阅读说明：本技术 一种治疗感冒的复方液体制剂及其制备方法 (Compound liquid preparation for treating cold and preparation method thereof ) 是由 曲韵智 于 2020-12-18 设计创作，主要内容包括：本发明一种治疗感冒的复方液体制剂及其制备方法,是将一种抗组织胺药物与盐酸去氧肾上腺素组合后,与适宜的辅料制备成口服液体制剂。本发明具有暂时缓解由于普通感冒、花粉症(过敏性鼻炎)或其他上呼吸道过敏引起的以下症状,如鼻充血、鼻道的肿胀、流鼻涕、打喷嚏、鼻子或喉咙痒、眼睛发痒和流眼泪等感冒症状。本发明制备方法简单,口感好,疗效好,是感冒患者首选药物之一。(The invention relates to a compound liquid preparation for treating cold and a preparation method thereof, wherein an antihistamine drug and phenylephrine hydrochloride are combined and then prepared into an oral liquid preparation together with proper auxiliary materials. The present invention has the effect of temporarily relieving cold symptoms such as nasal congestion, swelling of the nasal passages, runny nose, sneezing, itching of the nose or throat, itching of the eyes and tearing due to common cold, pollinosis (allergic rhinitis) or other upper respiratory allergies. The invention has simple preparation method, good taste and good curative effect, and is one of the preferred medicines for cold patients.)

1. The compound liquid preparation for treating cold is characterized by that every 1000ml of said liquid preparation contains phenylephrine hydrochloride 0.15g-0.70g, antihistamine 1.5g-4.0g and proper adjuvant and solvent.

2. The compound liquid preparation for treating cold and the preparation method thereof according to claim 1, wherein each 1000ml of the compound liquid preparation comprises phenylephrine hydrochloride 0.17g-0.67g, antihistamine 1.67g-3.33g, and proper excipients and solvents.

3. The compound liquid preparation for treating cold and the preparation method thereof according to claim 1, wherein each 1000ml of the compound liquid preparation comprises phenylephrine hydrochloride 0.17g, antihistamine 1.67g, and proper excipients and solvents.

4. The compound liquid preparation for treating cold and the preparation method thereof according to claim 1, wherein each 1000ml of the compound liquid preparation comprises phenylephrine hydrochloride 0.67g, antihistamine 3.33g, and proper excipients and solvents.

5. The liquid compound preparation for treating cold and its preparing process according to any one of claims 1-4, wherein said antihistamine includes, but is not limited to, tripelennamine, chlorpheniramine, clopidogrel, and zizipramine.

6. The compound liquid preparation for treating cold and the preparation method thereof according to any one of claims 1 to 4, wherein the auxiliary materials include but are not limited to stabilizers, flavoring agents, pH regulators, preservatives, aromatics.

7. The liquid compound preparation for treating cold of claim 6, wherein the stabilizer includes but is not limited to propyl gallate, sodium thiosulfate, hydroquinone, tocopherol, tert-butylhydroquinone, and is used in an amount of 1-2g per 1000 ml.

8. The compound liquid preparation for treating cold and the preparation method thereof according to claim 6, characterized in that the flavoring agents include but are not limited to sorbitol, sucrose, steviosin, sucralose, glycyrrhizic acid, and the dosage is 0.5-700g per 1000 ml.

9. The liquid compound preparation for treating cold as claimed in claim 6, wherein the pH regulator includes, but is not limited to, citric acid anhydrous, potassium dihydrogen phosphate or sodium dihydrogen phosphate in proper amount.

10. The compound liquid preparation for treating cold and the preparation method thereof according to claim 6, wherein the preservative includes but is not limited to benzoic acid, sodium benzoate, sorbic acid, sodium sorbate, and the dosage is 1-2g per 1000 ml.

11. The compound liquid preparation for treating cold and the preparation method thereof according to claim 6, wherein the flavoring agents include but are not limited to blueberry flavor, orange flavor, apple flavor, and the amount thereof is 1-5ml per 1000 ml.

12. The compound liquid preparation for treating cold and the preparation method thereof according to claim 6, wherein the solvent includes but is not limited to propylene glycol, glycerin, purified water.

13. The compound liquid preparation for treating cold and the preparation method thereof according to any one of claims 1 to 12, characterized in that the preparation method comprises the following steps:

13.1 precisely weighing the antihistamine, placing the antihistamine in a clean container, adding a small amount of solvent, stirring for dissolving, adding the stabilizer, the flavoring agent and the preservative, and continuously stirring until the stabilizer, the flavoring agent and the preservative are dissolved to obtain a solution 1 for later use;

13.2 precisely weighing the hydrochloric acid for removing adrenaline, placing the hydrochloric acid into a clean container, adding a small amount of solvent, and stirring to dissolve the hydrochloric acid to obtain a solution 2 for later use;

13.3 under stirring, slowly adding the solution 2 into the solution 1, adding aromatic, adjusting pH to 4.5-6.5 with pH regulator, adding solvent to 1000ml, stirring, filtering, and bottling.

14. The compound liquid preparation for treating cold and the preparation method thereof according to any one of claims 1 to 13, characterized in that the preferred preparation method is:

14.1, precisely weighing 1.67g of the ziprasidone, putting the medicine into a clean container, adding a small amount of purified water, stirring and dissolving, then adding 1.0g of propyl gallate, 0.5g of sucralose and 1.5g of sodium benzoate, and continuously stirring until the mixture is dissolved to obtain a solution 1 for later use;

14.2, precisely weighing 0.17g of hydrochloric acid for removing adrenaline, placing the hydrochloric acid into a clean container, adding a small amount of purified water, and stirring to dissolve the hydrochloric acid and the adrenaline to obtain a solution 2 for later use;

14.3, slowly adding the solution 2 into the solution 1 under stirring, adding 1.0ml of orange essence, adjusting the pH to 4.5-5.5 with disodium hydrogen phosphate, adding a solvent to 1000ml, stirring uniformly, filtering, and filling to obtain the final product.

15. The compound liquid preparation for treating cold and the preparation method thereof according to any one of claims 1 to 13, characterized in that the preferable preparation method can also be:

15.1, precisely weighing 0.67g of the ziprasidone, placing the obtained product in a clean container, adding a small amount of purified water, stirring and dissolving, then adding 2g of propyl gallate, 0.60g of steviosin and 1.5g of benzoic acid, and continuously stirring until the obtained product is dissolved to obtain a dissolved solution 1 for later use;

15.2, precisely weighing 3.33g of hydrochloric acid deprived of adrenaline, placing the hydrochloric acid deprived of adrenaline into a clean container, adding a small amount of purified water, and stirring to dissolve the hydrochloric acid deprived of adrenaline to obtain a solution 2 for later use;

15.3, slowly adding the solution 2 into the solution 1 under stirring, adding 2.0ml of orange essence, adjusting pH to 4.5-5.5 with sodium dihydrogen phosphate, adding purified water to 1000ml, stirring, filtering, and bottling.

16. The compound liquid preparation for treating cold and the preparation method thereof according to any one of claims 1 to 15, wherein the present invention has the effect of temporarily relieving cold symptoms such as nasal congestion, swelling of nasal passages, runny nose, sneezing, itching nose or throat, itching eyes, headache and watery eyes due to common cold, pollinosis (allergic rhinitis) or other upper respiratory allergy.

Technical Field

The invention belongs to the technical field of drug research and development, and particularly relates to a compound liquid preparation for treating cold and a preparation method thereof. More specifically, the oral liquid preparation is prepared by combining an antihistamine and phenylephrine and then adding proper auxiliary materials.

Background

The common cold is a common disease and is mostly caused by the inhalation of viruses or germs through the respiratory tracts of the nose and the pharynx. The common viruses comprise coronavirus, influenza virus, parainfluenza virus and the like, the symptoms of the common viruses are mainly fever, nasal obstruction, watery nasal discharge, cough, sneeze or headache and the like, and if the common viruses are not treated in time, a plurality of complications can be caused, so that the common viruses bring serious harm to human bodies.

The common cold medicines in the market are various in types and varieties, and comprise Chinese patent medicines, chemical medicines, oral medicines, injections, mucosa medicines and the like, wherein the oral medicines are in various dosage forms such as syrups, tablets, capsules, oral liquids and the like.

Disclosure of Invention

The invention relates to a compound liquid preparation for treating cold and a preparation method thereof, in particular to an innovative cold drug, which is an oral liquid preparation prepared by combining an antihistamine drug and phenylephrine hydrochloride and proper auxiliary materials. The present invention has the effect of temporarily relieving cold symptoms such as nasal congestion, swelling of the nasal passages, runny nose, sneezing, itching of the nose or throat, itching of the eyes, headache and tearing due to common cold, pollinosis (allergic rhinitis) or other upper respiratory allergies.

The antihistamine is a commonly used medicament in the daily medical treatment process of a hospital, has an important effect on the recovery of the state of an illness of a patient, and is an antiallergic medicament widely applied. The anti-histamines are various in types, different anti-histamines have different anti-allergy effects, and ethylenediamine, alkylamine and the like are mainly used at present. Such as ethylenediamine-type tripelennamine, alkylamine-type chlorpheniramine, clopidogrel, and sonzilamine.

The technical scheme for realizing the invention is as follows:

the invention relates to a compound liquid preparation for treating cold and a preparation method thereof, wherein the liquid preparation comprises 0.15g-0.70g of phenylephrine hydrochloride, 1.5g-4.0g of antihistamine and proper auxiliary materials and solvents in each 1000ml of the liquid preparation.

Or 1000ml contains phenylephrine hydrochloride 0.17-0.67 g, antihistamine 1.67-3.33 g, and proper adjuvant and solvent.

Or 1000ml of the composition contains 0.17g of phenylephrine hydrochloride, 1.67g of antihistamine and proper auxiliary materials and solvents.

Or 1000ml of the composition contains 0.67g of phenylephrine hydrochloride, 3.33g of antihistamine and proper auxiliary materials and solvents.

The antihistamine includes, but is not limited to, tripelennamine, chlorpheniramine, clopidogrel, and zizipramine, preferably, zizipramine.

The auxiliary materials include but are not limited to stabilizers, flavoring agents, pH regulators, preservatives and aromatics.

The stabilizer includes but is not limited to propyl gallate, sodium thiosulfate, hydroquinone, tocopherol, tert-butyl hydroquinone, and the dosage of the stabilizer is 1-2g per 1000 ml.

The flavoring agent includes, but is not limited to, sorbitol, sucrose, steviosin, sucralose, and glycyrrhizic acid, and its amount is 0.5-700g per 1000 ml.

The pH regulator includes, but is not limited to, citric acid anhydrous, potassium dihydrogen phosphate or sodium dihydrogen phosphate, and is used in a suitable amount.

The antiseptic includes but is not limited to benzoic acid, sodium benzoate, sorbic acid, sodium sorbate, and is used in an amount of 1-2g per 1000 ml.

The flavoring agent includes, but is not limited to, blueberry essence, orange essence, and apple essence, and is used in an amount of 1-5ml per 1000 ml.

Such solvents include, but are not limited to, propylene glycol, glycerol, purified water.

The pH value of the liquid medicine is stable and is 4.5-6.5.

The compound liquid preparation for treating cold and the preparation method thereof are as follows:

prepared according to 1000 ml:

a. accurately weighing the antihistamine, placing into a clean container, adding a small amount of solvent, stirring for dissolving, adding the stabilizer, the correctant and the preservative, and continuously stirring until the stabilizer, the correctant and the preservative are dissolved to obtain a solution 1 for later use;

b. precisely weighing the hydrochloric acid to remove adrenaline, placing the hydrochloric acid into a clean container, adding a small amount of solvent, and stirring to dissolve the hydrochloric acid to obtain a solution 2 for later use;

c. slowly adding the solution 2 into the solution 1 under stirring, adding aromatic, adjusting pH to 4.5-6.5 with pH regulator, adding solvent to 1000ml, stirring, filtering, and packaging.

Advantageous effects

The invention relates to a compound liquid preparation for treating cold and a preparation method thereof, wherein an antihistamine drug and phenylephrine hydrochloride are combined and then prepared into an oral liquid preparation together with proper auxiliary materials. The present invention has the effect of temporarily relieving cold symptoms such as nasal congestion, swelling of the nasal passages, runny nose, sneezing, itching of the nose or throat, itching of the eyes and tearing due to common cold, pollinosis (allergic rhinitis) or other upper respiratory allergies.

The invention has simple preparation method, good taste and good curative effect, and is one of the preferred medicines for cold patients.

The present invention will now be further elucidated with respect to several pharmacodynamic tests.

1. Test materials and reagents:

1.1 Experimental animals:

selecting Kunming mice with the weight of 18 +/-2.5 g and male and female functions provided by Beijing university of traditional Chinese medicine; new Zealand breeding rabbits (2.8 + -0.5) kg in weight, can be used for both male and female; guinea pigs: weight (300 + -30 g), combined male and female.

1.2 Experimental drugs:

1.2.1 test drugs: oral solution of the invention (using the oral solution prepared in example 1 below, denoted by KQY): developed by Beijing Borda oasis medicine science and technology research Co., Ltd;

1.2.2 control drugs: compound aspirin tablet (APC representation): manufactured by Gansu Lanzhou pharmaceutical Co., Ltd;

1.2.3 reagents: acetic acid and formaldehyde are analytically pure and provided by Beijing chemical reagent factory.

Experiment one: the analgesic effect is as follows:

1. acetic acid writhing experiment:

mice were randomly divided into 4 groups of 10 mice by weight, each group was a blank control group, a positive control group (APC group), a KQY large (100ml/kg) and a small dose group (50ml/kg), and after 45min of gastric lavage, each group of mice was intravenously injected with 0.6% acetic acid (0.2 ml each), and then the number of writhing of the mice within 10min was observed and recorded (see Table 1).

The experimental result shows that KQY and APC can both significantly inhibit the writhing reaction of mice caused by pain caused by acetic acid, and compared with a blank control group, the difference has statistical significance (P is less than 0.01).

2. Formaldehyde pain test:

randomly dividing the mice into 4 groups according to the weight, 10 mice in each group, namely a blank control group, a positive control group (APC group), a KQY large (100ml/kg) and a small dose group (50ml/kg), injecting 25 mu l of 3% formaldehyde solution under the right front instep and the back of the foot of the mice while performing gastric lavage, observing the pain reaction for the first 5min after 1h, and scoring according to the following performance characteristics: and (3) 0 minute: the front foot on the side of injecting formaldehyde and the front foot on the other side without injecting formaldehyde can contact the ground and move freely; 1 minute: the forefoot on the side injected with formaldehyde can contact the ground, the body weight shifts to the side not injected, and significant lameness occurs: 2 minutes: the forefeet at the side of injecting formaldehyde are lifted and can not contact the ground; 3 minutes: mice lick, bite or shake the injection side of the forefoot.

The results show that KQY and APC can both significantly inhibit the pain reaction of mice caused by formaldehyde, and compared with a blank control group, the difference has statistical significance (P is less than 0.01), and the experimental results are shown in Table 2.

Table 1: mouse acetic acid writhing experiment observation result (-x + -s)

Group of	Animal number (only)	Number of times of body twisting
			Blank control group	10	39.2±8.7
APC group (100mg/kg)	10	13.5±7.9*
			GYT high dose group (100mg/kg)	10	20.3±8.7*
GYT small dose group (50mg/kg)	10	21.6±9.7*

P < 0.01 in comparison with the blank control group

Table 2: observation result (-x +/-s) of mouse formaldehyde pain-relieving experiment

Group of	Animal number (only)	Pain response scoring
			Blank control group	10	3.05±0.28
APC group (100mg/kg)	10	1.26±0.43*
			GYT high dose group (100mg/kg)	10	1.85±0.39*
GYT small dose group (50ng/kg)	10	2.01±0.38*

Note: p < 0.01 in comparison with the blank control group

Experiment two:

the antipyretic effect is as follows:

new Zealand species rabbits were randomly divided into 4 groups of 8 rabbits each with half male and female according to weight balance, and the groups were blank control group, positive control group (APC group 75mg/kg), KQY large (100ml/kg), and small dose group (50ml/kg), respectively. The normal anal temperature is measured by an anal thermometer for 2 times (each time interval is 0.5h), the average value is taken as the normal body temperature of the rabbits before administration, then each group of rabbits is administered with the corresponding drug according to the dose of 5.5ml/kg, and the typhoid and paratyphoid A/B triple vaccine (1.5ml/kg) is injected intravenously at the same time, and the body temperature is measured for 3h at intervals of 30min after administration.

The experimental results show that KQY and APC have significant antipyretic effect (P is less than 0.05) on rabbits compared with the blank control group, and the results are shown in Table 3.

Table 3: results of rabbit fever reduction experiment (-x + -s)

Time of administration	Blank control group	APC group	KQY high dose group	KQY Small dose group
					Before administration	40.05±0.23	39.92±0.45	39.50±0.37	39.75±0.53
0.5h after administration	40.07±0.32	39.57±0.58	40.02±0.60*	40.05±0.37
					1h after administration	41.00±0.28	40.18±0.39	40.56±0.60*	40.00±0.33
1.5h after administration	40.86±0.35	39.87±0.56	40.67±0.35*	39.97±0.62
					2h after administration	41.10±0.23	39.78±0.59	40.55±0.28	40.87±0.65
2.5h after administration	41.23±0.31	40.04±0.28	40.57±0.40	40.86±0.42
					3h after administration	41.22±0.19	39.87±0.44	40.20±0.41	40.85±0.54

And (3) test III:

anti-inflammatory action: effect on mouse foot sole Carrageenan swelling

The mice are evenly and randomly divided into 4 groups according to the weight, 10 mice in each group are respectively a blank control group, a positive control group (APC group), a KQY large (100ml/Kg) group and a small dose group (50ml/Kg), 30min after gastric lavage administration, 0.25ml of right hind foot sole SC 2% carrageenan, the thickness of the foot sole of the mice before and after 1, 2 and 3h of the right hind foot sole carrageenan is respectively measured by a micrometer, so that the thickness difference of the foot sole before and after inflammation is swelling degree, and the experimental result is recorded.

The results show that: compared with the blank control group, the KQY high-dose group (100ml/kg) has obvious inhibition effect on the carrageenan swelling of the foot sole of the mouse, and the results are shown in the table 4

Group of	Blank control group	APT(100mg/kg)	KQY(100ml/kg)	KQY(50ml/kg)
					Swelling degree of 1h	69.87±24.8	50.90±12.9**	29.98±38.6***	52.90±16.6**
Swelling degree of 2h	82.70±16.4	74.90±9.0**	50.10±42.8**	91.00±21.0*
					Swelling degree of 3h	90.40±7.9	76.70±13.4*	58.00±21.2**	95.10±20.9**

Note: p > 0.05, P < 0.01, compared to the blank control group

Experiment four:

effect on mucosal sensitization in guinea pigs:

guinea pigs were divided into 4 groups of 8 animals per group at random according to weight balance, histamine (2.5%) prepared with physiological saline was dropped into the nose of guinea pigs (0.03 ml/animal) 1 hour after gastric administration (1ml/100g), the number of nasal scratching and sneezing of guinea pigs was observed after 10min, and then the guinea pigs were killed by decapitation, the anterior trachea and nasal respiratory mucosa were removed, embedded, cut skin, HE stained, and examined histologically under a light microscope. The results show that after the administration of KQY (50ml/kg and 100ml/kg) by gastric lavage, the nasal grasping times of the guinea pigs are obviously reduced, and the administration of KQY by gastric lavage also has obvious inhibiting effect on the sneeze reaction of the guinea pigs, and the results are shown in Table 7.

TABLE 7 Experimental observations of allergic nasal and sneezing reaction of nasal mucosa of guinea pigs caused by histamine (-x + -s)

Group of	Animal number (only)	Number of nasal griping	Number of sneezes
				Blank control group	10	17.0±11.0	30.0±6.0
APC group (100mg/kg)	10	13.0±12.0*	29.0±16.0*
				KQY Large dose group (100ml/kg)	10	1.3±2.3**	0.3±0.6***
KQY Small dose group (50ml/kg)	10	1.4±2.2***	3.2±5.5***

Note: comparison with blank control: p > 0.05, P < 0.01

Description of the drawings: the statistical treatment method of the test comprises the following steps: the experimental data were statistically analyzed using SAS software using analysis of variance and t-test with a test level α of 0.05.

Detailed Description

The invention will now be further elucidated with respect to several sets of examples:

prepared in 1000 ml.

Example 1

a. Accurately weighing 1.70g of tripelennamine, placing the tripelennamine in a clean container, adding a small amount of purified water, stirring and dissolving, adding 1.2g of propyl gallate, 0.5g of sorbitol and 1.2g of sodium benzoate, and continuously stirring until the propyl gallate, the sorbitol and the sodium benzoate are dissolved to obtain a solution 1 for later use;

b. precisely weighing 0.15g of hydrochloric acid for removing adrenaline, placing the hydrochloric acid into a clean container, adding a small amount of purified water, and stirring to dissolve the hydrochloric acid to obtain a solution 2 for later use;

c. slowly adding the solution 2 into the solution 1 under stirring, adding 1.2ml of fructus Citri Tangerinae essence, adjusting pH to 4.5-5.5 with sodium dihydrogen phosphate, adding purified water to 1000ml, stirring, filtering, and bottling.

Example 2

a. Precisely weighing 3.33g of chlorpheniramine, placing the chlorpheniramine in a clean container, adding a small amount of propylene glycol, stirring and dissolving, adding 1.0g of hydroquinone, 650g of cane sugar and 1.75g of benzoic acid, and continuously stirring until the mixture is dissolved to obtain a solution 1 for later use;

b. precisely weighing 0.17g of hydrochloric acid for removing adrenaline, placing the hydrochloric acid into a clean container, adding a small amount of propylene glycol, and stirring to dissolve the hydrochloric acid to obtain a solution 2 for later use;

c. slowly adding the solution 2 into the solution 1 under stirring, adding blueberry essence 4.0ml, adjusting pH to 5.5-6.5 with sodium dihydrogen phosphate, adding purified water to 1000ml, stirring, filtering, and bottling.

Example 3

a. Precisely weighing 1.67g of the sonzilazine, placing the medicine into a clean container, adding a small amount of purified water, stirring and dissolving, then adding 1.0g of propyl gallate, 0.5g of sucralose and 1.5g of sodium benzoate, and continuously stirring until the mixture is dissolved to obtain a solution 1 for later use;

b. precisely weighing 0.17g of hydrochloric acid for removing adrenaline, placing the hydrochloric acid into a clean container, adding a small amount of purified water, and stirring to dissolve the hydrochloric acid to obtain a solution 2 for later use;

c. slowly adding the solution 2 into the solution 1 under stirring, adding 1.0ml of orange essence, adjusting pH to 4.5-5.5 with disodium hydrogen phosphate, adding solvent to 1000ml, stirring, filtering, and bottling.

Example 4

a. Accurately weighing 0.67g of the sonzilazine, placing the sonzilazine in a clean container, adding a small amount of purified water, stirring and dissolving, adding 2g of propyl gallate, 0.60g of steviosin and 1.5g of benzoic acid, and continuously stirring until the materials are dissolved to obtain a dissolved solution 1 for later use;

b. precisely weighing 3.33g of hydrochloric acid for removing adrenaline, placing the hydrochloric acid into a clean container, adding a small amount of purified water, and stirring to dissolve the hydrochloric acid to obtain a solution 2 for later use;

c. slowly adding the solution 2 into the solution 1 under stirring, adding fructus Citri Tangerinae essence 2.0ml, adjusting pH to 4.5-5.5 with sodium dihydrogen phosphate, adding purified water to 1000ml, stirring, filtering, and bottling.

Example 5

The following stability test was performed using the drug prepared in example 4 as a test sample to verify the stability of the compound liquid preparation of the present invention.

High temperature, high humidity and light test

The test method comprises the following steps: 900ml of the sample prepared in example 4 was taken, 10ml of each sample was filled, and each sample was filled in a white glass bottle, sealed, divided into 3 groups, and 30 samples were placed in one group, and each group was placed at a high temperature (60 ℃) for 30 days, at a high humidity (92% ± 5%) for 60 days, and under illumination (illuminance 4500Lx ± 500Lx) for 60 days, and sampling and detection were performed for 10 days, 30 days, and 60 days, respectively, using phenylephrine hydrochloride content as a detection index. The results are shown in Table 1.

TABLE 1 table of samples tested under high temperature, high humidity and light conditions

The results show that: the invention is stored at the high temperature of 60 ℃, so that the phenylephrine hydrochloride content is obviously reduced; the content change is not obvious under the conditions of high humidity and illumination. The invention is demonstrated that the invention can be preserved under the condition of normal temperature.