Probiotic composition comprising tablet dosage form and preparation method and application thereof

Abstract

The invention provides a probiotic composition comprising a tablet dosage form and a preparation method and application thereof, and relates to the technical field of medicines. The probiotic composition disclosed by the invention is prepared from the following components in parts by weight: 15 to 35 parts of lactobacillus crispatus Lcr-MH175, 38 to 70 parts of microcrystalline cellulose, 15 to 35 parts of lactose, 0.5 to 4 parts of compound acidity adjusting anti-caking agent and 0.5 to 4 parts of chitosan oligosaccharide. According to the invention, the auxiliary materials with specific components and proportions are used for preparing the probiotic composition, the composition is applied to preparation of medicines for improving reproductive organs, the number of lactic acid bacteria in the obtained medicines is relatively high, and the probiotic composition can keep relatively high activity and stability of lactobacillus in the medicines.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and in particular relates to a probiotic composition in tablet form, a preparation method and an application thereof. Background Art

[0002] Lactobacillus is a common bacterium in the normal vaginal flora. It is a resident and dominant bacterium in the vagina of mature women. The separation rate in vaginal discharge is 80%-100%, which plays an important role in maintaining the balance of vaginal microecology. Lactobacillus breaks down the glycogen in the vaginal epithelial cells into lactic acid, maintains the normal acidic environment of the vagina (pH <4.5), can defend against the invasion of external pathogens, and reduce the occurrence of vaginal infection. In addition, the acidic environment of the vagina is also conducive to the biological effects of lactobacillus, and is also conducive to maintaining the activity of H2O2 produced by lactobacillus and the activity of bacteriocins. Therefore, using lactobacillus to acidify the vaginal environment is conducive to the growth of lactobacillus and the function of regulating its microecology.

[0003] The occurrence of vaginitis is related to the decrease in the number of lactobacilli, the massive reproduction of other anaerobic and facultative anaerobic bacteria, and the increase in vaginal pH. Therefore, while killing pathogenic bacteria, restoring the dominant position of vaginal lactobacilli, restoring the acidic environment of the vagina, and maintaining the normal vaginal microecological environment and pH value are the keys to treating vaginitis. At present, there are some deficiencies and irregularities in the drugs used to treat vaginal infections. For example, the use of antibacterial drugs to directly kill pathogenic bacteria can make the detected pathogens turn negative, but antibacterial drugs cannot quickly restore the balance of vaginal microecology, mainly because they cannot quickly restore the number and quality of lactobacilli in the vagina, nor can they quickly restore the vaginal pH value, resulting in the persistence of vaginal discomfort symptoms in some patients after treatment; some drugs have poor therapeutic effects on vaginitis, and are prone to recurrence or secondary infection with other pathogens due to the imbalance of vaginal microecology.

[0004] Chinese invention patent CN111893057A discloses a strain of Lactobacillus crispatus Lcr-MH175 for preventing and treating urogenital tract infections in women. It has strong antibacterial ability and can effectively inhibit the growth of foreign pathogens and other conditional pathogens. At the same time, it has a strong adhesion to Hela cells, ensuring the colonization of the strain in the vaginal epithelium. The Lactobacillus crispatus Lcr-MH175 provided by the invention has certain application prospects in the prevention and treatment of urogenital tract infections. However, the content of Lactobacillus crispatus in the solid medicine of the invention is only 1×10 5 -1×10 9 CFU / g. Due to the influence of auxiliary ingredients and preparation process, the activity of Lactobacillus crispatus was significantly reduced.

[0005] Chinese invention patent CN1259874A discloses a vaginal lactobacillus drug, which contains an in vitro strain of Lactobacillus and a preservation matrix, wherein the preservation matrix contains a bioactive adhesive, an antioxidant, a polyol, a carbohydrate and a protein material, wherein the bioactive adhesive is selected from a water-soluble gum, carboxymethyl cellulose and gelatin; the matrix can be preserved for at least about 10 to 12 months in vitro. 6 The vaginal lactobacillus drug has the ability to produce at least 10 ppm of hydrogen peroxide under effective culture conditions. However, in the process of preparing the vaginal lactobacillus drug, its ability to maintain the activity of lactobacillus still needs to be improved.

[0006] Considering that the activity of Lactobacillus plays a vital role in the therapeutic effect of the drug, in the preparation process of probiotic drugs containing Lactobacillus, further research is needed on the composition, ratio and preparation process of the drug to ensure the high activity and high stability of Lactobacillus crispatus. Summary of the invention

[0007] In view of the problems existing in the prior art, the present invention provides a probiotic composition including a tablet dosage form and a preparation method and application thereof. The probiotic composition is prepared using auxiliary materials with specific ingredients and proportions, and the probiotic composition is applied to the preparation of a drug for antagonizing pathogenic bacteria in the female reproductive tract, improving female urogenital tract infections, restoring vaginal microecological environment, and improving prostate health. The obtained drug still has a high number of lactic acid bacteria, thereby maintaining a high activity of lactobacilli in the drug and improving the stability of the drug efficacy.

[0008] Terms and Claims of the Present Invention:

[0009] 1. As used herein, the articles "a", "an" and "the" include plural referents unless expressly limited to one or more referents otherwise.

[0010] 2. As used herein, numerical range: Unless otherwise expressly indicated, all ranges or ratios disclosed herein will be understood to include any and all sub-ranges or sub-ratios contained therein. For example, a range or ratio of 1 to 30 stated should be considered to be included between a minimum value of 1 and a maximum value of 30, and any sub-range or sub-ratio, integer, decimal, or sub-range or sub-ratio consisting of integers or decimals including the end points.

[0011] 3. As used herein, the terms "comprises," "including," "have," "have," "may," "contain" and variations thereof are open-ended conjunctions or terms that do not exclude the possibility of additional compositions or structures.

[0012] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0013] Firstly, the present invention provides a probiotic composition, comprising components: Lactobacillus crispatus Lcr-MH175, microcrystalline cellulose, lactose, a compound acidity regulating anti-caking agent and chitosan oligosaccharide.

[0014] Preferably, the probiotic composition comprises the following components in parts by weight: 15-35 parts of Lactobacillus crispatus Lcr-MH175, 38-70 parts of microcrystalline cellulose, 15-35 parts of lactose, 0.5-4 parts of a compound acidity regulating anti-caking agent and 0.5-4 parts of chitosan oligosaccharide.

[0015] Further preferably, the probiotic composition comprises the following components, in parts by weight: 20-30 parts of Lactobacillus crispatus Lcr-MH175, 40-55 parts of microcrystalline cellulose, 16-31 parts of lactose, 1-3 parts of a compound acidity regulating anti-caking agent and 1-3 parts of chitosan oligosaccharide.

[0016] More preferably, the probiotic composition comprises the following components, in parts by weight: 25 parts of Lactobacillus crispatus Lcr-MH175, 40-50 parts of microcrystalline cellulose, 21-31 parts of lactose, 2 parts of compound acidity regulating anti-caking agent and 2 parts of chitosan oligosaccharide.

[0017] More preferably, the probiotic composition comprises the following components, in parts by weight: 25 parts of Lactobacillus crispatus Lcr-MH175, 50 parts of microcrystalline cellulose, 21 parts of lactose, 2 parts of compound acidity regulating anti-caking agent and 2 parts of chitosan oligosaccharide.

[0018] Preferably, the preservation number of the Lactobacillus crispatus Lcr-MH175 (Lactobacillus crispatus) is CGMCC No.15938, the preservation unit is the General Microbiology Center of China National Microbiological Culture Collection Administration, and the preservation date is June 11, 2018.

[0019] In the present invention, the compound acidity regulating anti-caking agent comprises lactic acid, calcium lactate and silicon dioxide.

[0020] Then, the present invention provides a method for preparing the probiotic composition, comprising the steps of: mixing the components according to a proportion to obtain the probiotic composition.

[0021] Furthermore, the present invention provides a probiotic medicine, the components of which include the above-mentioned probiotic composition.

[0022] Preferably, the dosage form of the probiotic drug is not limited to pills, capsules, granules, oral liquids, powders, tablets, lozenges, and pastes.

[0023] More preferably, the probiotic drug is in the form of a tablet.

[0024] Furthermore, the present invention provides a method for preparing the above-mentioned probiotic tablet medicine, comprising the steps of: uniformly mixing the components of the above-mentioned probiotic composition, and performing tableting treatment at a pressure of 2-3N for 0.5-2s.

[0025] Preferably, the tableting pressure is 2.5N and the tableting time is 1s.

[0026] Finally, the present invention provides the use of the above-mentioned probiotic composition in the preparation of medicines for antagonizing pathogenic bacteria in the female reproductive tract, improving female urogenital tract infections, restoring vaginal microecological environment, and improving prostate health.

[0027] Preferably, the pathogenic bacteria include Candida albicans, Staphylococcus aureus and Escherichia coli.

[0028] The probiotics medicine containing the component probiotic composition provided by the present invention, the pharmaceutical carrier used can be solid, liquid or gas. The solid carrier example includes lactose, white clay, sucrose, talcum powder, gelatin, agar, pectin, gum arabic, magnesium stearate and stearic acid. The example of liquid carrier includes syrup, peanut oil, olive oil and water. The example of gas carrier includes carbon dioxide and nitrogen.

[0029] When preparing the composition for oral dosage form, any convenient pharmaceutical medium can be used. For example, water, ethanol, oil, alcohol, flavoring agent, preservative, coloring agent, etc. can be used to form oral liquid preparations, such as suspensions and solutions; while carriers, such as starch, sugars, microcrystalline cellulose, diluents, granulating agents, emulsifiers, lubricants, binders, disintegrants can be used to form oral solid preparations, such as powders, capsules and tablets. Tablets and capsules are the preferred oral dosage units using solid pharmaceutical carriers due to their ease of administration. Tablets can be coated using standard aqueous or non-aqueous techniques.

[0030] Tablets containing the Chinese medicine composition or extract of the present invention can be prepared by tableting or molding, and one or more auxiliary ingredients or adjuvants can be used. The active ingredient can be tableted in a free-flowing form (such as powder or granules) in a suitable machine, and can be mixed with a binder, a lubricant, an inert diluent, a surfactant or a dispersant to prepare a tablet. Molded tablets can be molded in a suitable machine, i.e., a powdered compound mixture moistened with an inert liquid diluent. Each tablet preferably contains about 0.05 mg to about 5 g of active ingredient, and each sachet or capsule preferably contains about 0.05 mg to about 5 g of active ingredient. For example, a preparation intended for oral administration to humans may contain about 0.5 mg to about 5 g of active drug, mixed with an appropriate and convenient carrier material, which may account for about 5% to 95% of the total composition. The unit dosage form usually contains about 1 mg to about 2 g of active ingredient, usually 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

[0031] The pharmaceutical composition suitable for parenteral administration of the present invention can be prepared as an aqueous solution or suspension of the active compound. Suitable surfactants such as hydroxypropylcellulose can be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycol and oil mixtures thereof. In addition, preservatives can be added to prevent the harmful growth of microorganisms.

[0032] Medicine of the present invention can be in the form suitable for topical use, for example aerosol, cream, ointment, lotion, powder or the like. In addition, composition can be in the form suitable for transdermal administration device. Can use Chinese medicine composition of the present invention, prepare these prescriptions by conventional processing method. For example, by mixing hydrophilic material and water, and about 5wt% to about 10wt% of compound, prepare cream or ointment with required consistency.

[0033] The medicine of the present invention can be in a form suitable for rectal administration, wherein the carrier is a solid. Preferably, the mixture is made into a unit dose suppository. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be prepared by first forming a composition containing a softened or melted carrier, followed by cooling and shaping in a mold.

[0034] In addition to the above-mentioned carrier components, the above-mentioned pharmaceutical preparations may include (if applicable) one or more additional carrier components, such as diluents, buffers, flavoring agents, adhesives, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc. In addition, other excipients, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc., colorants and flavoring agents, etc., may be added. The preparation is made isotonic with the blood of the intended recipient. The components containing the Chinese medicine composition of the present invention can also be prepared in the form of powder or concentrate.

[0035] Compared with the prior art, the present invention has the following beneficial effects:

[0036] 1. The probiotic composition of the present invention adopts a specific Lactobacillus crispatus Lcr-MH175, which can increase the number of beneficial bacteria such as Lactobacillus crispatus in the intestine, inhibit the growth of harmful bacteria, and maintain the balance of intestinal microecology; can improve intestinal function, reduce intestinal discomfort symptoms such as constipation and diarrhea; can stimulate the intestinal immune system, promote the production and activity of immune cells, and enhance the body's resistance; and can improve the health of the reproductive system.

[0037] 2. The probiotic composition of the present invention helps to maintain the acidic environment of the vagina for women, prevent and treat gynecological diseases such as vaginitis; and enhances prostate health for men. The probiotic composition of the present invention has a high inhibitory effect on pathogenic bacteria such as Candida albicans, Staphylococcus aureus and Escherichia coli.

[0038] 3. The probiotic composition of the present invention is convenient to carry and use, has a small size, light weight, and is easy to carry.

[0039] 4. The probiotic composition of the present invention adopts auxiliary materials with specific components and proportions to prepare the medicine, which ensures that the medicine has a higher number of Lactobacillus curli, thereby maintaining a higher activity of Lactobacillus in the medicine and improving the stability of the drug effect. DETAILED DESCRIPTION

[0040] The following non-limiting examples can enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way. The following content is merely an exemplary description of the scope of the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, which should also fall within the scope of the present invention.

[0041] When the embodiments give numerical ranges, it should be understood that, unless otherwise specified in the present invention, both endpoints of each numerical range and any numerical value between the two endpoints can be selected. Unless otherwise defined, all technical and scientific terms used in the present invention have the same meanings as those generally understood by those of ordinary skill in the art to which the present invention belongs.

[0042] The present invention is further described below by way of specific examples. Unless otherwise specified, the various chemical reagents used in the examples of the present invention are obtained through conventional commercial channels.

[0043] In the following examples, the compound acidity regulating anti-caking agent was purchased from Henan Jindan Lactic Acid Technology Co., Ltd.; the microcrystalline cellulose was purchased from Shandong Luxi Pharmaceutical Co., Ltd.; and the chitosan oligosaccharide was purchased from Zhejiang Jinke Pharmaceutical Co., Ltd.

[0044] Example 1

[0045] The probiotic composition comprises the following components by weight: 25 parts of Lactobacillus crispatus Lcr-MH175, 50 parts of microcrystalline cellulose, 21 parts of lactose, 2 parts of compound acidity regulating anti-caking agent and 2 parts of chitosan oligosaccharide.

[0046] The above components are mixed evenly according to the proportions to obtain a probiotic composition.

[0047] Example 2

[0048] The probiotic composition comprises the following components by weight: 25 parts of Lactobacillus crispatus Lcr-MH175, 40 parts of microcrystalline cellulose, 31 parts of lactose, 2 parts of compound acidity regulating anti-caking agent and 2 parts of chitosan oligosaccharide.

[0049] The above components are mixed evenly according to the proportions to obtain a probiotic composition.

[0050] Example 3

[0051] The probiotic composition comprises the following components by weight: 25 parts of Lactobacillus crispatus Lcr-MH175, 45 parts of microcrystalline cellulose, 26 parts of lactose, 2 parts of compound acidity regulating anti-caking agent and 2 parts of chitosan oligosaccharide.

[0052] The above components are mixed evenly according to the proportions to obtain a probiotic composition.

[0053] Example 4

[0054] The probiotic composition comprises the following components by weight: 25 parts of Lactobacillus crispatus Lcr-MH175, 55 parts of microcrystalline cellulose, 16 parts of lactose, 2 parts of compound acidity regulating anti-caking agent and 2 parts of chitosan oligosaccharide.

[0055] The above components are mixed evenly according to the proportions to obtain a probiotic composition.

[0056] Comparative Example 1

[0057] The difference from Example 1 is that in the probiotic composition, microcrystalline cellulose is replaced by sodium carboxymethyl cellulose (purchased from Shanghai Shenguang Food Chemicals Co., Ltd., with a substitution degree of 0.6). The rest is the same as Example 1.

[0058] Comparative Example 2

[0059] The difference from Example 1 is that in the probiotic composition, lactose is replaced by sucrose. The rest is the same as Example 1.

[0060] Comparative Example 3

[0061] The difference from Example 1 is that the proportions and amounts of the components are different.

[0062] The probiotic composition comprises the following components by weight: 25 parts of Lactobacillus crispatus Lcr-MH175, 30.5 parts of microcrystalline cellulose, 40.5 parts of lactose, 2 parts of compound acidity regulating anti-caking agent and 2 parts of chitosan oligosaccharide.

[0063] The above components are mixed evenly according to the proportions to obtain a probiotic composition.

[0064] Comparative Example 4

[0065] The difference from Example 1 is that the components and proportions of the probiotic composition are different.

[0066] The probiotic composition comprises the following components by weight: 25 parts of Lactobacillus crispatus Lcr-MH175, 16.4 parts of fucoidan, 0.6 parts of vitamin C, 29 parts of lactose and 29 parts of microcrystalline cellulose.

[0067] The above components are mixed evenly according to the proportions to obtain a probiotic composition.

[0068] Application Examples

[0069] The probiotic compositions of the examples and comparative examples were respectively used to prepare probiotic tablets: the components were mixed evenly, and tableting was performed under a pressure of 2.5 N for 1 second to obtain the probiotic tablets (0.4 g / tablet) of the examples and comparative examples.

[0070] Experiment 1 Lactic acid bacteria count experiment

[0071] The national standard GB 4789.35-2003 "Food Microbiology Examination - Lactic Acid Bacteria Examination" was used for testing.

[0072] Test 2: Disintegration time test

[0073] The disintegration time determination method in the "Chinese Pharmacopoeia 2020 Edition" was used for testing.

[0074] Test 3: Friability test

[0075] The friability determination method in the "Chinese Pharmacopoeia 2020 Edition" was used for testing.

[0076] Test 4: Moisture detection test

[0077] The first method in GB5009.3-2016 standard is used for testing.

[0078] Test 5 Ash content detection experiment

[0079] The ash content determination method in the GB5009.4-2016 standard is used for testing.

[0080] The test results of the lactic acid bacteria count, disintegration time, friability, moisture content and ash content of the probiotic tablets prepared in each embodiment and comparative example are shown in Table 1.

[0081] Table 1

[0082] Number of lactic acid bacteria (CFU / g) Disintegration time (min) Friability (%) Moisture (%) Ash content (%) Example 1 <![CDATA[2.0×10 10 ]]> 14 0.30 4.15 2.05 Example 2 <![CDATA[1.8×10 10 ]]> 20 0.19 4.05 2.03 Example 3 <![CDATA[1.3×10 10 ]]> 19 0.25 4.18 2.01 Example 4 <![CDATA[0.8×10 10 ]]> 28 0.88 4.1 1.99 Comparative Example 1 <![CDATA[0.7×10 10 ]]> 35 0.40 4.3 2.0 Comparative Example 2 <![CDATA[0.6×10 10 ]]> 33 0.28 4.2 1.1 Comparative Example 3 <![CDATA[0.5×10 10 ]]> 48 0.30 4.1 1.2 Comparative Example 4 <![CDATA[0.4×10 10 ]]> 55 0.20 4.0 3.0

[0083] It can be seen from Table 1 that the probiotic tablets prepared from the probiotic composition of the present invention can maintain a high lactic acid bacteria count and a high activity of Lactobacillus crispatus. The probiotic tablets of the present invention have a short disintegration time limit and achieve a significant effect of rapid release.

[0084] Test 6 Antibacterial performance experiment

[0085] The probiotic compositions of Examples 1 to 3 and Comparative Examples 1 to 4 were subjected to antibacterial experiments to detect the antibacterial rates at different action times (2 min, 10 min, 20 min). The positive control group was not added with the probiotic composition and was only used to detect the colony count of the test strain.

[0086] The test strains were: Candida albicans, Staphylococcus aureus and Escherichia coli.

[0087] The colony count results of the positive control group are shown in Table 2.

[0088] Table 2

[0089] Colony count of positive control group (CFU / mL) Candida albicans <![CDATA[1.27×10 4 ]]> Staphylococcus aureus <![CDATA[1.57×10 4 ]]> Escherichia coli <![CDATA[1.70×10 4 ]]>

[0090] The antibacterial rate (%) of the probiotic composition of each embodiment and comparative example is shown in Table 3.

[0091] Table 3

[0092]

[0093] It can be seen from Table 3 that the probiotic composition of the present invention has significant ability to inhibit Candida albicans, Staphylococcus aureus and Escherichia coli.

[0094] Test 7 Antibacterial stability test

[0095] The probiotic compositions of Example 1 and Comparative Example 2 were placed in a 37° C. incubator for 90 days, and the antibacterial experiment was repeated with an action time of 20 min. The inhibition rate (%) of Candida albicans was shown in Table 4.

[0096] Table 4

[0097]

[0098] As can be seen from Table 4, the probiotic composition of the present invention still has a significant inhibitory effect on Candida albicans after being stored for 90 days, and the inhibition rate of 20 minutes after storage for 90 days is 53.36%, which is close to the inhibition rate of 58.35% after storage for 0 days, and the inhibition rate has no significant change. The probiotic composition of the present invention has stable antibacterial performance.

[0099] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A probiotic composition, characterized in that: The invention comprises the following components: Lactobacillus crispatus Lcr-MH175, microcrystalline cellulose, lactose, compound acidity regulating anticaking agent and chitosan oligosaccharide.

2. The probiotic composition according to claim 1, characterized in that The composition comprises the following components in parts by weight: 15-35 parts of Lactobacillus crispatus Lcr-MH175, 38-70 parts of microcrystalline cellulose, 15-35 parts of lactose, 0.5-4 parts of compound acidity regulating anticaking agent and 0.5-4 parts of chitosan oligosaccharide.

3. The probiotic composition according to claim 2, characterized in that The composition comprises the following components in parts by weight: 20-30 parts of Lactobacillus crispatus Lcr-MH175, 40-55 parts of microcrystalline cellulose, 16-31 parts of lactose, 1-3 parts of compound acidity regulating anti-caking agent and 1-3 parts of chitosan oligosaccharide.

4. The probiotic composition according to claim 3, characterized in that The composition comprises the following components in parts by weight: 25 parts of Lactobacillus crispatus Lcr-MH175, 40-50 parts of microcrystalline cellulose, 21-31 parts of lactose, 2 parts of compound acidity regulating anticaking agent and 2 parts of chitosan oligosaccharide.

5. The probiotic composition according to claim 4, characterized in that The composition comprises the following components in parts by weight: 25 parts of Lactobacillus crispatus Lcr-MH175, 50 parts of microcrystalline cellulose, 21 parts of lactose, 2 parts of compound acidity regulating anticaking agent and 2 parts of chitosan oligosaccharide.

6. The probiotic composition according to any one of claims 1 to 5, characterized in that The compound acidity regulating anti-caking agent comprises: lactic acid, calcium lactate and silicon dioxide.

7. The method for preparing the probiotic composition according to any one of claims 1 to 6, characterized in that: The method comprises the steps of: mixing the components according to a proportion to obtain a probiotic composition.

8. A probiotic drug, characterized in that: The components include the probiotic composition according to any one of claims 1 to 6; the dosage form of the probiotic drug is not limited to pills, capsules, granules, oral liquids, powders, tablets, lozenges, and pastes.

9. A method for preparing a probiotic tablet drug, characterized in that: The method comprises the steps of: uniformly mixing the components of the probiotic composition according to any one of claims 1 to 6, and performing tabletting treatment for 0.5 to 2 seconds under a pressure of 2 to 3N.

10. Use of the probiotic composition according to any one of claims 1 to 6 in the preparation of a drug for antagonizing pathogenic bacteria in the female reproductive tract, improving female urogenital tract infections, restoring vaginal microecological environment, and improving prostate health.

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