CN111603456A - Carbixamine maleate controlled-release dry suspension and preparation method thereof - Google Patents

Carbixamine maleate controlled-release dry suspension and preparation method thereof Download PDF

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CN111603456A
CN111603456A CN202010651968.6A CN202010651968A CN111603456A CN 111603456 A CN111603456 A CN 111603456A CN 202010651968 A CN202010651968 A CN 202010651968A CN 111603456 A CN111603456 A CN 111603456A
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dry suspension
carbinoxamine maleate
controlled release
essence
resin
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丁月萍
江永红
徐益明
陶冬梅
袁菊凤
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Jiangsu Four Rings Biopharmaceutical Co ltd
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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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • 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
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

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Abstract

The invention discloses a carbinoxamine maleate controlled release dry suspension and a preparation method thereof, belonging to the technical field of pharmaceutical dosage forms. The controlled-release dry suspension of the carbinoxamine maleate contains 10-90% of the carbinoxamine maleate and 10-90% of auxiliary materials in percentage by weight. Compared with the quick release preparation, the controlled release preparation can keep the effective blood concentration within 24 hours, improve the curative effect, has small toxic and side effect, is convenient to take and carry, and reduces the taking times; compared with a sustained release preparation, the controlled release preparation can keep more stable blood concentration within 24 hours, improves the curative effect, has small toxic and side effect and only needs to be administrated once a day. Therefore, the carbinoxamine maleate controlled release dry suspension provided by the invention has wide prospect in clinical application.

Description

Carbixamine maleate controlled-release dry suspension and preparation method thereof
Technical Field
The invention relates to a carbinoxamine maleate controlled release dry suspension and a preparation method thereof, belonging to the technical field of pharmaceutical dosage forms.
Background
Carbinoxamine Maleate (CAM) is a mild sedative antihistamine used clinically to treat seasonal and perennial allergic rhinitis in children. Besides treating allergic rhinitis, it has significant therapeutic effects on irritative cough, nausea, vomiting, vertigo and even car sickness. The CAM does not inhibit the release of histamine, but competes with histamine for the binding site of H1 receptor in human uterus, gastrointestinal tract, trachea, and bronchial muscle, thereby achieving the purpose of histamine antagonism. The CAM was a white crystalline powder in appearance, with no pungent odor. The relative molecular weight is 406.84, the melting point is 116-121 ℃, the aqueous CAM solution (1 → 100) is soluble in water, artificial gastric juice and pH 6.8 phosphate buffer, the pH is 4.6-5.1, and the maximum absorption wavelength is at 260 nm.
Carbinoxamine maleate is very effective in treating allergy in children, and is commonly used for relieving symptoms of anaphylaxis, cold and cough, but is not generally used as first line treatment. However, the standard of the common tablet of the maleic acid carbinoxamine is generally 4 mg/tablet, in order to provide enough blood concentration and ensure good treatment effect, patients need to take the tablet 3-4 times every day, including children taking the tablet once at school, which is inconvenient for the children at school, so the compliance is poor.
Therefore, the controlled-release suspension of the maleic acid carbinoxamine is provided, and has wide market prospect in clinical application.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a carbinoxamine maleate controlled-release dry suspension and a preparation method thereof, and a patient only needs to take the obtained carbinoxamine maleate controlled-release dry suspension once a day to achieve a treatment effect.
The technical scheme of the invention is as follows:
the invention provides a carbinoxamine maleate controlled release dry suspension which comprises the following components in percentage by mass:
10-90% of carbinoxamine maleate;
10-90% of auxiliary materials with controlled release function;
the balance of other auxiliary materials;
the auxiliary materials with the controlled release function are one or more of cation exchange resin and methylcellulose, ethyl cellulose, acrylic resin and hydroxypropyl methylcellulose.
Further, the other auxiliary materials are selected from one or more of impregnant, plasticizer, suspending agent, flavoring agent, antioxidant and preservative.
Further, the impregnant is selected from one or more of methyl cellulose, glycerol and PEG 4000.
The plasticizer is one or more selected from diethyl phthalate, dibutyl sebacate and PEG 400.
The suspension is one or more selected from PVP, HPMC, tragacanth, Carbopol, and Avicel RC 591.
The correctant is selected from one or more of mannitol, xylitol, stevioside, lactose, fructose, sucrose, aspartame, glycyrrhizin, sodium cyclamate, gelatin, aspartame, banana essence, pineapple essence, vanillin, orange essence, peppermint essence, ginseng essence, strawberry essence, citric acid, and citric acid.
Further, the preparation is a solid dry suspension.
The invention also provides a method for preparing the controlled-release dry suspension of the carbinoxamine maleate, which is characterized by comprising the following steps:
1) preparing medicine carrying resin carrying carbinoxamine maleate;
2) impregnating the drug-loaded resin obtained in the step 1);
3) preparing a drug-loaded resin microcapsule;
4) preparing the dry suspension by using the medicine-carrying resin microcapsule obtained in the step 3).
The beneficial technical effects of the invention are as follows:
the controlled-release dry suspension of the carbinoxamine maleate provided by the invention contains 10-90% of the carbinoxamine maleate and 10-90% of the auxiliary material in percentage by weight. Compared with the quick release preparation, the controlled release preparation can keep the effective blood concentration within 24 hours, improve the curative effect, has small toxic and side effect, is convenient to take and carry, and reduces the taking times; compared with a sustained release preparation, the controlled release preparation can keep more stable blood concentration within 24 hours, improves the curative effect, has small toxic and side effect and only needs to be administrated once a day. Therefore, the carbinoxamine maleate controlled release dry suspension provided by the invention has wide prospect in clinical application.
Drawings
Figure 1 is an in vitro release profile of a controlled release dry suspension of carbinoxamine maleate prepared according to example 1.
Figure 2 is a graph of the beagle in vivo release of a controlled release dry suspension of carbinoxamine maleate prepared according to example 1 with a commercially available sustained release tablet.
Detailed Description
The specific process for preparing the controlled release dry suspension of carbinoxamine maleate of the invention in the following examples is as follows:
(1) preparation of the drug resin: adding proper amount of deionized water into cation exchange resin, adding the medicine under stirring, mixing, sampling at regular time, and determining the concentration of the medicine in the solution; when the concentration of the medicine does not change along with the time, the medicine is balanced, the deionized water is used for washing away the unbound medicine on the surface of the resin, and the resin is dried at the temperature of 40-60 ℃ to obtain the medicine-carrying resin;
(2) impregnation of the drug resin: taking a proper amount of drug-loaded resin, adding the drug-loaded resin into a 20% PEG4000 aqueous solution, stirring for 0.5 hour, drying and sieving to obtain impregnated drug resin;
(3) preparation of the drug resin microcapsules: adopting bottom-spraying fluidized bed equipment, putting 150g of the impregnated drug resin with the particle size of 180-200 mu m into a fluidization chamber, using a spray gun with the nozzle diameter of 1mm, adjusting the air quantity to enable the particles to be in an ideal fluidization state in the fluidization chamber, adjusting the atomizing air pressure to 0.2Mpa, and pumping coating liquid at a constant speed by using a constant flow pump, so that the coating liquid has good atomization effect, continuous coating has no intermittent drying time, and the phenomenon that micro particles are basically not adhered in the coating process is ensured;
(4) preparing a medicine resin microcapsule dry suspension: taking a certain amount of the medicine-resin microcapsule, and a proper amount of suspending agent (one or more of PVP, HPMC, tragacanth, Carbopol, Avicel RC591, etc.), and mixing well to obtain medicine-resin controlled release dry suspension. In addition, in order to improve the taste of the dry suspension, a proper amount of flavoring agent can be added, such as mannitol, xylitol, stevioside, lactose, fructose, sucrose, aspartame, maltitol, glycyrrhizin, sodium cyclamate, gelatin, aspartame, banana essence, pineapple essence, vanillin, orange essence, mint essence, ginseng essence, strawberry essence, citric acid and the like. In order to ensure the stability of the main drug, a proper amount of antioxidant, preservative and the like can be added.
The present invention will be described in detail with reference to examples.
Example 1:
the controlled release dry suspension of carbinoxamine maleate is prepared according to the following formula.
Figure BDA0002575308820000031
Example 2:
the controlled release dry suspension of carbinoxamine maleate is prepared according to the following formula.
Figure BDA0002575308820000032
Figure BDA0002575308820000041
Example 3:
the controlled release dry suspension of carbinoxamine maleate is prepared according to the following formula.
Figure BDA0002575308820000042
Test example 1 in vitro Release test
In vitro tests are important means for screening prescription determination processes, play an important role in quality control of preparations and are mainly investigated through dissolution rates. The invention adopts degassed 900mL0.15mol/l Nacl as a release medium: the rotation speed is 50r/min, and the temperature is 37 ℃. According to the paddle method operation in the appendix of the 2000 edition of Chinese pharmacopoeia, sampling 5mL at 0.5, 1, 2, 4, 6, 8 and 12h respectively, filtering through a 0.45 mu m microporous membrane, discarding the primary filtrate, taking the subsequent filtrate for later use, supplementing corresponding media with the same temperature and the same volume in time, measuring the absorbance of the subsequent filtrate at 307nm, calculating the concentration of sample liquid at different times according to a standard curve, and investigating the relationship between the accumulated release amount for 12 hours and the time.
The results of the experiment are shown in fig. 1. The results show that the in vitro release rate of the controlled release dry suspension of carbinoxamine maleate prepared in example 1 is 75-85% in 12 hours, so that the drug can be slowly released into the body.
Test example 2 stability test
The carbinoxamine maleate controlled release dry suspension prepared according to the invention is subjected to high temperature, high humidity, illumination and air exposure experiments, and the result shows that the stability of the product is better under the conditions of high temperature, high humidity, illumination and air exposure.
Test example 3 in vivo pharmacokinetic study of controlled release dry suspension of carbinoxamine maleate
Pharmacokinetics is the science of applying the principle of kinetics and mathematical processing methods to quantitatively describe the dynamic change rules of absorption, distribution, metabolism, excretion and other processes of drugs entering the body through various ways, i.e., to study the relationship between the existing site, concentration and time of drugs in the body and to provide mathematical relations needed to explain these data.
High performance liquid chromatography is adopted as a detection method, and the in vivo pharmacokinetics research of beagle dogs of the carbinoxamine maleate controlled release dry suspension is carried out. The results are shown in FIG. 2. The result shows that the controlled release dry suspension of the carbinoxamine maleate has more stable drug release in vivo and longer duration of drug effect than the sustained release tablet.
Although the present invention has been described with reference to the preferred embodiments, it should be understood that various changes and modifications can be made therein by those skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.

Claims (5)

1. The controlled-release dry suspension of the carbinoxamine maleate is characterized by comprising the following components in percentage by mass:
10-90% of carbinoxamine maleate;
10-90% of auxiliary materials with controlled release function;
the balance of other auxiliary materials;
the auxiliary materials with the controlled release function are one or more of cation exchange resin and methylcellulose, ethyl cellulose, acrylic resin and hydroxypropyl methylcellulose.
2. The controlled release dry suspension of carbinoxamine maleate according to claim 1 wherein the other excipients are selected from one or more of an impregnating agent, a plasticizer, a suspending agent, a flavoring agent, an antioxidant and a preservative.
3. The controlled release dry suspension of carbinoxamine maleate according to claim 2 wherein the impregnating agent is selected from one or more of methylcellulose, glycerol, PEG 4000.
The plasticizer is one or more selected from diethyl phthalate, dibutyl sebacate and PEG 400.
The suspension is one or more selected from PVP, HPMC, tragacanth, Carbopol, and Avicel RC 591.
The correctant is selected from one or more of mannitol, xylitol, stevioside, lactose, fructose, sucrose, aspartame, glycyrrhizin, sodium cyclamate, gelatin, aspartame, banana essence, pineapple essence, vanillin, orange essence, peppermint essence, ginseng essence, strawberry essence, citric acid, and citric acid.
4. The controlled release dry suspension of carbinoxamine maleate according to claim 1 wherein the formulation is a solid dry suspension.
5. A process for the preparation of a controlled release dry suspension of carbinoxamine maleate according to any of claims 1 to 4 comprising the steps of:
1) preparing medicine carrying resin carrying carbinoxamine maleate;
2) impregnating the drug-loaded resin obtained in the step 1);
3) preparing a drug-loaded resin microcapsule;
4) preparing the dry suspension by using the medicine-carrying resin microcapsule obtained in the step 3).
CN202010651968.6A 2020-07-08 2020-07-08 Carbixamine maleate controlled-release dry suspension and preparation method thereof Pending CN111603456A (en)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050232987A1 (en) * 2004-03-12 2005-10-20 Viswanathan Srinivasan Dosage form containing a morphine derivative and another drug
US20090092670A1 (en) * 2007-09-13 2009-04-09 Edwards Jr Robert J Long acting dual release product containing carbinoxamine and pseudoephedrine
CN103860464A (en) * 2014-03-19 2014-06-18 广州帝奇医药技术有限公司 Antiallergic drug sustained release suspension and preparation method of suspension
CN105663038A (en) * 2016-02-03 2016-06-15 北京诺康达医药科技有限公司 Liquid slow-release preparation and preparation method thereof
CN106913519A (en) * 2017-03-10 2017-07-04 江苏大学 A kind of preparation method of carbinoxamine maleate slow-release suspension
CN106963736A (en) * 2016-01-14 2017-07-21 刘宏飞 Dextromethorphan hydrobromide sustained-release dry suspensoid agent and preparation method thereof
CN108420791A (en) * 2018-05-14 2018-08-21 山东达因海洋生物制药股份有限公司 A kind of carbinoxamine maleate oral sustained release suspension and preparation method thereof

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050232987A1 (en) * 2004-03-12 2005-10-20 Viswanathan Srinivasan Dosage form containing a morphine derivative and another drug
US20090092670A1 (en) * 2007-09-13 2009-04-09 Edwards Jr Robert J Long acting dual release product containing carbinoxamine and pseudoephedrine
CN103860464A (en) * 2014-03-19 2014-06-18 广州帝奇医药技术有限公司 Antiallergic drug sustained release suspension and preparation method of suspension
CN106963736A (en) * 2016-01-14 2017-07-21 刘宏飞 Dextromethorphan hydrobromide sustained-release dry suspensoid agent and preparation method thereof
CN105663038A (en) * 2016-02-03 2016-06-15 北京诺康达医药科技有限公司 Liquid slow-release preparation and preparation method thereof
CN106913519A (en) * 2017-03-10 2017-07-04 江苏大学 A kind of preparation method of carbinoxamine maleate slow-release suspension
CN108420791A (en) * 2018-05-14 2018-08-21 山东达因海洋生物制药股份有限公司 A kind of carbinoxamine maleate oral sustained release suspension and preparation method thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
陈成: "马来酸卡比沙明口服液体缓释给药系统的构建及其体内外评价", 《中国优秀硕士学位论文全文数据库 (医药卫生科技辑)》 *

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