CN112121013B - Pharmaceutical composition and preparation method and application thereof - Google Patents
Pharmaceutical composition and preparation method and application thereof Download PDFInfo
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- 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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A61K9/00—Medicinal preparations characterised by special physical form
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- 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 pharmaceutical composition, a preparation method and application thereof, wherein the pharmaceutical composition comprises bepotastine besilate, a tackifier, a tension agent, a preservative and a pH regulator, wherein the granularity D of the bepotastine besilate 90 At 2-10 μm. The preparation method of the pharmaceutical composition comprises the following steps: (1) pretreatment of bepotastine besilate; and (2) preparation of the pharmaceutical composition. The preparation method is simple and easy to implement, the prepared medicinal composition enters the nasal cavity through a portable spraying device, the administration is convenient, the effect is quick, the medicament can be slowly released, the bioavailability is high, the product quality is stable, the irritation to the nasal cavity is small, and the medicinal composition can be used as an antihistamine medicament.
Description
Technical Field
The invention relates to a pharmaceutical composition, a preparation method and application thereof, in particular to a pharmaceutical composition for effectively treating respiratory tract inflammation, a preparation method and application thereof.
Background
Bepotastine Besilate (Bepotastine Besilate) has the chemical name (+) - (S) -4- (4- (4-chlorphenyl-2-pyridylmethoxy) piperidine) butyric acid benzene sulfonate and the chemical structure as follows:
histamine H, jointly developed by Tanabe Seiyaku and by the Japanese division of Japan (Ube Industries) 1 The receptor antagonist, first marketed in japan in 2000 under the trade name Talion (tankmen), is a 10mg white film-coated tablet. Has been imported domestically and is used for treating allergic rhinitis, urticaria, pruritus (eczema, dermatitis, prurigo, skin pruritus) caused by skin diseases, and nervous insomnia.
Betustine and its pharmacologically acceptable salt to histamine H 1 The receptor has selective inhibitory effect on 5-HT 2 、a 1 、a 2 Has no affinity, and can inhibit allergic inflammation with fine eosinophilic granuleInfiltration of cells into inflammatory sites inhibits the production of activated eosinophilic IL-5. Pharmacodynamic tests show that: bepotastine besilate can inhibit skin reaction caused by histamine; the in vitro test can inhibit histamine-induced contraction of guinea pig isolated smooth muscle, inhibit passive intradermal anaphylaxis (PCA) of I-type anaphylaxis model, inhibit nasal cavity resistance increase and antigen-induced nasal mucosa vascular hyperpermeability of experimental allergic rhinitis model, inhibit eosinophil infiltration caused by platelet activating factor and antigen, and inhibit antigen-induced eosinophil increase in peripheral blood.
In 2006, ISTA pharmaceutical company had granted bepotastine besilate eye drops in north america from the thousand shou company, and in 2007, the company had granted oral use of the drug in north america from the field side company. 2009. The FDA was licensed to produce bepotastine besilate eye drops, sold under the name Bepreve, with the specification of 1.5% eye drops, 10 ml/bottle, at 8 months of the year. Can be used for treating allergic conjunctivitis-related eye pruritus.
Bepotastine Besilate (Bepotastine Besilate) is mainly prepared into tablets and eye drops on the market globally, and is used for treating allergic rhinitis in a systemic administration mode, so that the treatment effect on the allergic rhinitis is not strong, and the symptoms such as rhinitis cannot be quickly inhibited.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a pharmaceutical composition with stable product quality and small nasal irritation; the second purpose is to provide a preparation method of the pharmaceutical composition; the third purpose is to provide the application of the pharmaceutical composition in preparing antihistamine medicines.
The technical scheme is as follows: the pharmaceutical composition comprises bepotastine besilate, a tackifier, a tension agent, a preservative and a pH regulator, wherein the granularity D of the bepotastine besilate 90 At 2-10 μm; further, the pharmaceutical composition further comprises a suspending agent, a buffering agent or a chelating agent.
Preferably, the viscosity increasing agent is acacia, sodium carboxymethylcellulose or colloidal microcrystalline cellulose.
Preferably, the bepotastine besilate concentration is 3%W/V-5%W/V, the tackifier concentration is 0.2% W/V-0.6% W/V, the suspending agent concentration is 0.001% W/V-0.002% W/V, the buffer concentration is 0.5% W/V-0.9% W/V, the tonicity agent concentration is 0.2% W/V-0.4% W/V, the chelating agent concentration is 0.01% W/V-0.03% W/V, and the preservative concentration is 0.01% W/V-0.03% W/V.
Preferably, the suspending agent is polysorbate 80, the buffering agent is disodium hydrogen phosphate or hydrate thereof, the tonicity agent is sodium chloride or mannitol, the chelating agent is disodium edetate, the preservative is benzalkonium chloride or ethylparaben, and the pH regulator is sodium hydroxide.
Preferably, the pH of the pharmaceutical composition is 5.0-6.5; further preferably, the pH of the pharmaceutical composition is 6.0-6.5.
The preparation method of the pharmaceutical composition comprises the following steps:
(1) Pretreatment of bepotastine besilate;
(2) And (3) preparation of the pharmaceutical composition.
The specific method of the step (1) comprises the following steps: micronizing bepotastine besilate, more specifically, carrying out jet milling or mechanical milling; the specific method of the step (2) is as follows: and (2) fully and uniformly mixing bepotastine besilate meeting the granularity requirement after pretreatment in the step (1), other auxiliary materials except the pH regulator and the preservative and water, regulating the pH, finally adding the preservative, and adding water to a sufficient amount.
The pharmaceutical composition can be used for preparing antihistamine drugs, in particular pharmaceutical preparations for nasal administration, more particularly sprays, nasal drops, gels and the like; among them, a spray is preferable.
The nasal administration has the following advantages:
(1) Can avoid the stimulation of the drug to the gastrointestinal tract and the degradation of the drug by the gastrointestinal tract;
(2) The first pass effect of the liver can be avoided, the medicine can directly enter the systemic circulation after being absorbed by nasal cavities without passing through a portal system, and the bioavailability of the medicine is greatly improved;
(3) The compliance of patients is good, the administration is convenient, and the drug is suitable for the old and children to administer for a long time;
(4) The absorption is rapid after the administration, and the effect is fast;
(5) Has brain targeting property, and the water soluble medicine can not penetrate blood brain barrier, and can be absorbed through nasal mucosa, and directly introduced into brain via olfactory nerve pathway and olfactory mucosa epithelial pathway to exert drug effect.
Has the advantages that: compared with the prior art, the invention has the following remarkable advantages:
(1) Controlling the particle size D of the active ingredient 90 The granularity of the active ingredients is stable when the sample is tested by a low-temperature freeze-thaw test at 2-10 mu m;
(2) The pharmaceutical composition improves the use compliance of patients, is convenient to carry, and can be used at any time and any place; meanwhile, the pH value and the osmotic pressure are consistent, so that the irritation to the nasal cavity is reduced, and the nasal mucosa is effectively protected; the medicine composition has rapid and complete nasal cavity absorption speed, and can effectively treat various diseases caused by allergy when being used as antihistamine medicine, in particular allergic rhinitis;
(3) The preparation method is simple and convenient, is easy for process amplification, does not use organic reagents, and has stable product quality.
Drawings
FIG. 1 is a graph showing the particle size distribution of bepotastine besilate according to the present invention.
Detailed Description
The technical solution of the present invention is further explained below with reference to the examples and the accompanying drawings.
1. Experimental Material
Carboxymethylcellulose sodium (Hunan Erkang pharmaceutical Co., ltd.), colloidal microcrystalline cellulose CL-611 (DuPont Nutrition USA, inc.), mannitol (Hunan Jiuchang Hongyang pharmaceutical Co., ltd.), benzalkonium chloride (Hubei Ge shop Fu pharmaceutic adjuvant Co., ltd.), sodium chloride (Hubei Ge shop Fu pharmaceutic adjuvant Co., ltd.), ethylparaben (Jinnan Cheng biotech Co., ltd.), acacia gum (Hubei Ge shop Fu pharmaceutic adjuvant Co., ltd.), polysorbate 80 (Hunan Erkang pharmaceutical Co., ltd.), disodium hydrogen phosphate heptahydrate (Hunan Jiuchan Hongyang pharmaceutical Co., ltd.), disodium ethylenediaminetetraacetate (Jinnan Cheng Zheng Biotech Co., ltd.), new Zealand rabbit (2.5 kg-3.0kg in body weight, 2.5 kg-0011 in Nanjing, qinglong mountain animal farm in Jianning area, nanjing) with a production permit number of SCXK (ScXK) 2017-0011.
2. Experimental equipment
pH meter (S210-K, mettler-Tollido International trade (Shanghai) Co., ltd.), laser particle sizer (Marwin 3000, marwin Pnapaceae), high performance liquid chromatograph (Shimadzu LC-20AT, UV detector).
3. Detection method
Particle size determination is carried out by referring to Marwin 3000 dry determination and wet determination SOP; the determination is carried out by referring to the content determination method of bepotastine besilate and bepotastine besilate tablets and the determination method of related substances in Japanese pharmacopoeia JP 17.
Example 1
1. Prescription
2. Preparation method
Pulverizing bepotastine besilate to granularity D 90 And (2) fully and uniformly mixing the raw and auxiliary materials (except the pH regulator and the preservative) and water according to the prescription amount at the particle size of 2-10 mu m, regulating the pH of the mixed solution to 6.5 by using 0.1mol/L sodium hydroxide, finally adding benzalkonium chloride, uniformly mixing, filling, and adding a spray pump to obtain the suspension type nasal spray.
Example 2
1. Prescription
2. Preparation method
Pulverizing bepotastine besilate to granularity D 90 Mixing the above raw materials (except pH regulator and antiseptic) and water at 2-10 μm, and dissolvingAdjusting pH of the solution to 5.0 with 0.1mol/L sodium hydroxide, adding benzalkonium chloride, mixing, packaging, and adding spray pump to obtain suspension type nasal spray.
Example 3
1. Prescription
2. Preparation method
Pulverizing bepotastine besilate to granularity D 90 And (2) fully and uniformly mixing the raw and auxiliary materials (except the pH regulator and the preservative) and water according to the prescription amount at the particle size of 2-10 mu m, adjusting the pH of the mixed solution to 6.0 by using sodium hydroxide, finally adding benzalkonium chloride, uniformly mixing, filling, and adding a spray pump to obtain the suspension type nasal spray.
Example 4
1. Prescription
2. Preparation method
Pulverizing bepotastine besilate to granularity D 90 And (2) fully and uniformly mixing the raw and auxiliary materials (except the pH regulator and the preservative) and water according to the prescription amount at the particle size of 2-10 mu m, adjusting the pH of the mixed solution to 6.5 by using sodium hydroxide, finally adding benzalkonium chloride, uniformly mixing, filling, and adding a spray pump to obtain the suspension type nasal spray.
Example 5
1. Prescription
2. Preparation method
Pulverizing bepotastine besilate to granularity D 90 Mixing the above materials (except pH regulator and antiseptic) with water at 2-10 μm, adjusting pH to 5.5 with sodium hydroxide, and addingAdding ethylparaben, mixing, bottling, and adding spray pump to obtain suspension type nasal spray.
Comparative example 1
1. Prescription
2. Preparation method
Pulverizing bepotastine besilate to granularity D 90 And (3) more than 50 mu m, fully and uniformly mixing the formula amount of raw and auxiliary materials (except the pH regulator and the preservative) and water, adjusting the pH of the mixed solution to 8.0 by using sodium hydroxide, finally adding benzalkonium chloride, uniformly mixing, filling, and adding a spray pump to obtain the suspension type nasal spray.
Comparative example 2
1. Prescription
2. Preparation method
Pulverizing bepotastine besilate to granularity D 90 And (2) fully and uniformly mixing the raw and auxiliary materials (except the pH regulator and the preservative) and water according to the prescription amount at the position of 20-50 mu m, adjusting the pH of the mixed solution to 4.0 by using sodium hydroxide, finally adding ethylparaben, uniformly mixing, filling, and adding a spray pump to obtain the suspension type nasal spray.
Example 6: stability test
1. Low temperature freeze thaw test
Taking the nasal spray prepared in the examples 1-5 and the comparative examples 1-2, respectively carrying out low temperature test for 3 cycles, wherein each cycle is carried out for 2 days at 4 ℃, then, the nasal spray is examined for 2 days at 40 ℃ under the accelerating condition, and sampling detection is carried out respectively at 0 day and the test end point; the nasal spray is respectively subjected to freeze thawing test for 3 times, each time of cycle is 2 days at minus 10 ℃, then 2 days are examined under 40 ℃ acceleration condition, and sampling detection is respectively carried out on 0 day and test end point. The results of the above tests are shown in Table 1.
TABLE 1 Low temperature Freeze thaw test results
2. Accelerated test
The nasal sprays prepared in examples 1 to 5 and comparative examples 1 to 2 were sampled and tested at 40 ℃ for 180 days, 0 day, 7 days, 30 days, 60 days, 90 days and 180 days, and the test results are shown in Table 2.
TABLE 2 accelerated test results
As can be seen from tables 1-2, compared with the comparative examples, the nasal spray prepared by the application has the granularity, the pH and the content of the raw material medicines substantially consistent with those of 0 day after low-temperature and freeze-thaw tests; after accelerated tests, the content of impurities of the nasal spray prepared by the method is not obviously increased compared with that of the nasal spray prepared by the method in 0 day and is within a quality control range, and the tests show that the quality of the nasal spray prepared by the method is more stable.
Example 7: nasal irritation test
1. Test method
Nasal spray prepared in examples 1-5 and comparative examples 1-2 were administered to New Zealand rabbits for a number of nasal irritation tests.
The above 40 rabbits were divided into 8 groups of 5 rabbits by weight. The test was carried out by using example 1 group, example 2 group, example 3 group, example 4 group, example 5 group, comparative example 1 group, comparative example 2 group and negative control group. The nasal administration was performed 1/d for each animal, two nasal sprays were performed for each nasal cavity, and the negative control group was administered the blank matrix control for 28 consecutive days in the same manner. Systemic irritation (such as respiration) and local irritation (such as asthma) were observed 1h after administration and before administration again. The animals are sacrificed 24h after the last administration, the phenomena of congestion, red swelling and the like of the mucous membrane tissues of the local respiratory tract are observed by naked eyes after dissection, and the pathological histology examination is carried out on the local respiratory tract (nose, throat, trachea, bronchus).
2. Test results
TABLE 3 nasal irritation test results
As can be seen from table 3, compared with the comparative examples, the nasal spray prepared by the present application has no obvious irritation reaction in the administration process and after the administration is finished, which indicates that the nasal spray of the present application preferably reduces irritation to nasal cavity through the prescription, and can effectively protect nasal mucosa.
Example 8: transdermal mucosal test
1. Test method
The nasal sprays prepared in examples 1-5 and comparative examples 1-2 were subjected to in vitro transdermal mucosal testing.
(1) Preparation of mucous membrane of nasal cavity of pig
The nasal part of the pig within 1h of death is taken down, the nasal cavity is cut open, the nasal septum and the turbinates on two sides are exposed, the nasal cavity film is carefully stripped by a round-head thin glass rod and tweezers, the residual bloodstain on the film is washed away by normal saline, and the film is put on a piece of aluminum foil and spread for immediate use.
(2) Conditions of the experiment
The effective diffusion area is 3.14cm by Franz diffusion cell method 2 The receiving tank had a volume of 14ml. An electromagnetic stirring bar and 14ml of normal saline are added into the receiving chamber, and air bubbles are discharged in time. Fixing the mucous membrane layer of pig nose between the receiving chamber and the supplying chamber, placing on a constant temperature magnetic stirrer with water bath temperature of 37 deg.C and 3000r/min, and balancing for 20min. Then 0.2g/ml of different particle sizes were preparedThe bepotastine besilate nasal spray is respectively taken 1ml and added to nasal mucosa of a supply room, 1ml is respectively sampled at 0min, 15 min, 30 min, 45 min, 60 min, 90 min, 120 min, 150 min, 180 min, 240 min and 300min, and fresh receiving liquid with the same amount is added after each sampling, so that 10 samples are totally taken. After the obtained sample is filtered by a 0.22 mu m filter membrane, 20 mu l of the sample is injected into a liquid chromatograph to measure the peak area of bepotastine besilate, and the amount of bepotastine besilate is calculated. Calculating the cumulative Permeability per unit area (Q) n )。
C n And C i Respectively represent the mass concentration (g/ml) of the drug, V and V measured at the n and i sampling points 0 Respectively representing the receiving cell volume and the sampling volume (ml), A representing the permeation area (cm) 2 )。
2. Test results
TABLE 4 in vitro transdermal nasal mucosa test results (Q) n ，g/cm 2 )
| Time (min) | Example 1 | Example 2 | Example 3 | Example 4 | Example 5 | Comparative example 1 | Comparative example 2 |
| 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 15 | 0.04 | 0.01 | 0.02 | 0.01 | 0.04 | 0.01 | 0.01 |
| 30 | 0.08 | 0.02 | 0.05 | 0.02 | 0.08 | 0.02 | 0.04 |
| 45 | 0.13 | 0.04 | 0.07 | 0.05 | 0.12 | 0.02 | 0.05 |
| 60 | 0.2 | 0.12 | 0.18 | 0.1 | 0.15 | 0.03 | 0.07 |
| 90 | 0.4 | 0.20 | 0.38 | 0.25 | 0.25 | 0.05 | 0.11 |
| 120 | 0.6 | 0.28 | 0.59 | 0.31 | 0.38 | 0.1 | 0.15 |
| 150 | 0.8 | 0.40 | 0.75 | 0.44 | 0.52 | 0.15 | 0.2 |
| 180 | 1.0 | 0.55 | 0.93 | 0.55 | 0.70 | 0.2 | 0.25 |
| 240 | 1.2 | 0.72 | 1.08 | 0.68 | 0.85 | 0.25 | 0.35 |
| 300 | 1.4 | 0.88 | 1.28 | 0.88 | 1 | 0.34 | 0.46 |
As can be seen from table 4, compared with the comparative example, the nasal spray prepared by the present application has faster penetration speed and higher penetration amount in the in vitro nasal mucosa experiment process, which indicates that the selected particle size range of the nasal spray of the present application improves the penetration of the active ingredient.
Claims (8)
1. A pharmaceutical preparation for nasal administration, which comprises bepotastine besilate, a viscosity increasing agent, a tension agent, a preservative, a pH regulator and water,wherein, the granularity D of the bepotastine benzenesulfonate 90 At 2-10 μm; the concentration of bepotastine besilate is 3-5% W/V, the concentration of tackifier is 0.2-0.6% W/V, the concentration of tension agent is 0.2-0.4% W/V, and the concentration of preservative is 0.01-0.03% W/V.
2. The pharmaceutical formulation of claim 1, further comprising a suspending agent, a buffering agent, or a chelating agent; the concentration of the suspending agent is 0.001-0.002% W/V, the concentration of the buffering agent is 0.5-0.9% W/V, and the concentration of the chelating agent is 0.01-0.03% W/V.
3. The pharmaceutical formulation according to claim 1 or 2, wherein the viscosity-increasing agent is acacia, sodium carboxymethylcellulose or colloidal microcrystalline cellulose, the tonicity agent is sodium chloride or mannitol, the preservative is benzalkonium chloride or ethylparaben, and the pH-adjusting agent is sodium hydroxide.
4. The pharmaceutical formulation as claimed in claim 2, wherein the suspending agent is polysorbate 80, the buffering agent is disodium phosphate or a hydrate thereof, and the chelating agent is disodium edetate.
5. The pharmaceutical formulation according to claim 1 or 2, wherein the pH of the pharmaceutical formulation is between 5.0 and 6.5.
6. The pharmaceutical formulation of claim 5, wherein the pharmaceutical formulation has a pH of 6.0 to 6.5.
7. A method of preparing a pharmaceutical formulation according to any one of claims 1 to 6, comprising the steps of:
(1) Pretreating bepotastine besilate;
(2) And (3) preparing a pharmaceutical preparation.
8. Use of a pharmaceutical formulation according to any one of claims 1 to 6 in the manufacture of an antihistamine.
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| CN103260623A (en) * | 2010-10-06 | 2013-08-21 | 伊斯塔制药公司 | Bepotastine compositions |
| CN106474062A (en) * | 2015-08-27 | 2017-03-08 | 重庆华邦制药有限公司 | A kind of external spraying agent containing desonide |
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| CN103816121B (en) * | 2014-03-07 | 2016-01-20 | 上海现代药物制剂工程研究中心有限公司 | Bepotastine besilate nasal mist and preparation method thereof |
| CN105943500B (en) * | 2016-07-08 | 2019-01-04 | 河南省立眼科医院 | A kind of antimycotic solution of ophthalmically acceptable nano-micelle containing Chinese mugwort Saperconazole |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103260623A (en) * | 2010-10-06 | 2013-08-21 | 伊斯塔制药公司 | Bepotastine compositions |
| CN106474062A (en) * | 2015-08-27 | 2017-03-08 | 重庆华邦制药有限公司 | A kind of external spraying agent containing desonide |
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Denomination of invention: A pharmaceutical composition, its preparation method and application Effective date of registration: 20230210 Granted publication date: 20221028 Pledgee: Nanjing Branch of Jiangsu Bank Co.,Ltd. Pledgor: Nanjing comer biomedical Co.,Ltd. Registration number: Y2023980032412 |
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