A loratadine liniment and a preparation method thereof

Abstract

The application belongs to the field of pharmaceutical preparations and relates to a chlorpheniramine maleate liniment, which contains chlorpheniramine maleate 1 part, a cosolvent 100-140 parts, a stabilizer 12-25 parts and a binder 5-15 parts. The solubility and stability of chlorpheniramine maleate are improved, and the content of related substances in the preparation is reduced by optimizing the types and proportions of the cosolvent and the stabilizer. The full dissolution of chlorpheniramine maleate and excipients is facilitated by optimizing the preparation process, in particular the dissolution step of chlorpheniramine maleate and the stabilizer. The preparation process is simple, suitable for industrial production and convenient for market promotion.

Description

TECHNICAL FIELD

[0001] The present application relates to a loratadine liniment and a preparation method thereof, and belongs to the field of pharmaceutical preparations. BACKGROUND

[0002] Loratadine was developed by Schering Plough Company, and was first marketed in Belgium in 1988. Loratadine is an orally effective third-generation antihistamine, which has the effect of selectively inhibiting peripheral H1 receptors. Loratadine is a potent antiallergic drug.

[0003] Loratadine and its metabolite desethyl loratadine can inhibit the release of histamine and other mediators from mast cells and basophils. Loratadine can reduce the expression of ICAM-1 on nasal epithelial cells, thereby blocking or reducing the delayed inflammatory response. In vivo studies also show that loratadine has a good effect on inflammatory reactions induced by allergens. Oral and intranasal administration can reduce the symptoms of rhinitis and the migration of inflammatory cells. Loratadine inhibits the uptake of Ca 2+ and inhibits the intracellular Ca 2+ of mast cells, inhibits the expression of adhesion molecules, inhibits eosinophils, and reduces the production of interleukins, thereby comprehensively inhibiting allergic reactions.

[0004] The clinically selected dosage forms of loratadine include tablets, syrups, granules, etc. Loratadine has poor water solubility, so it is difficult for the drug to dissolve in solid preparations such as tablets, which makes the drug fail to achieve the desired therapeutic effect. The liniment directly acts on the lesion, has a rapid onset, has no systemic effect, and reduces adverse reactions.

[0005] Chinese Patent CN100444841A discloses a topical preparation of loratadine, which contains methylparaben in the formula. In recent years, studies have shown that methylparaben can react with ultraviolet B on the skin, accelerate skin aging, and damage DNA, which is not suitable for topical application to the affected area.

[0006] Chinese Patent CN101991574A discloses a desloratadine topical preparation, which includes magnesium stearate, white vaseline, liquid paraffin, glycerol monostearate, Tween-80, azone, hydroxyphenyl ethyl ester, glycerol, sodium dodecyl sulfate, desloratadine, β-cyclodextrin, and purified water. The formula is relatively complex, and contains multiple surfactants, which poses a risk to the safety of the drug.

[0007] At present, the existing loratadine preparations in China are mainly tablets and syrup preparations. The present application provides a liniment that can increase patient adaptability, which meets the needs of the majority of patients. SUMMARY

[0008] One of the purposes of the present application is to provide a high-quality, loratadine liniment, which overcomes the shortcomings of the prior art, and greatly improves the stability of the preparation and the degradation impurities.

[0009] Specifically, the technical solutions of the present application are as follows:

[0010] The first purpose of the present application is to provide a loratadine liniment, which comprises loratadine, a cosolvent, a binder, a stabilizer, and purified water.

[0011] Further, the components are calculated by weight ratio as follows:

[0012]

[0013] Further, the cosolvent is one or more of glycerol, vegetable oil, methanol, propylene glycol, and ethanol.

[0014] Preferably, the cosolvent is ethanol and glycerol, and the weight ratio is 6:1.

[0015] Further, the binder is one of corn starch, povidone, polyethylene glycol, methyl cellulose, hypromellose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, gelatin, gum arabic, and sodium alginate, and is preferably hypromellose.

[0016] Further, the stabilizer is one or more of sodium alginate, citric acid, pregelatinized starch, povidone, sodium carboxymethyl cellulose, hydroxypropyl cellulose, glycerol, citric acid, and hypromellose.

[0017] Preferably, the stabilizer is a mixture of citric acid and glycerol.

[0018] Further preferably, the weight ratio of citric acid to glycerol is 7-15:5-10.

[0019] Specifically, the amount ratio of citric acid to glycerol is 9.6:7.5.

[0020] Based on the above, further preferred components are calculated by weight ratio as follows:

[0021]

[0022] The second purpose of the present application is to provide a method for preparing the above-mentioned loratadine liniment, which comprises the following steps:

[0023] Step (1): Dissolve loratadine in a cosolvent, stir to dissolve, and obtain solution I;

[0024] Step (2): Dissolve a stabilizer in another cosolvent to obtain solution II;

[0025] Step (3): slowly mix solution I, II, stir evenly, add adhesive, adjust pH value to 2.0-3.5, and add water to 1000ml, filter, and obtain.

[0026] Specifically, the steps are as follows:

[0027] Step (1): dissolve loratadine in ethanol, stir to dissolve, and obtain solution I;

[0028] Step (2): dissolve citric acid and glycerol in propylene glycol to obtain solution II;

[0029] Step (3): slowly mix solution I, II, stir evenly, add hydroxypropyl methyl cellulose, adjust pH value to 2.3-3.1 with tartrate buffer solution, and add water to 1000ml, filter, and obtain.

[0030] Compared with the prior art, the technical scheme of the present application has the beneficial effects that:

[0031] (1) The present application improves the stability of the loratadine liniment by optimizing the stabilizer and its proportion, and the accelerated test shows that the content of related substances does not increase significantly.

[0032] (2) The present application optimizes the cosolvent, especially the combination of propylene glycol and ethanol in a certain proportion, to improve the solubility of loratadine.

[0033] (3) The present application optimizes the preparation process, dissolves loratadine and stabilizers in two different cosolvents respectively, improves the solubility, controls the pH of the solution, effectively improves the stability of the liniment, and the preparation process is simple, suitable for industrial production, and convenient for market promotion. DETAILED DESCRIPTION

[0034] Example 1: (1000ml)

[0035]

[0036] Preparation process:

[0037] Step (1): dissolve loratadine in ethanol, stir to dissolve, and obtain solution I;

[0038] Step (2): dissolve citric acid and glycerol in propylene glycol to obtain solution II;

[0039] Step (3): slowly mix solution I, II, stir evenly, add hydroxypropyl methyl cellulose, adjust pH value to 2.8 with tartrate buffer solution, and add water to 1000ml, filter, and obtain.

[0040] Example 2: (1000 ml)

[0041]

[0042] Preparation process reference example 1.

[0043] Example 3: (1000 ml)

[0044]

[0045] Preparation process reference example 1.

[0046] Example 4: (1000 ml)

[0047]

[0048] Preparation process reference example 1.

[0049] Example 5: (1000 ml)

[0050]

[0051] Preparation process reference example 1.

[0052] Example 6: (1000 ml)

[0053]

[0054] Preparation process reference example 1.

[0055] Example 7: (1000 ml)

[0056]

[0057] Preparation process reference example 1.

[0058] Example 8: (1000 ml)

[0059]

[0060]

[0061] Preparation process reference example 1, cosolvent, stabilizer, binder are replaced according to the formula.

[0062] Example 9: (1000 ml)

[0063]

[0064] Preparation process reference example 1, cosolvent, stabilizer, binder are replaced according to the formula.

[0065] Example 10: (1000ml)

[0066]

[0067] Reference example 1 of preparation process, cosolvent, stabilizer, binder according to formula corresponding replacement.

[0068] Example 11: (1000ml)

[0069]

[0070]

[0071] Preparation process:

[0072] Step (1): chlorpheniramine maleate was dissolved in ethanol, stirring to dissolve, solution I was obtained;

[0073] Step (2): citric acid, glycerol was dissolved in propylene glycol, solution II was obtained;

[0074] Step (3): solution I, II was slowly mixed, stirring uniform, adding hydroxypropyl methyl cellulose, pH value was adjusted to 2.3 with tartarate buffer solution, and water to 1000ml, filtration, was obtained.

[0075] Example 12: (1000ml)

[0076]

[0077] Preparation process:

[0078] Step (1): chlorpheniramine maleate was dissolved in ethanol, stirring to dissolve, solution I was obtained;

[0079] Step (2): citric acid, glycerol was dissolved in propylene glycol, solution II was obtained;

[0080] Step (3): solution I, II was slowly mixed, stirring uniform, adding hydroxypropyl methyl cellulose, pH value was adjusted to 3.1 with tartarate buffer solution, and water to 1000ml, filtration, was obtained.

[0081] Comparative example 1: (1000ml)

[0082]

[0083] Preparation process:

[0084] The same as example 1.

[0085] Comparative example 2: (1000ml)

[0086]

[0087] Preparation process:

[0088] The same as Example 1.

[0089] Comparative Example 3: (1000ml)

[0090]

[0091] Preparation process:

[0092] The same as Example 1.

[0093] Comparative Example 4: (1000ml)

[0094]

[0095] Preparation process:

[0096] The same as Example 1.

[0097] Comparative Example 5: (1000ml)

[0098]

[0099] Preparation process:

[0100] Step (1): chlorpheniramine maleate was dissolved in ethanol, stirred and dissolved to obtain solution I;

[0101] Step (2): citric acid and glycerol were dissolved in propylene glycol to obtain solution II;

[0102] Step (3): solution I and II were slowly mixed and stirred uniformly, hydroxypropyl methyl cellulose was added, the pH value was adjusted to 5.0 with tartarate buffer solution, and water was added to 1000ml, and then filtered.

[0103] Comparative Example 6: (1000ml)

[0104]

[0105] Preparation process:

[0106] Step (1): chlorpheniramine maleate was dissolved in ethanol, stirred and dissolved to obtain solution I;

[0107] Step (2): citric acid and glycerol were dissolved in propylene glycol to obtain solution II;

[0108] Step (3): solution I and II were slowly mixed and stirred uniformly, hydroxypropyl methyl cellulose was added, the pH value was adjusted to 5.0 with tartarate buffer solution, and water was added to 1000ml, and then filtered.

[0109] Comparative Example 7: (1000 ml)

[0110]

[0111]

[0112] Preparation process:

[0113] Step (1): chlorpheniramine maleate was dissolved in propylene glycol, stirred to dissolve, to obtain solution I;

[0114] Step (2): citric acid, glycerol was dissolved in ethanol, to obtain solution II;

[0115] Step (3): solution I, II was slowly mixed, stirred to uniform, hydroxypropyl methyl cellulose was added, pH value was adjusted to 2.8 by tartarate buffer solution, and water was added to 1000 ml, filtered, to obtain.

[0116] Comparative Example 8: (1000 ml)

[0117]

[0118] Preparation process:

[0119] Step (1): chlorpheniramine maleate was dissolved in ethanol, propylene glycol, stirred to dissolve, to obtain solution I;

[0120] Step (2): hydroxypropyl methyl cellulose was added to solution I, mixed, pH value was adjusted to 2.8 by tartarate buffer solution, and water was added to 1000 ml, filtered, to obtain.

[0121] Verification example

[0122] Stability test

[0123] The stability of liniments of Example 1, 2, 8, 11, Comparative Example 1, 2, 3, 4, 5, 6, 7 of the application was determined, and after 6 months of accelerated test, it was retested under the condition of 40℃±2℃, relative humidity 75%±5%, sampling analysis was carried out at 0, 3, 6 months, and the results are shown in Table 1.

[0124] Table 1 stability evaluation of liniments of various examples

[0125]

[0126]

[0127]

[0128] As shown in Table 1, the stability of the liniment is good when glycerol and citric acid mixture is used as stabilizer. The preparation without citric acid has a large change in related substances, and the prescription is unstable. The test proves that the preparation with citric acid has good stability. The stability test results show that the accelerated and long-term 6-month stability of the chlorpheniramine maleate liniment of the application has no significant change in properties and content. The total related substances do not obviously increase in the accelerated stability test for 6 months.

Claims

1. A chlorpheniramine hydrochloride liniment, characterized by, The chlorpheniramine eye drops have the following formula: Chlorpheniramine 1g, Propylene glycol 100g, Ethanol 20g, Citric acid 9.6g, Glycerin 7.5g, Hydroxypropyl methyl cellulose 10g, Purified water to 1000ml; The preparation method of the chlorpheniramine eye drops is as follows: Step (1): dissolving chlorpheniramine in ethanol, stirring and dissolving to obtain solution I; Step (2): dissolving citric acid and glycerin in propylene glycol to obtain solution II; Step (3): slowly mixing solution I and II, stirring uniformly, adding hydroxypropyl methyl cellulose, adjusting pH value to 2.3-3.1 with tartrate buffer solution, and adding water to 1000ml, and filtering to obtain the product.

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