight of the chlorpheniramine maleate and/or the brompheniramine maleate accounts for 0.5 to 4 percent of the weight of the renin phenamine preparation.
5. The renin sensitivity formulation of claim 1, wherein the weight of the first coating film is from 2% to 5% of the weight of the first core; and/or
The weight of the second coating film accounts for 2-5% of the weight of the second core; and/or;
the material for forming the first coating film is at least one selected from polyvinyl alcohol and hydroxypropyl methylcellulose; and/or
The material for forming the second coating film is at least one selected from polyvinyl alcohol and hydroxypropyl methylcellulose.
6. The renin namine formulation according to any one of claims 1 to 5 wherein the first pharmaceutically active agent comprises at least one of an antipyretic analgesic, a central stimulant, an expectorant; and/or
The first auxiliary material comprises at least one of a filling agent, a bonding agent, a disintegrating agent, a glidant and a lubricant; and/or
The second pharmaceutically active agent comprises at least one of an antipyretic analgesic, a central stimulant, an expectorant; and/or
The second auxiliary material comprises at least one of a filling agent, a bonding agent, a disintegrating agent, a glidant and a lubricant.
7. The renin namine formulation according to claim 6 wherein the weight of the antipyretic analgesic is 60% to 80% of the weight of the renin namine formulation;
the weight of the central stimulant accounts for 3% -10% of the weight of the renin-resistant preparation;
the weight of the expectorant accounts for 1-4% of the weight of the renin resistant preparation;
the weight of the filler accounts for 5% -10% of the weight of the renin namine preparation;
the weight of the binder accounts for 5% -10% of the weight of the renin-resistant formulation;
the weight of the disintegrant accounts for 2 to 5 percent of the weight of the renin namine preparation;
the weight of the glidant accounts for 0.5 to 1.5 percent of the weight of the renin namine preparation;
the weight of the lubricant accounts for 0.5-1.5% of the weight of the renin phenamine preparation.
8. The renin namine formulation according to claim 6 wherein the antipyretic analgesic is acetaminophen;
the central stimulant is caffeine;
the expectorant is bromhexine hydrochloride;
the filler is at least one selected from microcrystalline cellulose and corn starch;
the adhesive is selected from at least one of pregelatinized starch and povidone;
the disintegrant is at least one selected from crospovidone, croscarmellose sodium and carboxymethyl starch sodium;
the glidant is colloidal silicon dioxide;
the lubricant is magnesium stearate.
9. A preparation method of a renin namine preparation is characterized by comprising the following steps:
providing a first core, a first coating material, a second core and a second coating material, wherein the first core is a mixture of phenylephrine or a pharmaceutically acceptable salt thereof and a first pharmaceutically active agent and/or a first adjuvant, and the second core is a mixture of chlorpheniramine maleate and/or brompheniramine maleate and a second pharmaceutically active agent and/or a second adjuvant;
coating the first coating core with the first coating material to obtain a first coating;
coating the second coating core by using the second coating material to obtain a second coating;
and mixing the first coating and the second coating to obtain the renin namine preparation.
10. The method of claim 9, wherein the first core is a micro-tablet and the first core comprises granulating and compressing a mixture of the phenylephrine or a pharmaceutically acceptable salt thereof and at least one of the first pharmaceutically active agent and the first excipient to form the first core; and/or
The second core-spun is a micro-tablet, and the preparation method of the second core-spun comprises the steps of granulating and compressing the mixture of the chlorpheniramine maleate and/or the brompheniramine maleate and at least one of the second pharmaceutical active agent and the second auxiliary material to obtain the second core-spun.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113181128A (en) * | 2021-04-27 | 2021-07-30 | 南京恒远科技开发有限公司 | Salicophenol caffeine and chlorphenamine maleate three-layer tablet and preparation method thereof |
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| CN101820862A (en) * | 2007-08-13 | 2010-09-01 | 麦克内尔-Ppc股份有限公司 | Method for stabilizing phenylephrine |
| CN104758935A (en) * | 2015-04-10 | 2015-07-08 | 海口世康药物研究有限公司 | Composition for improving stability of compound ibuprofen preparations and preparation method of composition |
| WO2015137829A1 (en) * | 2014-03-12 | 2015-09-17 | Angeles Relinda G | Stable and palatable liquid pharmaceutical composition of phenylephrine and a maleate salt of an antihistamine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101820862A (en) * | 2007-08-13 | 2010-09-01 | 麦克内尔-Ppc股份有限公司 | Method for stabilizing phenylephrine |
| WO2015137829A1 (en) * | 2014-03-12 | 2015-09-17 | Angeles Relinda G | Stable and palatable liquid pharmaceutical composition of phenylephrine and a maleate salt of an antihistamine |
| CN104758935A (en) * | 2015-04-10 | 2015-07-08 | 海口世康药物研究有限公司 | Composition for improving stability of compound ibuprofen preparations and preparation method of composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113181128A (en) * | 2021-04-27 | 2021-07-30 | 南京恒远科技开发有限公司 | Salicophenol caffeine and chlorphenamine maleate three-layer tablet and preparation method thereof |
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Application publication date: 20210312 |