Amoxicillin clavulanate potassium dry suspension composition and method for preparing the same

Abstract

The application belongs to the technical field of pharmaceutical preparations, and discloses a kind of amoxicillin potassium clavulanate dry suspension and its preparation method, the composition of amoxicillin potassium clavulanate dry suspension in the application is composed of amoxicillin, potassium clavulanate, diluent, disintegrant, glidant, lubricant, flavoring agent, pH regulator, suspending agent, aromatic agent and the like, and is prepared by adopting the preparation method of dry granulation of part of materials and direct mixing of part of materials, and directly filling mixed granules.The prescription composition and preparation method adopted by the application are simple and easy to operate, low in cost, and the prepared amoxicillin potassium clavulanate dry suspension mixed granules are good in flowability, easy to fill, small in weight difference, and similar in quality to reference preparations.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical preparations, in particular to a composition of amoxicillin and potassium clavulanate dry suspension and a preparation method thereof. BACKGROUND

[0002] Amoxicillin is chemically named as (2S, 5R, 6R)-3, 3-dimethyl-6-[(R)-(-)-2-amino-2- (4-hydroxyphenyl)acetylamino]-7-oxo-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxylic acid trihydrate, and its chemical structural formula is as follows:

[0003]

[0004] It is white or white-like crystalline powder, slightly soluble in water and methanol, extremely slightly soluble in ethanol, and has significant pH dependence. Its solubility (37℃) in each pH value dissolution medium is as follows: pH 1.2: 30.7 mg / ml, pH 4.0: 3.8 mg / ml, pH 6.8: 4.9 mg / ml, water: 3.6 mg / ml, and it belongs to Class 1 in the BCS classification published by WHO.

[0005] Potassium clavulanate is chemically named as (Z)-(2R, 5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-l-azabicyclo[3.2.0]heptane-2-carboxylic acid potassium salt, and its chemical structural formula is as follows:

[0006]

[0007] It is white to slightly yellow crystalline powder, slightly smelly, extremely moisture-absorbing, extremely soluble in water, easily soluble in methanol, slightly soluble in ethanol, insoluble in diethyl ether, and has no pH dependence. Its solubility (37℃) in each pH value dissolution medium is as follows: pH 1.2: 2.5 g / ml, pH 4.0: 2.5 g / ml, pH 6.8: 2.5 g / ml, water: 2.5 g / ml, and it belongs to Class 1 or Class 3 in the BCS classification published by WHO.

[0008] Amoxicillin is a semi-synthetic broad-spectrum antibiotic, which has effect on many gram-positive bacteria and gram-negative bacteria, but is easy to produce drug resistance for Haemophilus influenzae, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, and so on. Clavulanic acid is a β-lactam structure similar to penicillin, which has inhibitory effect on the common β-lactamase existing in microorganisms. Therefore, amoxicillin and potassium clavulanate are used together in clinic, so as to expand and enhance the antibacterial spectrum of amoxicillin. The compound preparation has a compound composition ratio of 2:1, 4:1, 7:1, 8:1, and 14:1. The compound preparation with a ratio less than 2:1 is used for general infection, and the compound preparation with a ratio greater than 4:1 is used for severe or respiratory tract infection. The compound preparation with a ratio of 7:1 can be used for treating infection caused by sensitive strains of microorganisms.

[0009] At present, the compound preparation of amoxicillin and potassium clavulanate mainly includes tablets, capsules and dry suspensions. Since tablets and capsules are not suitable for children, the elderly and patients with swallowing difficulties, the dry suspension shows strong clinical compliance. The dry suspension can be administered in divided doses, is convenient to take, and has high dissolution rate. However, amoxicillin and potassium clavulanate have poor stability in acid-base medium, and patients are prone to adverse reactions after taking the drug. Therefore, it is difficult to ensure the stability of the product quality in the development of the preparation.

[0010] Patent CN103127099A discloses a dry suspension of amoxicillin and potassium clavulanate (4:1) and a production process thereof. The dry suspension is prepared by mixing amoxicillin, a phospholipid complex of potassium clavulanate containing silicon dioxide, hydroxypropyl methyl cellulose, sodium dodecyl sulfate and the like. Although the stability of the dry suspension is improved, the preparation process is complex. The potassium clavulanate and the phospholipid are dissolved in chloroform, silicon dioxide is added, stirring is performed, chloroform is evaporated under reduced pressure at a temperature below 40℃, and then the mixture is sieved and mixed with other materials to obtain the dry suspension. The preparation process needs to use organic solvent chloroform, and there is a safety hazard of organic solvent residue.

[0011] Patent CN102614174A discloses a dry suspension containing amoxicillin and potassium clavulanate, which comprises the following components: amoxicillin 200 parts, potassium clavulanate 20-50 parts, sodium carboxymethyl cellulose 80-115 parts, cyclodextrin 1500-1600 parts, polyethylene glycol 6000 42-55 parts, mixed flavoring 18-25 parts, and magnesium stearate 4-8 parts. Although the patent solves the degradation problem of potassium clavulanate caused by strong hygroscopicity, the large amount of auxiliary materials leads to large weight of each package of the drug and high cost.

[0012] Patent CN110859801 A discloses a kind of amoxicillin clavulanate potassium dry suspension and its preparation method, the amoxicillin clavulanate potassium dry suspension is composed of the following parts of raw and auxiliary materials: amoxicillin 16-18 parts, amoxicillin clavulanate potassium mixed powder 10-12 parts, sucrose 70-85 parts, xanthan gum 1-9 parts, hydroxypropyl methyl cellulose 2-10 parts, aspartate 2-3 parts, silicon dioxide 1-12 parts, fruit milk essence 1-2 parts;Wherein the mass ratio of amoxicillin and clavulanate potassium in amoxicillin clavulanate potassium mixed powder is 2:1.Its preparation process is powder direct filling, but the particle size of mixed powder is fine, and the bulk density is small, and high precision is required for filling equipment to ensure the quality of product. SUMMARY

[0013] Based on the deficiencies of the prior art, the present application provides a composition of amoxicillin clavulanate potassium dry suspension and its preparation method, which is composed of common solid pharmaceutical excipients, and the preparation process is a combination of dry granulation and direct mixing of part of the materials, which is simple in operation steps, can ensure the quality of the product and the flowability of the mixed granules, and solves the problems of unstable filling amount caused by the properties of mixed granular powder during filling.The prescription process designed in the present application can be used for multi-dose bottle packaging and single-dose bag packaging of mixed granules according to market, patient and production needs.

[0014] The amoxicillin clavulanate potassium dry suspension composition comprises the following components: amoxicillin, clavulanate potassium, diluent, disintegrant, glidant, lubricant, flavoring agent, pH adjuster, suspending agent and aromatic agent.

[0015] Specifically, the weight ratio of amoxicillin to clavulanate is 1:2-10, preferably 1:7.

[0016] Specifically, the amoxicillin clavulanate potassium dry suspension contains the following components: amoxicillin 35%~70%, clavulanate potassium 5%~10%, diluent 10%~35%, disintegrant 1%~10%, glidant 1%~5%, lubricant 0.5%~2%, flavoring agent 1%~5%, suspending agent 1.5%~20%, pH adjuster 0.05%~0.5%, and aromatic agent 0.01%~10%.

[0017] In the above-mentioned amoxicillin clavulanate potassium dry suspension:

[0018] The diluent is selected from one or more of malt dextrin, starch, pregelatinized starch, lactose, microcrystalline cellulose, mannitol and sorbitol;Preferably, the diluent is selected from malt dextrin, starch, lactose, microcrystalline cellulose and mannitol.

[0019] The disintegrant is selected from one or more of crospovidone, sodium carboxymethyl starch, croscarmellose sodium, low-substituted hydroxypropyl methylcellulose, preferably sodium carboxymethyl starch, crospovidone, croscarmellose sodium.

[0020] The glidant is selected from one or more of silicon dioxide, colloidal silicon dioxide, talc, preferably silicon dioxide, colloidal silicon dioxide.

[0021] The lubricant is selected from one or more of talc, magnesium stearate, glyceryl behenate, stearic acid, sodium stearyl fumarate, silicon dioxide, colloidal silicon dioxide, preferably magnesium stearate, silicon dioxide, colloidal silicon dioxide.

[0022] The flavoring agent is selected from one or more of aspartame, sucrose, sodium alginate, preferably aspartame, sucrose.

[0023] The suspending agent is selected from one or more of colloidal silicon dioxide, silicon dioxide, acacia, sodium alginate, agar, sodium carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, xanthan gum, preferably xanthan gum, colloidal silicon dioxide, silicon dioxide, hydroxypropyl methylcellulose.

[0024] The pH adjuster is selected from one or more of succinic acid, citric acid, lactic acid, tartaric acid, fumaric acid, acetic acid, hydrochloric acid, phosphoric acid, malic acid; preferably succinic acid, citric acid.

[0025] The flavoring agent is selected from one or more of aspartame, sucrose, sodium alginate, preferably aspartame, sucrose.

[0026] The present application also provides a preparation process of the above-mentioned amoxicillin and potassium clavulanate dry suspension, which mainly comprises the following steps:

[0027] Step 1: mixing amoxicillin, potassium clavulanate with diluent, disintegrant, glidant, lubricant, and then performing dry granulation;

[0028] Step 2: mixing the granules prepared in step 1 with flavoring agent, suspending agent, pH adjuster, and flavoring agent, and then obtaining the product.

[0029] Specifically, the preparation method comprises the following steps:

[0030] Step 1: weighing the raw and auxiliary materials according to the prescription composition, wherein the maltodextrin and microcrystalline cellulose are low-moisture.

[0031] Step 2, mixing granulation: ambient temperature 18-26℃, ambient humidity ≤35%, first put amoxicillin, potassium clavulanate, malt dextrin or microcrystalline cellulose, sodium carboxymethyl starch, silicon dioxide, magnesium stearate into the mixer, set the mixer speed 40Hz, mix for 10 minutes. Then put the mixed powder into the dry granulator, control the roller speed 5rpm-30rpm, roller pressure 45bar-90bar, the thickness of the material plate 1.0mm-1.5mm, the first level of granulation speed 80rpm-150rpm, the second level of granulation speed 100rpm-180rpm, 30 mesh sieve granulation, collect the granules;

[0032] Step 3, total mixing: mix the granules obtained in step 2 with xanthan gum, aspartame, colloidal silicon dioxide (sifted through a 60 mesh sieve before use), succinic acid, and essence evenly;

[0033] Step 4, detect the content of the mixed granules and calculate the theoretical loading

[0034] Step 5, according to the production requirements, carry out multi-dose or single-dose packaging of the mixed granules, and obtain the product. DETAILED DESCRIPTION

[0035] The application will be further described below in combination with examples, and the examples are given only to illustrate the application, but are not limited by the examples.

[0036] Example 1

[0037]

[0038] Preparation method:

[0039] 1. Weigh the raw and auxiliary materials according to the prescription composition, wherein the malt dextrin is low in moisture.

[0040] 2. Mixing granulation: ambient temperature 18-26℃, ambient humidity ≤35%, first put malt dextrin, silicon dioxide, amoxicillin, potassium clavulanate, sodium carboxymethyl starch, and magnesium stearate into the mixer, set the mixer speed 40Hz, mix for 10 minutes. Then put the mixed powder into the dry granulator, control the roller speed 5rpm-30rpm, roller pressure 45bar-90bar, the thickness of the material plate 1.0mm-1.5mm, the first level of granulation speed 80rpm-150rpm, the second level of granulation speed 100rpm-180rpm, 30 mesh sieve granulation, collect the granules;

[0041] 3. Total mixing: mix the granules obtained in step 2 with xanthan gum, aspartame, colloidal silicon dioxide (sifted through a 60 mesh sieve before use), succinic acid, and essence evenly;

[0042] 4. Detect the content of the mixed granules and calculate the theoretical loading

[0043] 5. According to the production needs, the mixed granules are packed in glass bottles with 14 doses or in composite bags with single dose.

[0044] * If colloidal silicon dioxide is used in the examples, it should be passed through a 60 mesh sieve before use.

[0045] Example 2

[0046]

[0047] Preparation method: refer to Example 1.

[0048] Example 3

[0049]

[0050]

[0051] Preparation method: refer to Example 1.

[0052] Example 4

[0053]

[0054] Preparation method: refer to Example 1.

[0055] Example 5

[0056]

[0057] Preparation method: refer to Example 1.

[0058] Example 6

[0059]

[0060]

[0061] Preparation method: refer to Example 1.

[0062] Example 7

[0063]

[0064] Preparation method: refer to Example 1.

[0065] Example 8

[0066]

[0067]

[0068] Preparation method: refer to Example 1.

[0069] Example 9

[0070]

[0071] Preparation method: refer to example 1.

[0072] Example 10

[0073]

[0074] Preparation method: refer to example 1.

[0075] Example verification:

[0076] Take the amoxicillin clavulanate potassium dry suspension prepared in examples 1-3, and use aluminum plastic composite bag small bag plus aluminum plastic composite bag form to package single dose, and carry out accelerated stability investigation, investigation condition: temperature 30℃, relative humidity: 65%±5%. The detection results are shown in table 1, 2, 3, 4, 5

[0077] Table 1: the detection results of amoxicillin clavulanate potassium dry suspension of examples 1-3 and reference preparation at 0 days

[0078]

[0079]

[0080] Dissolution: the dissolution amount in 30 minutes with water as dissolution medium, the limit is 80% of the labeled amount.

[0081] From the detection results, it can be seen that the appearance and quality of the products prepared according to the prescription composition and preparation method of examples 1-3 are consistent with the reference preparation, and the results of powder property detection show that the bulk density and flowability of the dry suspension prepared by the process are better than those of the reference preparation, which can better guarantee the quality of the product during filling process, and better filling.

[0082] Table 2: the detection results of accelerated stability of amoxicillin clavulanate potassium dry suspension of example 1

[0083]

[0084] Table 3: the detection results of accelerated stability of amoxicillin clavulanate potassium dry suspension of example 2

[0085]

[0086]

[0087] Table 4: the detection results of accelerated stability of amoxicillin clavulanate potassium dry suspension of example 3

[0088]

[0089] Table 5: Summary of the results of the accelerated stability test of the reference formulation amoxicillin clavulanate potassium dry suspension

[0090]

[0091] From the above table, it can be seen that the amoxicillin clavulanate potassium dry suspensions obtained in Examples 1-3 and the reference formulation have no substantial changes in the contents of amoxicillin and clavulanate potassium, dissolution rate, related substances and fluorescent substances under the accelerated storage condition, and the total impurities only increase by 0.2%.

Claims

1. A dry suspension of amoxicillin clavulanate potassium, characterized in that, The amoxicillin-clavulanate potassium dry suspension contains the following components: 35%–70% amoxicillin, 5%–10% potassium clavulanate, 10%–35% diluent, 1%–10% disintegrant, 1%–5% flow aid, 0.5%–2% lubricant, 1%–5% flavoring agent, 0.05%–0.5% pH adjuster, 1.5%–20% suspending agent, and 0.01%–10% flavoring agent; the weight ratio of amoxicillin to clavulanate is 2–10:1; the diluent is selected from one or more of maltodextrin, starch, pregelatinized starch, lactose, microcrystalline cellulose, mannitol, and sorbitol; the disintegrant is sodium carboxymethyl starch; and the flow aid is selected from one or more of silica, colloidal silica, and talc. The lubricant is selected from one or more of talc, magnesium stearate, glyceryl behenate, stearic acid, sodium stearate fumarate, silica, and colloidal silica; the flavoring agent is selected from one or more of aspartame, sucrose, and sodium alginate; the suspending agent is selected from one or more of colloidal silica, silica, gum arabic, sodium alginate, agar, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and xanthan gum; the pH adjuster is selected from one or more of succinic acid, citric acid, lactic acid, tartaric acid, fumaric acid, acetic acid, hydrochloric acid, phosphoric acid, and malic acid; and the flavoring agent is selected from one or more of peppermint flavoring, orange flavoring, raspberry powder flavoring, lemon flavoring, strawberry flavoring, banana flavoring, cream flavoring, and ginger oil flavoring.

2. The amoxicillin clavulanate potassium dry suspension as described in claim 1, characterized in that, The weight ratio of amoxicillin to clavulanic acid is 7:

1.

3. The amoxicillin clavulanate potassium dry suspension as described in claim 1, characterized in that, The diluent is maltodextrin, starch, lactose, microcrystalline cellulose, and mannitol.

4. The amoxicillin clavulanate potassium dry suspension as described in claim 1, characterized in that, The disintegrant is sodium carboxymethyl starch.

5. The amoxicillin clavulanate potassium dry suspension as described in claim 1, characterized in that, The flow aid is silica or colloidal silica.

6. The amoxicillin clavulanate potassium dry suspension as described in claim 1, characterized in that, The lubricant is magnesium stearate, silicon dioxide, or colloidal silicon dioxide.

7. The amoxicillin clavulanate potassium dry suspension as described in claim 1, characterized in that, The flavoring agent is aspartame and sucrose; the suspending agent is xanthan gum, colloidal silica, silica, and hydroxypropyl methylcellulose.

8. The amoxicillin clavulanate potassium dry suspension as described in claim 1, characterized in that, The pH adjuster is succinic acid and citric acid; the fragrance is orange essence and raspberry powder essence.

9. The amoxicillin clavulanate potassium dry suspension according to any one of claims 1-2, characterized in that, The preparation process of the amoxicillin clavulanate potassium dry suspension mainly includes the following steps: Step 1: Mix amoxicillin, potassium clavulanate, diluent, disintegrant, suspending agent, and lubricant, and then perform dry granulation; Step 2: Mix the granules obtained in Step 1 with flavoring agent, suspending agent, pH adjuster and flavoring agent to obtain the final product.

Images