Pharmaceutical composition as well as preparation method and application thereof

Abstract

The invention discloses a pharmaceutical composition as well as a preparation method and application thereof. The traditional Chinese medicine composition comprises an active pharmaceutical ingredient, a filling agent containing a cellulose-lactose co-treated substance and a stabilizer containing gel-method silicon dioxide, wherein the active pharmaceutical ingredient comprises at least one of penicillin or sutacillin. According to the invention, the filler containing the cellulose-lactose co-treated material and the stabilizer containing the gel-method silicon dioxide are simultaneously used in the pharmaceutical composition, especially in the preparation of pharmaceutical tablets, the required pressure is small, and the obtained pharmaceutical composition has good formability and good stability.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicine, and particularly relates to a pharmaceutical composition, a preparation method thereof and an application thereof. Background Art

[0002] The chemical name of sultamicillin is (+)-hydroxymethyl-(2S,5R,6R)-6-[(R)-2-amino-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid ester (2S,5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid ester S,S-dioxide. The molecular formula is C25H30N4O9S2, and the structural formula is as follows:

[0003]

[0004] Sultamicillin is a diester formed by linking the β-lactamase inhibitor sulbactam and the semi-synthetic penicillin ampicillin with a methylene group. It is easily absorbed in the gastrointestinal tract and rapidly hydrolyzed by esterase in the body into sulbactam and ampicillin. Sulbactam is a broad-spectrum β-lactamase inhibitor and has a strong inhibitory effect on β-lactamases produced by staphylococcus aureus and most gram-negative bacteria. Sultamicillin is suitable for the treatment of the following infections caused by sensitive bacteria: 1. Upper respiratory tract infections: sinusitis, otitis media, tonsillitis, etc. 2. Lower respiratory tract infections: bronchitis, pneumonia, etc. 3. Urinary tract infections and pyelonephritis. 4. Skin and soft tissue infections. 5. Gonorrhea.

[0005] Sultamicillin itself has poor stability. Under high humidity and high temperature conditions, it is prone to degradation, resulting in reduced drug efficacy and drug resistance. The oral bioavailability of sultamicillin is 80%, and it is not significantly affected by food, while the oral bioavailability of ampicillin is only 50%. If sultamicillin degrades into ampicillin and sulbactam before entering the body, these two active substances will further degrade rapidly, and the drug bioavailability will be greatly reduced. Therefore, it is necessary to avoid the degradation of sultamicillin. Currently, the commercially available sultamicillin preparations are mainly sultamicillin tosylate tablets, granules and capsules, etc. However, the taste of sultamicillin tosylate is inferior to that of sultamicillin, and p-toluenesulfonic acid may degrade to produce genotoxic impurities, which is not conducive to the safety of drug use. In related technologies, the dry granulation and tabletting process is used to prepare sultamicillin tablets. Although it avoids the wet and heat effects of the wet granulation process of drugs, generally, dry granulation and tabletting require a relatively high pressure (such as up to more than 0.2 Mpa), and sultamicillin is unstable under high pressure and is prone to degradation, resulting in an increase in related substances, which to a certain extent affects the application of sultamicillin. Summary of the Invention

[0006] The present invention aims to solve at least one of the technical problems existing in the above-mentioned prior art. To this end, the present invention provides a pharmaceutical composition which requires a small tableting pressure during the preparation of pharmaceutical tablets, has a low content of drug impurities and good stability. Moreover, this pharmaceutical composition is a single-dose preparation, which can be taken directly or dispersed in water for taking, is suitable for different patient groups, is convenient to take, has accurate dosage, and high patient medication compliance.

[0007] The present invention also provides a preparation method of the pharmaceutical composition.

[0008] The present invention also provides the application of the above-mentioned pharmaceutical composition.

[0009] In a first aspect of the present invention, there is provided a pharmaceutical composition comprising a pharmaceutically active ingredient, a filler containing a cellulose-lactose co-processed product, and a stabilizer containing fumed silica, wherein the pharmaceutically active ingredient comprises at least one of penicillins or sultamicillin.

[0010] Fumed silica is also known as colloidal silica.

[0011] In the present invention, by simultaneously using a filler containing a cellulose-lactose co-processed product and a stabilizer containing fumed silica in a pharmaceutical composition (such as a pharmaceutical composition containing sultamicillin), during the preparation process of pharmaceutical tablets, the composition excipient has good moisture isolation performance, requires a small pressure for deep concave tablets, the obtained pharmaceutical composition has good formability, low impurity content and good stability.

[0012] In some embodiments of the present invention, the penicillins include but are not limited to amoxicillin, ampicillin, etc.

[0013] In some embodiments of the present invention, the pharmaceutically active ingredient is sultamicillin.

[0014] In some embodiments of the present invention, by weight percentage, the pharmaceutical composition comprises 20% - 80% of a pharmaceutically active ingredient, 10% - 70% of a filler, and 0.5% - 20% of a stabilizer.

[0015] In some embodiments of the present invention, by weight percentage, the pharmaceutical composition comprises 30% - 65% of a pharmaceutically active ingredient, 20% - 60% of a filler, and 1% - 15% of a stabilizer.

[0016] In some embodiments of the present invention, the weight ratio of sultamicillin to the stabilizer is 15:1 - 25:1.

[0017] In some embodiments of the present invention, in the pharmaceutical composition, the weight percentage of the stabilizer is 2% to 10%. Optionally, the stabilizer is fumed silica. In the present invention, compared with a content of less than 2% of fumed silica, using a relatively large amount (more than 2% by ratio) of fumed silica can achieve a better moisture isolation effect in the preparation of pharmaceutical compositions, especially in pharmaceutical composition tablets, and can better maintain the stability of the active ingredient; at the same time, when taking the pharmaceutical tablets, a relatively large amount of fumed silica has a suspending effect, which can make the content uniformity of the tablets dispersed in water, and is helpful for the dose application according to body weight in the clinical pediatric population.

[0018] In some embodiments of the present invention, by weight percentage, the cellulose-lactose co-processed product comprises 20% to 30% of microcrystalline cellulose and 70% to 80% of lactose monohydrate. Optionally, by weight percentage, the cellulose-lactose co-processed product comprises 25% of microcrystalline cellulose and 75% of lactose monohydrate. Using this cellulose-lactose co-processed product in a pharmaceutical composition, the composition has good fluidity and compressibility, and is more suitable for direct compression of medium and high-dose tablets. At the same time, the composition has a high hardness yield rate and is particularly suitable for dispersible tablets and orally disintegrating tablets.

[0019] In some embodiments of the present invention, the cellulose-lactose co-processed product is selected from 80 or at least one of 100.

[0020] In some embodiments of the present invention, the pores of the fumed silica have a pore diameter of 1 to 200 nm, and can be optionally 2 to 50 nm.

[0021] In some embodiments of the present invention, the fumed silica is selected from 244FP silica, 72FP silica, AL-1FP / 63FP silica, XDF3050 silica, XDF3150 silica or at least one of 6035 silica.

[0022] In the pharmaceutical composition of the present invention, using Syloid series fumed silica as a stabilizer greatly improves the moisture-proof performance of the composition and enhances the stability of the pharmaceutical active ingredient.

[0023] In some embodiments of the present invention, the pharmaceutical composition further comprises a disintegrant.

[0024] In some embodiments of the present invention, the disintegrant includes at least one of sodium carboxymethylcellulose cross-linked, hypromellose phthalate, or polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus).

[0025] In some embodiments of the present invention, by weight percentage, the pharmaceutical composition includes 0.1% - 5% of the disintegrant, such as optionally 0.5% - 3%.

[0026] In some embodiments of the present invention, the pharmaceutical composition further includes a flavoring agent.

[0027] In some embodiments of the present invention, the flavoring agent includes at least one of sucrose, sucralose, aspartame, sweet orange essence, strawberry essence, or orange essence.

[0028] In some embodiments of the present invention, by weight percentage, the pharmaceutical composition includes 0.1% - 30% of the flavoring agent, such as optionally 0.1% - 20%.

[0029] In some embodiments of the present invention, the pharmaceutical composition is a sultamicillin tablet.

[0030] In some embodiments of the present invention, by weight percentage, the sultamicillin tablet contains 30% - 60% of sultamicillin, 20% - 50% of a filler, 0.5% - 3% of a disintegrant, 1% - 5% of a stabilizer, and 0.1% - 20% of a flavoring agent.

[0031] The sultamicillin tablets prepared by the present invention can be taken directly or dispersed in water before taking, which can overcome the problems of layering and slow dissolution during filling and storage that may occur in the granule dosage form. The single-dose tablet form can also avoid the content uniformity problem caused by layering of sultamicillin granules and sultamicillin dry suspension. Optionally, the sultamicillin tablets of the present invention are rapidly disintegrating tablets, suitable for different populations of users: including adults, low-age children who need dose adjustment, etc., and the tablets can be dispersed in an appropriate amount of water to meet the needs of people with difficulty in swallowing.

[0032] In the sultamicillin tablets of the present invention, cross-linked carboxymethyl cellulose sodium or the like is used as a disintegrant, which has low hygroscopicity and is more suitable for direct compression tableting, playing a function of promoting rapid disintegration and dispersion. Flavoring agents (such as crushed sucrose powder) can act as sweeteners and dry binders, can adjust the taste of sultamicillin tablets, and contribute to the medication compliance of pediatric patients. Flavoring agents such as orange essence meet the preferences of most children, have better safety without small molecule aldehydes, and when the flavoring agent is mixed with colloidal silicon dioxide, it is more helpful to maintain the slow and lasting release of aroma, thus well covering the peculiar smell of the active pharmaceutical ingredient; at the same time, the function of the dry binder possessed by the flavoring agent can be conducive to the uniform mixing of materials and tableting.

[0033] In the second aspect of the present invention, a preparation method of a pharmaceutical composition is provided, which includes the following steps: mixing raw materials for preparation containing a drug active ingredient, a filler and a stabilizer, and tableting to obtain the pharmaceutical composition.

[0034] In the present invention, the preparation process of the pharmaceutical composition adopts direct mixing and tableting. The materials all have the characteristics of good fluidity and strong compressibility, can meet the requirements of uniform mixing and tableting, and can avoid the influence of wet heat and high pressure in the related technologies where the active pharmaceutical ingredient adopts wet granulation or dry granulation. The preparation method in the present invention has a simple process and is more suitable for commercial production.

[0035] In some embodiments of the present invention, the drug active ingredient is sultamicillin.

[0036] In some embodiments of the present invention, the preparation method includes: mixing sultamicillin, a stabilizer, a filler, a disintegrant and a flavoring agent, and tableting to obtain the pharmaceutical composition.

[0037] The present invention adopts direct mixing and tableting, in combination with a composite auxiliary material cellulose-lactose co-processed product and a novel auxiliary material colloidal silicon dioxide, as well as a disintegrant with high disintegration performance. Under multiple designs, the compressibility and quality stability of high drug-loading tablets are better guaranteed.

[0038] In some embodiments of the present invention, in the tableting step of the preparation method, a stamping die is used to tablet the raw materials for preparation.

[0039] In some embodiments of the present invention, in the preparation method, the diameter of the stamping die is 1-50 mm, and can be selected as 5-15 mm, for example.

[0040] In some embodiments of the present invention, in the preparation method, the depth of the female die of the stamping die is more than 2 mm, and can be selected as 2-5 mm, for example.

[0041] In the present invention, during the tabletting process, optionally, a die with a diameter of 10 mm and a deep recess (≥2 mm) is used for tabletting, which can bear a high drug load and is suitable for preparing high-specification thick tablets. At the same time, the deep recess design can meet the requirement that less pressure is needed to form the tablets from the granules of the pharmaceutical composition, that is, it can press relatively fragile composition granules under low pressure, avoid the material being affected by excessive pressure and affecting the quality, and meet the general requirements of the Chinese Pharmacopoeia for the disintegration time limit and friability of tablets.

[0042] In some embodiments of the present invention, the pressure for tabletting is 4 - 8 kN, and can be optionally 5 - 6 kN.

[0043] In some embodiments of the present invention, in the mixing step of the preparation method: sultamicillin and a stabilizer are pre-mixed and then mixed with a filler, a disintegrant and a flavoring agent.

[0044] In some embodiments of the present invention, the preparation method comprises the following steps:

[0045] S1, passing both sultamicillin and the stabilizer through a 30 - 100 mesh sieve and then pre-mixing to obtain a premix;

[0046] S2, mixing the premix with a filler, a disintegrant and a flavoring agent to obtain a mixed material, granulating and then mixing again to obtain mixed granules;

[0047] S3, tabletting the mixed granules to obtain the pharmaceutical composition.

[0048] In the present invention, sultamicillin and the stabilizer are sieved and dispersed first and then mixed with other materials. Among them, the stabilizer colloidal silica is easy to form smooth spherical particles and is not easy to disperse due to its good lubricity. Optionally, sultamicillin and the stabilizer are passed through a 30 - 100 mesh sieve together by co-sieving. After the colloidal silica stabilizer and sultamicillin are co-sieved, they can be better dispersed and are not easy to form spherical particles. At the same time, the colloidal silica can be fully mixed with and wrap sultamicillin to play a protective role.

[0049] In some embodiments of the present invention, in step S1, in the premix, the particle size of sultamicillin is 40 - 80 mesh.

[0050] In the third aspect of the present invention, there is provided the use of the above-mentioned pharmaceutical composition in the preparation of a drug for treating respiratory tract infections and in the preparation of a drug for treating urinary tract infections. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] The present invention will be further described below in conjunction with the drawings and embodiments, wherein:

[0052] Figure 1Comparison chart of dissolution curves of the examples, comparative examples and commercially available sultamicillin preparations of the present invention on day 0;

[0053] Figure 2 Comparison chart of dissolution curves of the examples, comparative examples and commercially available sultamicillin preparations of the present invention after one month of acceleration;

[0054] Figure 3 Comparison chart of dissolution curves of the examples, comparative examples and commercially available sultamicillin preparations of the present invention after three months of acceleration. Detailed implementation manners

[0055] The concept of the present invention and the technical effects produced will be clearly and completely described below in conjunction with the examples to fully understand the purpose, features and effects of the present invention. Obviously, the described examples are only a part of the examples of the present invention, rather than all the examples. Based on the examples of the present invention, other examples obtained by those skilled in the art without creative work all fall within the scope of protection of the present invention.

[0056] For the experimental methods without specific conditions noted in the following examples, they are usually carried out according to the conventional conditions in the art or according to the conditions recommended by the manufacturer; for the raw materials, reagents, etc. used, unless otherwise specified, they are all raw materials and reagents that can be obtained from commercial channels such as conventional markets.

[0057] Example 1

[0058] This example discloses a sultamicillin tablet, which includes the following components by weight percentage:

[0059]

[0060] The preparation process of the sultamicillin tablet includes:

[0061] After passing sultamicillin and colloidal silica through a 60-mesh sieve and pre-mixing in a mixer, other materials are added for pre-total mixing. After the pre-mixed materials are granulated by a granulator, the granulated materials are then subjected to total mixing to obtain intermediate product granules. Then, tableting is carried out using a die with a diameter of 10 mm and a deep recess (3 mm), and filling is carried out to obtain sultamicillin tablets (total weight per tablet: 800 mg, API specification: 375 mg / tablet).

[0062] Example 2

[0063] This example discloses a sultamicillin tablet, which includes the following components by weight percentage:

[0064]

[0065]

[0066] The preparation process of the sultamicillin tablet includes:

[0067] Sulbactam and silica gel prepared by the gel method are passed through a 60-mesh sieve and pre-mixed in a mixer, then other materials are added for pre-total mixing. After the pre-mixed materials are granulated by a granulator, the granulated materials are further mixed to obtain the intermediate product granules. Then, tableting is carried out using a punch die with a diameter of 10 mm and a shallow concave (1.0 mm), and filling is carried out to obtain sulbactam tablets (total weight per tablet: 800 mg, API specification: 375 mg / tablet).

[0068] Example 3

[0069] This example discloses a sulbactam tablet, which comprises the following components by weight percentage:

[0070]

[0071] The preparation process of the sulbactam tablet includes:

[0072] Sulbactam and silica gel prepared by the gel method are passed through a 60-mesh sieve and pre-mixed in a mixer, then other materials are added for pre-total mixing. After the pre-mixed materials are granulated by a granulator, the granulated materials are further mixed to obtain the intermediate product granules. Then, tableting is carried out using a punch die with a diameter of 10 mm and a deep concave (3 mm), and filling is carried out to obtain sulbactam tablets (total weight per tablet: 800 mg, API specification: 320 mg / tablet).

[0073] Example 4

[0074] This example discloses a sulbactam tablet, which comprises the following components by weight percentage:

[0075]

[0076] The preparation process of the sulbactam tablet includes:

[0077] Sulbactam and silica gel prepared by the gel method are passed through a 60-mesh sieve and pre-mixed in a mixer, then other materials are added for pre-total mixing. After the pre-mixed materials are granulated by a granulator, the granulated materials are further mixed to obtain the intermediate product granules. Then, tableting is carried out using a punch die with a diameter of 10 mm and a deep concave (3 mm), and filling is carried out to obtain sulbactam tablets (total weight per tablet: 800 mg, API specification: 400 mg / tablet).

[0078] Example 5

[0079] This example discloses a sulbactam tablet, which comprises the following components by weight percentage:

[0080]

[0081]

[0082] The preparation process of sultamicillin tablets includes:

[0083] After pre-mixing sultamicillin and silica gel by the gel method through a 60-mesh sieve in a mixer, other materials are added for pre-total mixing. After the pre-mixed materials are granulated by a granulator, the granulated product is further mixed to obtain the intermediate product granules. Then, tableting is carried out using a punch die with a diameter of 10 mm and a deep recess (3 mm), and filling is carried out to obtain sultamicillin tablets (total weight per tablet: 800 mg, API specification: 400 mg / tablet).

[0084] Example 6

[0085] This example discloses a sultamicillin tablet, which includes the following components by weight percentage:

[0086]

[0087] The preparation process of sultamicillin tablets includes:

[0088] After pre-mixing sultamicillin and silica gel by the gel method through a 60-mesh sieve in a mixer, other materials are added for pre-total mixing. After the pre-mixed materials are granulated by a granulator, the granulated product is further mixed to obtain the intermediate product granules. Then, tableting is carried out using a punch die with a diameter of 10 mm and a deep recess (3 mm), and filling is carried out to obtain sultamicillin tablets (total weight per tablet: 800 mg, API specification: 400 mg / tablet).

[0089] Example 7

[0090] This example discloses a sultamicillin tablet, which includes the following components by weight percentage:

[0091]

[0092]

[0093] The preparation process of sultamicillin tablets includes:

[0094] After pre-mixing sultamicillin and silica gel by the gel method through a 60-mesh sieve in a mixer, other materials are added for pre-total mixing. After the pre-mixed materials are granulated by a granulator, the granulated product is further mixed to obtain the intermediate product granules. Then, tableting is carried out using a punch die with a diameter of 10 mm and a deep recess (3 mm), and filling is carried out to obtain sultamicillin tablets (total weight per tablet: 800 mg, API specification: 400 mg / tablet).

[0095] Example 8

[0096] This example discloses a sultamicillin tablet, which includes the following components by weight percentage:

[0097]

[0098] The preparation process of sultamicillin tablets includes:

[0099] After pre-mixing sultamicillin and silica gel by the gel method through a 60-mesh sieve in a mixer, other materials are added for pre-total mixing. After the pre-mixed materials are granulated by a granulator, the granulated materials are then subjected to total mixing to obtain intermediate product granules. Then, tableting is carried out using a punch die with a diameter of 10 mm and a deep recess (3 mm), and filling is performed to obtain sultamicillin tablets (total weight per tablet: 800 mg, API specification: 375 mg / tablet).

[0100] Comparative Example 1

[0101] This comparative example discloses a kind of sultamicillin tablet, and its preparation process of the preparation is carried out by the dry tableting process. The specific components are as follows:

[0102] Material Name Prescription Dosage (g) Weight Ratio / % Sultamicillin 73.53 73.75 Crospovidone 2.64 2.65 Croscarmellose Sodium 7.35 7.37 Povidone K25 7.35 7.37 Lactose GranuLac 200 7.35 7.37 Magnesium Stearate 0.74 0.74 Stevioside 0.37 0.37 Strawberry Powder Flavor 0.37 0.37

[0103] The preparation process of sultamicillin tablets includes:

[0104] After drying the raw materials except sultamicillin to a water content ≤ 1%, they are mixed with sultamicillin in a mixer for 30 minutes to obtain a mixed material; the mixed material is made into 40-mesh granules by a dry granulator; the granules are placed in a tableting machine for tableting, with the tablet weight being 0.323 - 0.357 g / tablet, and filling is performed to obtain sultamicillin tablets.

[0105] Comparative Example 2

[0106] This comparative example discloses a kind of sultamicillin granule, and its external processing technology is to mix the active pharmaceutical ingredient and blank granules. The specific components are as follows:

[0107]

[0108] The preparation process of sultamicillin granules includes:

[0109] Sultamicillin, sweetener, ionic regulators (sodium hydrogen phosphate, sodium dihydrogen phosphate), and powdered flavor are respectively pulverized and passed through a 60-mesh sieve. According to the ratio in the table, 330.5 g of sucralose, 1.45 g of sodium dihydrogen phosphate, and 6.65 g of sodium hydrogen phosphate are weighed and put into a wet granulator for pre-mixing for 6 minutes. 20 g of wetting agent isopropanol is added uniformly by a peristaltic pump, and granulation is carried out for another 5 minutes. The obtained wet granules are transferred to an oven and dried at 60 °C to control the residual solvent of isopropanol to 0.23 wt%, and then passed through a 60-mesh sieve to obtain dry materials. The obtained dry materials are added to a mixer, and 25.01 g of pulverized and sieved sultamicillin and 16.34 g of strawberry-flavored powdered flavor are weighed and added to the mixer for total mixing (mixing for 18 minutes), passed through a 40-mesh sieve, and filling is performed to obtain the sultamicillin granule preparation.

[0110] Comparative Example 3

[0111] This comparative example discloses a sultamicillin tablet, which comprises the following components by weight percentage:

[0112]

[0113] The preparation process of the sultamicillin tablet includes:

[0114] After premixing sultamicillin and colloidal silicon dioxide through a 60-mesh sieve in a mixer, other materials are added for pre-total mixing. After the premixed materials are granulated by a granulator, the granulated materials are further mixed to obtain intermediate product granules. Then, tableting is carried out using a punch die with a diameter of 10 mm and a deep recess (3 mm), and filling is carried out to obtain sultamicillin tablets (total weight per tablet: 800 mg, API specification: 375 mg / tablet).

[0115] Comparative Example 4

[0116] This comparative example discloses a sultamicillin tablet, which comprises the following components by weight percentage:

[0117]

[0118]

[0119] The preparation process of the sultamicillin tablet includes:

[0120] After premixing sultamicillin and colloidal silicon dioxide through a 60-mesh sieve in a mixer, other materials are added for pre-total mixing. After the premixed materials are granulated by a granulator, the granulated materials are further mixed to obtain intermediate product granules. Then, tableting is carried out using a punch die with a diameter of 10 mm, and sultamicillin tablets are obtained (total weight per tablet: 800 mg, API specification: 375 mg / tablet).

[0121] Comparative Example 5

[0122] This comparative example discloses a sultamicillin tablet, which comprises the following components by weight percentage:

[0123]

[0124] The preparation process of the sultamicillin tablet includes:

[0125] After premixing sultamicillin and silica gel method silicon dioxide through a 60-mesh sieve in a mixer, other materials are added for pre-total mixing. After the premixed materials are granulated by a granulator, the granulated materials are further mixed to obtain intermediate product granules. Then, tableting is carried out using a punch die with a diameter of 10 mm, and sultamicillin tablets are obtained (total weight per tablet: 800 mg, API specification: 375 mg / tablet).

[0126] For the specific components and parameters of each example and Comparative Examples 3-5, see Table 1 for details.

[0127] Table 1

[0128]

[0129] Test Example

[0130] In this test example, performance tests were carried out on the sultamicillin tablets or granules obtained from the examples and comparative examples. Unless otherwise specified, the test methods for performance tests were all in accordance with the requirements of the general rules of the Chinese Pharmacopoeia. For example, hardness was detected using a tablet hardness tester, friability was detected using a tablet friability tester, and disintegration was detected using an intelligent disintegration tester. Specifically, the performance tests specifically included:

[0131] 1) Physical property test of sultamicillin tablets, and the results are shown in Table 2 for details:

[0132] Table 2

[0133]

[0134]

[0135] As can be seen from Table 2, in Example 1, tablets can be formed with a relatively small tableting pressure, and the hardness and friability of the prepared tablets meet the requirements, and the disintegration is rapid; compared with the shallow concave punch of Example 2, Example 1 is more suitable for large-scale samples and has a faster disintegration; in Examples 3-8, some types of excipients were replaced and the contents were adjusted accordingly, and the prepared tablets are good, and the hardness and friability meet the requirements, and the disintegration is rapid.

[0136] In Comparative Example 1, the proportion of the active pharmaceutical ingredient is large, and a very large dry granulation pressure is required to form, and the disintegration rate is average after tableting. Compared with the examples, in Comparative Examples 3-5, different fillers or stabilizers were used, the tableting formability was poor, and at the same time, the tableting pressure needed to be increased, and the tablet weight variation, hardness and friability were unqualified.

[0137] 2) Physicochemical detection of the sultamicillin tablets on the 0th day of the finished product, and the results are shown in Table 3 for details:

[0138] Table 3

[0139]

[0140] * Impurities D, F, and G are the same as Impurity D, F, and G in the sultamicillin preparations of the European Pharmacopoeia.

[0141] As can be seen from Table 3, when the sultamicillin tablets of Comparative Example 1 were tableted with different pressures, the impurities in the finished product were greatly affected. It was proved that the active pharmaceutical ingredient was unstable under high pressure and was prone to degradation, resulting in an increase in the impurity content.

[0142] 3) Test for the content uniformity of sultamicillin tablets / granules, and the results are shown in Table 4 as follows:

[0143] Table 4

[0144]

[0145]

[0146] Note: "Intermediate product" in Table 4: When the finished product is sultamicillin granules, it refers to the sample before filling after total mixing; when the finished product is sultamicillin tablets, it refers to the sample after tabletting and before filling.

[0147] Moreover: In Comparative Example 2, it is sultamicillin granules, and samples are taken and tested from the upper, middle and lower parts inside the bottle respectively.

[0148] As can be seen from Table 4, in terms of the test data of content uniformity, Examples 1, 3, 4, and 5 are tablets, and the content uniformity is good; the impurities in the tablets of Comparative Example 1 are relatively large under the influence of high pressure, so the content is relatively low. While Comparative Example 2 and the commercially available granules are both granules. Due to the differences in particle size and density of the granules, stratification is likely to occur during storage, resulting in uneven content in different parts of the drug granules. Compared with Example 1, the dosage ratio of colloidal silica to sultamicillin in Example 8 is relatively low, resulting in incomplete adsorption of the raw material drug sultamicillin, and then partial aggregation of the raw material drug leads to uneven content.

[0149] 4) Test for the stability of sultamicillin tablets. Among them, the accelerated condition: 40 °C, 75% RH. The long-term condition: 25 °C, 60% RH. The results are shown in Table 5 as follows:

[0150] Table 5

[0151]

[0152]

[0153] Note: The degradation products ampicillin and impurity G of this product have secondary degradation, the content decreases during the stability process, and the total impurities increase.

[0154] 5) Test for dissolution behavior. Among them, the dissolution medium: pH 4.5 acetate buffer solution; the volume of the medium: 900 mL; the rotation speed: 50 rpm; the temperature: 37 °C; the sampling time: 5, 10, 15, 30, 60, 90 min. The results are shown in Table 6 as follows:

[0155] Table 6

[0156]

[0157]

[0158] In terms of dissolution behavior, it can be seen that the dissolution trend during the stability process of Example 1 did not slow down significantly, while significant slowdowns occurred in both the comparative example and the commercial product. It is speculated that during storage, due to the influence of temperature and humidity and the physical and chemical properties of the raw material drug sultamicillin in the granule agent, aggregation occurred, resulting in larger raw material particles and poorer wettability, thus affecting dissolution.

[0159] The present invention provides a sultamicillin composition and a preparation process. The quality of the obtained sultamicillin composition tablets meets the requirements of the Chinese Pharmacopoeia. The related substances, content uniformity, and stability during use and dissolution behavior related to clinical applications are all superior to those of the commercial product, and the quality remains stable during the storage stability process of the product, solving problems such as production and quality stability that the related technical products fail to meet.

[0160] Unless otherwise specified, the "about" in the present invention actually means that the allowable error is within the range of ±2%. For example, about 100 is actually 100 ± 2% × 100. The "normal temperature" and "room temperature" in the present invention are about 20 - 30°C unless otherwise specified. The "between... and..." in the present invention includes the endpoints. For example, "between 2 and 3" includes the endpoint values 2 and 3.

[0161] The embodiments of the present invention have been described in detail above in conjunction with the accompanying drawings. However, the present invention is not limited to the above embodiments. Various changes can be made without departing from the gist of the present invention within the knowledge scope of those of ordinary skill in the art. In addition, the embodiments of the present invention and the features in the embodiments can be combined with each other without conflict.

Claims

1. A pharmaceutical composition, characterized in that The invention comprises a pharmaceutically active ingredient, a filler containing a cellulose-lactose co-processed product and a stabilizer containing gel-processed silicon dioxide, wherein the pharmaceutically active ingredient comprises at least one of penicillins or sultamicillin.

2. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition comprises, by weight percentage, 20% to 80% of a pharmaceutical active ingredient, 10% to 70% of a filler, and 0.5% to 20% of a stabilizer; Preferably, the pharmaceutical active ingredient is sultamicillin; and / or the weight ratio of sultamicillin to stabilizer is 15:1 to 25:

1.

3. The pharmaceutical composition according to claim 1, characterized in that The cellulose-lactose co-processed product comprises 20% to 30% of microcrystalline cellulose and 70% to 80% of lactose monohydrate by weight percentage; Preferably, the cellulose-lactose co-processed product is selected from 80 or At least one of 100.

4. The pharmaceutical composition according to claim 1, characterized in that The pores contained in the gel-processed silica have a pore diameter of 1 to 200 nm; Preferably, the gel-process silica is selected from 244FP Silica, 72FP silica, AL-1FP / 63FP Silica Silica, XDF3050 silica, XDF3150 Silica or At least one of 6035 silicon dioxide.

5. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition further comprises a disintegrant; Preferably, the disintegrant comprises at least one of cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; and / or, by weight percentage, the pharmaceutical composition comprises 0.1% to 5% of the disintegrant.

6. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition also includes a flavoring agent; Preferably, the flavoring agent includes at least one of sucrose, sucralose, aspartame, sweet orange flavor, strawberry flavor or orange flavor; and / or, by weight percentage, the pharmaceutical composition includes 0.1% to 30% of the flavoring agent.

7. A method for preparing the pharmaceutical composition according to claim 1, characterized in that: The method comprises the following steps: mixing raw materials containing active pharmaceutical ingredients, fillers and stabilizers, and tableting to obtain the pharmaceutical composition.

8. The method for preparing the pharmaceutical composition according to claim 7, characterized in that: The preparation method comprises: mixing sultamicillin, a stabilizer, a filler, a disintegrant and a flavoring agent, and tableting to obtain the pharmaceutical composition; Preferably, in the tableting step of the preparation method, a stamping die is used to tablet the preparation raw material; and / or the tableting pressure is 4 to 8 kN; Preferably, in the preparation method, the diameter of the stamping die is 1 to 50 mm; and / or the depth of the die of the stamping die is greater than 2 mm.

9. The method for preparing the pharmaceutical composition according to claim 8, characterized in that: The preparation method comprises the following steps: S1, sultamicillin and a stabilizer are sieved through a 30-100 mesh sieve and premixed to obtain a premix; S2, mixing the premix with a filler, a disintegrant and a flavoring agent to obtain a mixed material, granulating the premix and then mixing the premix to obtain mixed granules; S3, tableting the mixed granules to obtain the pharmaceutical composition.

10. Use of the pharmaceutical composition according to any one of claims 1 to 6 and the pharmaceutical composition obtained by the method according to any one of claims 7 to 9 in the preparation of a medicament for treating respiratory system infection and a medicament for treating urinary system infection.

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