A process for the preparation of effervescent granules comprising a composition of phenylephrine hydrochloride

Abstract

The application discloses a preparation process of effervescent granules of a composition containing phenylephrine hydrochloride, which is prepared by taking phenylephrine hydrochloride as a main active ingredient, and by adding antiallergic agents, expectorants, antitussives, antipyretics, anti-inflammatory agents and combinations thereof. In order to prevent degradation of phenylephrine hydrochloride, the phenylephrine hydrochloride is first wrapped with PEG together with an alkali source, and then mixed with other components to prepare the effervescent granules. The effervescent granules prepared by the method have the advantages of high drug stability, rapid effect, high bioavailability, convenient carrying and low cost, and are suitable for children, the elderly and patients who cannot swallow solid preparations.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparation, and particularly relates to a preparation process of effervescent granules containing a composition of phenylephrine hydrochloride. BACKGROUND

[0002] Respiratory diseases include a variety of diseases, which are mostly caused by viruses or bacteria, such as cold and flu, and allergic rhinitis, etc. The main symptoms are fever, nasal congestion, runny nose, cough, sneezing or headache. If not treated in time, many complications can be caused, which seriously harm people's health.

[0003] There are many solid preparations containing phenylephrine hydrochloride for treating cold, and the dosage forms are various, such as tablets, capsules, granules, etc. As known by those skilled in the art, when preparing suitable products, the first problem to be considered is the stability of the drug and the release rate of the drug. Therefore, the selection of the dosage form and the setting of the process parameters are challenging work. If the prescription is unreasonable or the selection of the excipients and the process conditions are not considered during preparation, the active ingredients in the drug can be degraded, which can reduce the therapeutic effect and cause side effects. SUMMARY

[0004] SUMMARY:

[0005] The preparation process of the effervescent granules containing a composition of phenylephrine hydrochloride is prepared by using alpha adrenergic receptor agonist phenylephrine hydrochloride as the main active ingredient, and combining with antiallergic drugs, expectorants, antitussives, antipyretics, anti-inflammatory agents and their combinations. In order to prevent the degradation of phenylephrine hydrochloride, the phenylephrine hydrochloride is first coated with PEG and then mixed with other ingredients to prepare the effervescent granules. Through scientific analysis methods such as orthogonal test, the present application has prepared the drug with stability, rapid effect, high bioavailability, convenient carrying and low cost, which is suitable for children, the elderly and patients who cannot swallow solid preparations.

[0006] SUMMARY:

[0007] Unless otherwise specified, all weights in this paper are weighed at 18-25℃ for the active pharmaceutical ingredients in the composition and the excipients required for preparing the effervescent granules.

[0008] Unless otherwise specified, all percentages in this paper are calculated by weight, and all percentages are based on the total composition.

[0009] The present application discloses various embodiments in the specification examples, all combinations of which are implementable for those skilled in the art, some of which are preferred.

[0010] To prepare effervescent granules, the specific embodiments of the present application are as follows:

[0011] The preparation process of the effervescent granules containing the phenylephrine hydrochloride composition includes the following components and proportions:

[0012] Drug or excipient name Amount (%) Drug or excipient name Amount (%) Acetaminophen 1-5 Binder 1-10 Chlorpheniramine maleate 0-0.05 Filling agent 30-65 Dextromethorphan hydrobromide 0-0.05 Coating agent (lubricant) 1-5 Phenylephrine hydrochloride 0-0.1 Flavor 0-0.5 Acid source 10-25 Flavoring agent 0.5-5 Antioxidant 1-8 Colorant 0.1-0.5 Base source 10-20 Solvent q.s.

[0013] The preparation process of the effervescent granules containing the phenylephrine hydrochloride composition can also include the following components and proportions:

[0014] Drug or excipient name Amount (%) Drug or excipient name Amount (%) Acetaminophen 1-5 Binder 1-13 Chlorpheniramine maleate 0-0.05 Filling agent 30-60 Dextromethorphan hydrobromide 0-0.05 Coating agent (lubricant) 1-5 Phenylephrine hydrochloride 0-0.1 Flavor 0-0.4 Acid source 10-20 Flavoring agent 0.5-3 Antioxidant 1-8 Colorant 0.1-0.4 Base source 10-15 Solvent q.s.

[0015] The preparation process of the effervescent granules containing the phenylephrine hydrochloride composition can also include the following components and proportions:

[0016] Drug or excipient name Amount (%) Drug or excipient name Amount (%) Acetaminophen 1-5 Binder 5-13 Chlorpheniramine maleate 0-0.05 Filling agent 30-55 Dextromethorphan hydrobromide 0-0.05 Coating agent (lubricant) 1-4 Phenylephrine hydrochloride 0-0.1 Flavor 0-0.3 Acid source 15-20 Flavoring agent 1-3 Antioxidant 1-8 Colorant 0.1-0.3 Base source 12-15 Solvent q.s.

[0017] The acid source includes but is not limited to one or more of the following: citric acid, tartaric acid, fumaric acid, adipic acid, malic acid.

[0018] The alkali source includes but is not limited to one or more of the following: sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium carbonate.

[0019] The coating agent (which can also be used as a lubricant) includes but is not limited to one or more of the following: PEG4000 or PEG6000.

[0020] The filler includes but is not limited to one or more of the following: lactose, mannitol, sucrose, glucose.

[0021] The binder includes but is not limited to one or more of the following: PVP, ethanol, carboxymethyl cellulose, povidone K30.

[0022] The flavoring agent includes but is not limited to one or more of the following: peppermint oil, menthol, stevioside, sucralose.

[0023] The essence includes but is not limited to one or more of the following: sweet orange essence, lemon essence, orange essence, apple essence, pineapple essence.

[0024] The pigment includes but is not limited to one or more of the following: brilliant blue, orange yellow, orange red.

[0025] The antioxidant includes but is not limited to one or more of the following: vitamin C, sodium metabisulfite, propyl gallate.

[0026] The preparation process of the effervescent granules containing the phenylephrine hydrochloride composition,

[0027] The solvent includes purified water, deionized water, distilled water.

[0028] The preparation process is as follows:

[0029] 1. Raw material processing:

[0030] 1.1 The paracetamol is crushed and passed through a 150-200 mesh sieve to obtain paracetamol fine powder for use;

[0031] 1.2 The coating agent (which can also be used as a lubricant) is crushed and passed through a 150-160 mesh sieve to obtain coating agent fine powder for use;

[0032] 1.3 The binder is mixed with a certain amount of solvent to prepare a solution, and the binder solution is obtained for use;

[0033] 2. Preparation of acidic granules:

[0034] 2.1 The paracetamol fine powder, chlorpheniramine maleate, dextromethorphan hydrobromide are mixed uniformly to obtain a raw material mixture for use;

[0035] 2.2 The antioxidant, filler, and flavoring agent are mixed uniformly to obtain an auxiliary material mixture for use;

[0036] 2.3 The raw material mixture, auxiliary material mixture, and acid source are mixed uniformly, and the binder solution is added to prepare a soft material, granulated, dried, and sieved to obtain acid granules for use;

[0037] 3. Preparation of base granules:

[0038] 3.1 The coating agent is heated and dissolved at 60-70°C, and then the epinephrine hydrochloride and the base source are added and stirred uniformly, and then cooled, crushed, and sieved to obtain a base source coating;

[0039] 3.2 The base source coating is subjected to dry granulation, sieved, and obtained as base granules for use;

[0040] 4. Under the conditions of a temperature of 18-26°C and a humidity of less than 60%, a small amount of acid granules is added with an equal amount of increasing colorant and flavoring agent, and then the remaining acid granules and base granules are added and mixed uniformly, and then packaged to obtain the product.

[0041] The granulation refers to granulation with a swing granulator, and the granulation mesh size is 18-30 mesh;

[0042] The drying refers to drying under reduced pressure or hot air circulation drying at a temperature not higher than 60°C;

[0043] The granulation refers to granulation with a swing granulator, and the granulation mesh size is 18-30 mesh;

[0044] The sieving refers to sieving out the particles that do not pass through the first sieve, and then sieving out the particles that pass through the fifth sieve from the particles that pass through the first sieve, and taking the particles that pass through the first sieve but cannot pass through the fifth sieve.

[0045] In addition to the effervescent granules, the effervescent tablets can also be prepared.

[0046] Beneficial effects

[0047] The preparation process of the effervescent granules of the composition containing phenylephrine hydrochloride of the present application is that, in order to prevent phenylephrine hydrochloride from degrading, the phenylephrine hydrochloride is first wrapped with a wrapping agent and then mixed with other ingredients to prepare the effervescent granules. The granules prepared by the present application have strong drug stability, rapid effect, high bioavailability, convenient carrying and low cost, and are suitable for children, the elderly and patients who cannot swallow solid preparations. DETAILED DESCRIPTION

[0048] The following examples further describe and demonstrate embodiments within the scope of the present application, which are given for illustrative purposes only and are not to be construed as limiting the present application.

[0049] The present application can be prepared by the following non-limiting example method:

[0050] Example 1

[0051] Composition and ratio:

[0052] Drug or excipient name Amount (%) Drug or excipient name Amount (%) Acetaminophen 3.25 PVP 3 Chlorpheniramine maleate 0.02 Lactose 55 Dextromethorphan hydrobromide 0.01 PEG 6000 4.0 Phenylephrine hydrochloride 0.05 Orange flavor 0.37 Tartaric acid 18.0 Stevioside 1.0 Sodium metabisulfite 3.2 Brilliant blue 0.1 Sodium bicarbonate 12.0 Purified water q.s.

[0053] The preparation process is as follows:

[0054] 1. Raw material treatment:

[0055] 1.1 The acetaminophen is crushed and passed through a 150-mesh sieve to obtain acetaminophen fine powder for standby;

[0056] 1.2 The PEG6000 is crushed and passed through a 150-mesh sieve to obtain wrapping agent fine powder for standby;

[0057] 1.3 The PVP is added with a certain amount of purified water to prepare a solution to obtain a binder aqueous solution for standby

[0058] 2. Preparation of acidic granules:

[0059] 2.1 The acetaminophen fine powder, chlorpheniramine maleate and dextromethorphan hydrobromide are mixed uniformly to obtain a raw material mixture for standby;

[0060] 2.2 The sodium pyrosulfite, lactose and stevioside are mixed uniformly to obtain an auxiliary material mixture for standby;

[0061] 2.3 Mix the raw material mixture, the auxiliary material mixture and the acid source uniformly, add the adhesive aqueous solution to make a soft material, granulate with a 24-mesh screen, dry at 55°C under reduced pressure, size with a 24-mesh screen, sieve, obtain the acid granules, and reserve;

[0062] 3. Preparation of the base granules:

[0063] 3.1 After the PEG6000 is heated and dissolved at 60-70°C, add the phenylephrine hydrochloride and the sodium bicarbonate, stir uniformly, cool, crush, sieve with a 100-mesh screen, obtain the base source coating, and reserve;

[0064] 3.2 Dry granulate the base source coating, size with a 24-mesh screen, sieve, obtain the base granules, and reserve;

[0065] 4. Under the conditions of a temperature of 18-26°C and a humidity of below 60%, take a small amount of the acid granules, add the brilliant blue and the orange flavor in equal increments respectively, mix uniformly, then add the remaining acid granules and the base granules in sequence and continue to mix uniformly, package, and obtain the product.

[0066] Example 2

[0067] Drug or excipient name Amount (%) Drug or excipient name Amount (%) Acetaminophen 4.0 Carboxymethylcellulose 10.0 Chlorpheniramine maleate 0.03 Sucrose 44 Dextromethorphan hydrobromide 0.03 PEG 4000 4.0 Phenylephrine hydrochloride 0.04 Lemon flavor 0.2 Citric acid 18.0 Stevioside 2.0 Sodium metabisulfite 1.5 Crocins 0.2 Potassium carbonate 16.0 Purified water q.s.

[0068] The preparation process is as follows:

[0069] 1. Raw material treatment:

[0070] 1.1 Crush the acetaminophen to obtain acetaminophen fine powder with a particle size of 150-200 mesh, and reserve;

[0071] 1.2 Crush the PEG4000 to obtain coating agent fine powder with a particle size of 150 mesh, and reserve;

[0072] 1.3 Prepare an adhesive aqueous solution by adding a certain amount of purified water to carboxymethyl cellulose, and reserve;

[0073] 2. Preparation of the acid granules:

[0074] 2.1 Mix the acetaminophen fine powder, chlorpheniramine maleate and dextromethorphan hydrobromide uniformly to obtain a raw material mixture, and reserve;

[0075] 2.2 Mix the sodium pyrosulfite, sucrose and steviosin uniformly to obtain an auxiliary material mixture, and reserve;

[0076] 2.3 Mix the raw material mixture, the auxiliary material mixture and the citric acid uniformly, add the adhesive aqueous solution to make a soft material, granulate with a 24-mesh screen, dry at 60°C, size with a 24-mesh screen, sieve, obtain the acid granules, and reserve;

[0077] 3. Preparation of the base granules:

[0078] 3.1 The PEG4000 is heated and dissolved at 60-70°C, then the phenylephrine hydrochloride and potassium carbonate are added and stirred until uniform. The mixture is allowed to cool, then ground and passed through a 100 mesh sieve to obtain the base source coating;

[0079] 3.2 The base source coating is dry granulated and sieved through a 24 mesh sieve to obtain the base granules, which are reserved for later use;

[0080] 4. Under the conditions of 18-26°C and humidity below 60%, a small amount of the acid granules is taken and mixed with an equal amount of orange and lemon essence in an incremental manner. The remaining acid granules and base granules are then added and mixed until uniform. The mixture is packaged to obtain the product.

[0081] Example 3

[0082] Drug or excipient name Amount (%) Drug or excipient name Amount (%) Acetaminophen 3.50 PVP 10.00 Chlorpheniramine maleate 0.04 Sucrose 42.87 Dextromethorphan hydrobromide 0.01 PEG 6000 3.00 Phenylephrine hydrochloride 0.08 Orange flavor 0.40 Fumaric acid 20.00 Sucralose 1.00 Propyl gallate 5.00 Brilliant blue 0.10 Sodium carbonate 14.00 Solvent q.s.

[0083] The preparation process is as follows:

[0084] 1. Treatment of raw materials:

[0085] 1.1 The acetaminophen is ground and passed through a 150 mesh sieve to obtain the acetaminophen powder, which is reserved for later use;

[0086] 1.2 The PEG6000 is ground and passed through a 150-160 mesh sieve to obtain the coating agent powder, which is reserved for later use;

[0087] 1.3 The PVP is dissolved in a certain amount of solvent to obtain the binder solution, which is reserved for later use

[0088] 2. Preparation of acid granules:

[0089] 2.1 The acetaminophen powder, chlorpheniramine maleate, and dextromethorphan hydrobromide are mixed uniformly to obtain the raw material mixture, which is reserved for later use;

[0090] 2.2 The propyl gallate, sucrose, and sucralose are mixed uniformly to obtain the excipient mixture, which is reserved for later use;

[0091] 2.3 The raw material mixture, excipient mixture, and acid source are mixed uniformly, and the binder solution is added to form a soft material. The material is granulated through a 24 mesh sieve and dried at 60°C. The granules are sieved through a 24 mesh sieve to obtain the acid granules, which are reserved for later use;

[0092] 3. Preparation of base granules:

[0093] 3.1 The PEG6000 is heated and dissolved at 60-70°C, then the phenylephrine hydrochloride and potassium carbonate are added and stirred until uniform. The mixture is allowed to cool, then ground and passed through a 100 mesh sieve to obtain the base source coating;

[0094] 3.2 The base source coating is dry granulated and sieved through a 24 mesh sieve to obtain the base granules, which are reserved for later use;

[0095] 4. Under the conditions of temperature 18-26℃ and humidity below 60%, a small amount of acid granules is taken, and equal amount of increments of bright blue and orange essence are added respectively, mixed, and then the remaining acid granules and base granules are added and mixed, packaged, and obtained.

[0096] Example 4

[0097] The effervescent granules prepared in Example 1 are subjected to dissolution rate detection of phenylephrine hydrochloride, chlorpheniramine maleate, acetaminophen and dextromethorphan hydrobromide respectively, and the dissolution rates of the drugs at different times are compared.

[0098] The detection results are shown in the following table

[0099] Dissolution rate at different times

[0100]

[0101] From the detection results, it can be seen that the suspension prepared in Example 1 has good dissolution effect, which shows that the preparation process of the effervescent granules prepared by the present application is reasonable.

[0102] Example 5

[0103] The content of phenylephrine hydrochloride is taken as the detection object, and the stability of the effervescent granules prepared in Examples 1 to 3 is investigated.

[0104] Method:

[0105] 10g of the suspension prepared in Examples 1 to 3 is taken respectively, placed in a clean container, sealed, and placed in a constant temperature box, and stored under the conditions of 25℃, relative humidity 60%, 30℃, relative humidity 60%, 35℃, relative humidity 50%, and 40℃, relative humidity 50%, and the content of phenylephrine hydrochloride is checked at different times.

[0106]

[0107] Conclusion: The degradation rates of Examples 1 to 3 are low after 3 months and 6 months of stability test, which shows that the effervescent granules prepared by the present application have strong stability.

Claims

1. A process for preparing effervescent granules comprising phenylephrine hydrochloride composition, wherein the effervescent granules comprise the following components and ratios: acetaminophen 3.25-4%, chlorpheniramine maleate 0.02-0.04%, dextromethorphan hydrobromide 0.01-0.03%, phenylephrine hydrochloride 0.04-0.08%, acid source 10-25%, base source 10-20%, antioxidant 1-10%, binder 1-15%, filler 30-65%, coating agent 1-5%, essence 0.2-0.4%, flavoring agent 0.5-5%, pigment 0.1-0.5%, solvent in proper amount. The coating agent is PEG4000 or PEG6000 or a mixture of the two. The process for preparing the effervescent granules comprising phenylephrine hydrochloride composition is as follows: 1.1 Raw material processing: 1.1.1 Crush acetaminophen and pass it through a 150-200 mesh sieve to obtain acetaminophen fine powder for later use. 1.1.2 Crush the coating agent and pass it through a 150-160 mesh sieve to obtain coating agent fine powder for later use. 1.1.3 Prepare a binder solution by adding a certain amount of solvent to the binder. 1.2 Preparation of acid granules: 1.2.1 Mix acetaminophen fine powder, chlorpheniramine maleate, and dextromethorphan hydrobromide uniformly to obtain a raw material mixture for later use. 1.2.2 Mix antioxidant, filler, and flavoring agent uniformly to obtain an auxiliary material mixture for later use. 1.2.3 Mix the raw material mixture, auxiliary material mixture, and acid source uniformly, add the binder solution to make a soft material, granulate, dry, size, and sieve to obtain acid granules for later use. 1.3 Preparation of base granules: 1.3.1 Heat and melt the coating agent at 60-70°C, then add phenylephrine hydrochloride and base source, stir uniformly, cool, crush, and sieve to obtain base source coating. 1.3.2 The alkali source coating is dry granulated, sized, and sieved to obtain alkali granules for later use; 1.4 Under conditions of temperature 18-26℃ and humidity below 60%, take a small amount of acid granules and add pigment and fragrance in equal increments. After mixing, add the remaining acid granules and alkali granules in sequence and continue to mix evenly. Package to obtain the final product.

2. The preparation process of effervescent granules containing a composition of desoxyrepinephrine hydrochloride as described in claim 1, characterized in that... The acid source includes, but is not limited to, one or a mixture of two or more of citric acid, tartaric acid, fumaric acid, adipic acid, and malic acid.

3. The preparation process of effervescent granules containing a composition of desoxyrepinephrine hydrochloride as described in claim 1, characterized in that... The alkali source includes, but is not limited to, one or a mixture of two or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and calcium carbonate.

4. The preparation process of effervescent granules containing a composition of desoxyrepinephrine hydrochloride as described in claim 1, characterized in that... The filler includes, but is not limited to, one or a mixture of two or more of lactose, mannitol, sucrose, and glucose.

5. The preparation process of effervescent granules containing a composition of desoxyrepinephrine hydrochloride as described in claim 1, characterized in that... The adhesive includes, but is not limited to, one or a mixture of two or more of PVP, ethanol, and carboxymethyl cellulose.

6. The preparation process of effervescent granules containing a composition of desoxyrepinephrine hydrochloride as described in claim 1, characterized in that... The flavoring agents include, but are not limited to, peppermint oil, stevia, and sucralose, or a mixture of two or more of these.

7. The preparation process of effervescent granules containing a composition of desoxyrepinephrine hydrochloride as described in claim 1, characterized in that... The flavorings include, but are not limited to, one or a mixture of two or more of the following: sweet orange flavoring, lemon flavoring, tangerine flavoring, apple flavoring, and pineapple flavoring.

8. The preparation process of effervescent granules containing a composition of desoxyrepinephrine hydrochloride as described in claim 1, characterized in that... The pigments include, but are not limited to, one or a mixture of two or more of brilliant blue, orange yellow, and orange red.

9. The preparation process of effervescent granules containing a composition of desoxyrepinephrine hydrochloride as described in claim 1, characterized in that... The antioxidants include, but are not limited to, one or a mixture of two or more of vitamin C, sodium metabisulfite, and propyl gallate.

10. The preparation process of an effervescent granule containing a composition of norepinephrine hydrochloride as described in claim 1, characterized in that... The solvent includes either deionized water or distilled water.

11. The process of claim 1 wherein The granulation refers to granulation using a swing granulator, with a granulation mesh size of 18-30 mesh.

12. The process of claim 1 wherein The drying process refers to vacuum drying or hot air circulation drying at a temperature not exceeding 60°C.

13. The process of claim 1 wherein The granulation refers to granulation using a gyratory granulator, with a granulation mesh size of 18-30 mesh.

14. The process of claim 1 wherein The sieving process refers to first using a No. 1 sieve to remove particles that do not pass through, then using a No. 5 sieve to remove some of the particles that passed through the No. 1 sieve, and finally using the particles that passed through the No. 1 sieve but could not pass through the No. 5 sieve.

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