CN110935007B - Linaclotide compound composition, preparation, application and preparation method thereof - Google Patents
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Abstract
A linaclotide compound composition, a preparation, application and a preparation method thereof relate to the technical field of biological medicines and health care products and aim to develop a combined medication mode of linaclotide and bifidobacteria. Provided is a linaclotide compound composition comprising linaclotide or a salt thereof and a live bifidobacterium; also provided is an oral preparation of linaclotide, which comprises the compound linaclotide composition; also provided is a method of preparing a formulation comprising: dispersing live bifidobacteria in an aqueous solution of alginic acid or a salt thereof, atomizing the solution, uniformly spraying the atomized solution into an aqueous solution containing linaclotide or a salt thereof and calcium chloride, solidifying and drying to obtain the bifidobacteria. The linaclotide compound composition and the oral preparation thereof can be used for preparing medicines or health care products for treating and preventing constipation diseases.
Description
Technical Field
The invention relates to the technical field of biological medicines and health-care products, in particular to a compound composition and a preparation of linaclotide, and application and a preparation method thereof.
Background
Linaclotide (Linaclotide) is a polypeptide consisting of 14 amino acids, the amino acid sequence of which is Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr, is a novel intestinal epithelial cell guanylate cyclase C (GC-C) receptor agonist, and is a novel intestinal epithelial cell guanylate cyclase C (GC-C) receptor agonist, which activates GC-C receptors on the top surface of intestinal epithelial cells, causes an increase in intracellular and extracellular guanylate, increases secretion of chlorine and bicarbonate into the intestinal lumen, thereby promoting increased secretion of fluids and acceleration of stool passage, and is useful for treating gastrointestinal disorders and conditions, including constipation-predominant irritable bowel syndrome (IBS-C) and Chronic Idiopathic Constipation (CIC), which has been approved for marketing in the united states in the year 2012, month 8 and 30.
Constipation refers to the decrease of defecation times, and the difficulty of defecation and dry feces. Normal people can defecate 1-2 times a day or 1-2 times a day, constipation patients can defecate less than 3 times a week, and serious people can defecate once for 2-4 weeks, and the defecation is laborious, hard in stool and less in amount. Constipation is a common symptom of the elderly, about 1/3 of the elderly suffers from constipation, the life quality of the elderly is seriously affected, and researches show that the bifidobacterium quantity in the intestinal flora of the elderly is obviously reduced.
Bifidobacteria are gram-positive bacteria which do not move, have rod-shaped cells, have a forked end sometimes and are strictly anaerobic, widely exist in the habitat of the digestive tract, the vagina, the oral cavity and the like of human beings and animals, are important intestinal beneficial microorganisms, and have various important physiological functions of biological barrier, nutrition, anti-tumor effect, immunity enhancement effect, gastrointestinal tract function improvement, aging resistance and the like for human health. There are researches on that bifidobacteria can promote the absorption of minerals by human bodies, produce organic acids such as acetic acid, propionic acid, butyric acid and lactic acid, stimulate intestinal peristalsis, promote defecation, prevent constipation, inhibit intestinal putrefaction and purify the intestinal environment, but the number of bifidobacteria planted in human intestinal tracts can be changed along with the age and health state of the human bodies.
In view of the fact that linaclotide and bifidobacterium both have a function of promoting defecation, it is necessary to develop a combination mode of both in order to obtain a new drug with better effect of treating and preventing constipation.
Disclosure of Invention
In view of the fact that no composition product of linaclotide and bifidobacterium exists in the market at present, the invention aims to develop a combined drug mode of linaclotide and bifidobacterium so as to obtain a novel drug with better effect of treating and preventing constipation.
To achieve the above object, the inventors have conducted a comparative experimental study and have surprisingly found that linaclotide has a synergistic effect after co-administration with bifidobacteria, and for this purpose, the present invention provides, first, a compound linaclotide composition comprising linaclotide or a salt thereof and live bifidobacteria, wherein the linaclotide salt comprises linaclotide hydrochloride, citrate, acetate, malate and succinate.
Preferably, in the linaclotide compound composition provided by the invention, 140-300 parts by weight of linaclotide or salt thereof and 15000-30000 parts by weight of live bifidobacteria are adopted.
Preferably, in the linaclotide compound composition provided by the invention, the bifidobacterium is selected from one or more of bifidobacterium adolescentis, bifidobacterium horneri, bifidobacterium animalis, bifidobacterium starosum, bifidobacterium bifidum, bifidobacterium bovis, bifidobacterium breve, bifidobacterium denticola, bifidobacterium infantis, bifidobacterium lactis, bifidobacterium longum, bifidobacterium pseudocatenulatum, bifidobacterium thermophilum and bifidobacterium acidophilus.
More preferably, in the linaclotide compound composition provided by the invention, the bifidobacterium is one or more of bifidobacterium adolescentis, bifidobacterium animalis and bifidobacterium breve. The bifidobacteria belong to supplementary primordia, and can produce acetic acid after being taken, so that intestinal tracts are acidic, and intestinal peristalsis is stimulated, and the effect is more remarkable.
Secondly, the invention also provides an oral preparation of linaclotide, which comprises the linaclotide compound composition provided by the invention. The oral preparation can be various known common pharmaceutical dosage forms, such as tablets, pills, capsules, granules, powder, liquid preparations and the like.
Preferably, the linaclotide oral preparation provided by the invention is linaclotide microcapsule, which has better treatment and prevention effect compared with other oral preparations.
Preferably, the linaclotide microcapsule provided by the invention takes calcium alginate as a capsule wall material.
More preferably, in the linaclotide microcapsule provided by the invention, linaclotide or salt thereof is wrapped by a capsule material, and the live bifidobacterium is attached and inlaid on the surface of the capsule material. This particular structure allows the linaclotide microcapsule to have the following two functions: 1. the bifidobacterium living bacteria attached and inlaid on the surface of the capsule wall material can autonomously identify the action part, and can realize targeted drug delivery to a certain extent; 2. the linaclotide molecules wrapped in the capsule wall material can be released steadily from the holes left on the surface of the capsule wall material after the live bifidobacteria are removed from the capsule wall material, so that slow release administration can be realized to a certain extent.
Again, for the linaclotide microcapsule with special structure, which can realize special functions, the invention provides a preparation method thereof, which comprises the following steps: 1) Weighing a prescription amount of linaclotide or salt thereof, dissolving the linaclotide or salt thereof in an aqueous solution of calcium chloride, and regulating the pH value of the solution to be 2-7 to obtain a solution A; 2) Weighing the viable bifidobacterium bacteria with the prescription amount, and dispersing the viable bifidobacterium bacteria in an aqueous solution of alginic acid or a salt thereof to obtain a solution B; 3) Atomizing the solution B; 4) Uniformly spraying the atomized solution B into the solution A, and standing for solidifying the solution; 5) After the solidification is completed, filtering and collecting a solidified substance; 6) Drying to obtain linaclotide microcapsule.
In the step 1) of the preparation method of the linaclotide microcapsule provided by the invention, the pH value of the solution is preferably adjusted to 3-5, and experiments show that the linaclotide has the best solubility and higher stability under the condition of the pH value.
In the step 1) of the preparation method of the linaclotide microcapsule provided by the invention, one or more solutions of hydrochloric acid or a salt thereof, acetic acid or a salt thereof, nitric acid or a salt thereof and sulfuric acid or a salt thereof are preferably used for adjusting the pH value of the solution.
In the step 1) of the preparation method of the linaclotide microcapsule provided by the invention, the concentration of the linaclotide in the solution A is preferably 20-70 mug/mL, more preferably 40-50 mug/mL, and the microcapsule is easier to successfully prepare under the concentration, so that the drug wrapping degree is the best, and the release of the drug is facilitated.
In the step 1) of the preparation method of the linaclotide microcapsule provided by the invention, the concentration of calcium chloride in the solution A is preferably 0.1-05M, more preferably 0.2-0.3M, and the reaction is mild under the concentration, so that the microcapsule formation is facilitated.
In the step 2) of the preparation method of the linaclotide microcapsule provided by the invention, the alginate comprises sodium alginate and potassium alginate.
In the step 2) of the preparation method of the linaclotide microcapsule provided by the invention, the concentration of the aqueous solution of alginic acid or a salt thereof is preferably 0.5-5%, more preferably 2-3%.
In the step 2) of the preparation method of the linaclotide microcapsule provided by the invention, the concentration of the viable bifidobacteria in the solution B is preferably 50-150 mug/mL, more preferably 80-100 mug/mL, and the viable bifidobacteria of the concentration ensures that the number of holes generated on the surface of the capsule material is moderate, so that the release rate of linaclotide molecules from the holes is more moderate, and the drug effect is smoother and lasting.
In the step 6) of the preparation method of the linaclotide microcapsule provided by the invention, a freeze drying process is preferably adopted for drying treatment.
More preferably, in step 6) of the preparation method of linaclotide microcapsule provided by the invention, the freeze-drying process comprises the following steps: 1) Pre-freezing, cooling to-40deg.C at a cooling rate of 0.1-0.5deg.C/min, and maintaining for 2-4 hr; 2) Drying at-2-2deg.C to remove free water in the solidified material; 3) And (3) drying for the second time at the temperature of 20-30 ℃ to remove the bound water in the solidified product.
Finally, the invention also provides the linaclotide compound composition and an application of the linaclotide oral preparation, namely, a medicine for treating and preventing constipation diseases.
In the linaclotide compound composition and the application of the linaclotide oral preparation provided by the invention, constipation diseases are constipation type irritable bowel syndrome and/or chronic idiopathic constipation.
The beneficial effects are that:
the invention combines linaclotide and bifidobacterium for the first time to treat and prevent constipation, has pioneering significance, and has the following advantages compared with the prior art:
1. experiments prove that the linaclotide compound composition provided by the invention has a curative effect which is obviously higher than that of single linaclotide or bifidobacterium administration, has a synergistic effect between two drug molecules, can supplement bifidobacterium deleted in gastrointestinal tracts after administration, and simultaneously promotes the growth and propagation of bifidobacterium inherent in human bodies, and has a longer curative effect;
2. the linaclotide microcapsule provided by the invention is prepared by adopting a special process, has a special structure, can realize targeted administration and slow release administration to a certain extent, has higher bioavailability, and can reduce the dosage;
3. the preparation method of the linaclotide oral preparation provided by the invention has the advantages of simple process, easy operation, no special requirement on equipment, environmental protection, no toxicity and no pollution.
Detailed Description
The present invention will be described in further detail with reference to the following examples, which are illustrative of the present invention and are not intended to limit the present invention thereto.
The raw materials and reagents used in the following examples are all commercially available.
Example 1
145 μg linaclotide acetate was weighed into 5mL of 0.2M calcium chloride aqueous solution, and the pH was adjusted to 7 with 0.01M hydrochloric acid solution to obtain solution A. 20mg of live bifidobacterium adolescentis is weighed and dispersed in 200mL of 5% alginic acid aqueous solution to obtain solution B. And atomizing the solution B by adopting an atomizing spray gun, uniformly spraying the atomized solution B into the solution A, solidifying for 20min, and filtering under reduced pressure to collect a solidified substance. And (3) pre-freezing the obtained solidified substance at a cooling speed of 0.1 ℃/min, keeping for 3 hours after the temperature is reduced to-40 ℃, then performing primary drying at 2 ℃ until the vacuum degree is less than 20pa, and finally performing secondary drying at 25 ℃ and keeping for 48 hours to obtain the linaclotide microcapsule.
Example 2
180 μg linaclotide is weighed and dissolved in 4mL of 0.3M calcium chloride aqueous solution, and 0.01M hydrochloric acid is used for adjusting the pH value to 4.5, thus obtaining solution A. 22mg of live bifidobacterium animalis is weighed and dispersed in 220mL of an aqueous solution of alginic acid with the concentration of 0.5%, so as to obtain a solution B. And atomizing the solution B by adopting an atomizing spray gun, uniformly spraying the atomized solution B into the solution A, solidifying for 25min, and filtering under reduced pressure to collect a solidified substance. Pre-freezing the solidified material at a cooling speed of 0.2 ℃/min, and keeping the solidified material for 2 hours after cooling to-40 ℃; drying at 0deg.C until the vacuum degree is less than 20pa; and (3) performing secondary drying at 20 ℃ and keeping for 50 hours to obtain the linaclotide microcapsule.
Example 3
220 μg linaclotide is weighed and dissolved in 4mL of 0.4M calcium chloride aqueous solution, and 0.01M citric acid is used for adjusting the pH value to 5, thus obtaining solution A. 25mg of live bifidobacterium breve is weighed and dispersed in 250mL of an aqueous solution of alginic acid with the concentration of 3% to obtain a solution B. And atomizing the solution B by adopting an atomizing spray gun, uniformly spraying the atomized solution B into the solution A, solidifying for 25min, and filtering under reduced pressure to collect a solidified substance. Pre-freezing the solidified material at a cooling rate of 0.3 ℃/min, and keeping the solidified material for 3 hours after cooling to-40 ℃; drying at 0deg.C until the vacuum degree is less than 20pa; and (3) performing secondary drying at 20 ℃ and keeping for 50 hours to obtain the linaclotide microcapsule.
Example 4
290 μg linaclotide is weighed and dissolved in 4.5mL of 0.4M calcium chloride aqueous solution, and 0.01M acetic acid is used for adjusting the pH value to 3, thus obtaining solution A. 18mg of live bifidobacteria (bifidobacterium adolescentis and bifidobacterium animalis 1:1) are weighed and dispersed in 220mL of sodium alginate aqueous solution with concentration of 2%, so as to obtain solution B. And atomizing the solution B by adopting an atomizing spray gun, uniformly spraying the atomized solution B into the solution A, solidifying for 20min, and filtering under reduced pressure to collect a solidified substance. Pre-freezing the solidified material at a cooling rate of 0.5 ℃/min, and keeping the solidified material for 3 hours after cooling to-40 ℃; drying at-2deg.C until the vacuum degree is less than 20pa; and (3) performing secondary drying at 30 ℃ and keeping for 48 hours to obtain the linaclotide microcapsule.
Example 5
290 μg linaclotide is weighed and dissolved in 4.5mL of 0.4M calcium chloride aqueous solution, and 0.01M acetic acid is used for adjusting the pH value to 3.5, thus obtaining solution A. 210mL of sodium alginate aqueous solution with the concentration of 2% is weighed to obtain solution B. And atomizing the solution B by adopting an atomizing spray gun, uniformly spraying the atomized solution B into the solution A, solidifying for 20min, and filtering under reduced pressure to collect a solidified substance. Pre-freezing the solidified material at a cooling rate of 0.5 ℃/min, and keeping the solidified material for 3 hours after cooling to-40 ℃; drying at-2deg.C until the vacuum degree is less than 20pa; and (3) performing secondary drying at 25 ℃ and keeping for 48 hours to obtain the microcapsule. Mixing the obtained microcapsule with 18mg live bifidobacterium (Bifidobacterium adolescentis and Bifidobacterium animalis 1:1) and 0.05% magnesium stearate for 20min, and filling the mixed powder into size 2 gelatin capsule to obtain linaclotide hard capsule with weight error within + -5%.
Example 6
Pharmacological evaluation and comparison experiment research of rats
1. Constipation type irritable bowel syndrome model establishment
170 SD rats weighing 180-220g were selected and randomly divided into 6 groups: wherein the model group, linaclotide group, bifidobacterium group (bifidobacterium adolescentis and bifidobacterium animalis 1:1), hard capsule group and microcapsule group were 30 each, and the normal group was 20. In addition to the normal group, the other 5 groups of rats were given daily acetic acid stimulation in the rectum, replicating the Gao Minxing intestinal irritability model, and the combination of tail-biting anger resulted in constipation due to qi stagnation: the rats 5 are placed in the same cage, the tail parts of the rats are clamped by wrapping yarn blocks with the hemoclamp, so that the whole cage of rats is in an irritated state, and the whole cage of rats is torn with other rats, and is stimulated for 30min each time, 6 times/d, 2 times of stimulation intervals for 2 hours, and the total stimulation is 14d.
2. Drug dosing regimen
(1) Model group, physiological saline was administered 2 mL/time, 1 time/d.
(2) Linaclotide group, to which linaclotide 2.4 μg/kg was administered 1 time daily for 2 weeks.
(3) Bifidobacteria group was given 2.4 μg/kg of bifidobacteria 1 time daily for 2 weeks.
(4) The group of hard capsules was administered with the linaclotide hard capsule prepared in example 5 of the present invention, which corresponds to 2.4. Mu.g/kg, 1 time a day, for 2 weeks.
(5) The microcapsule group was administered with the linaclotide microcapsule prepared in example 4 of the present invention, corresponding to 2.4. Mu.g/kg, 1 time a day for 2 weeks.
(6) Normal group, physiological saline was administered 2 mL/time, 1 time/d.
3. Detection method and result
(1) Measurement of the water content of the rat feces: the stool was collected between 24 hours after administration of 6 groups of rats, the wet mass was weighed by an electronic balance, the dry mass was weighed after 10 minutes of microwave baking, and the water content percentage of the stool was calculated, and experimental data are shown in table 1.
TABLE 1 moisture content of faeces before and after treatment of rats
| Group of | Number of rats | 1d before treatment | Post-treatment 7d |
| Model group | 19 | 7.03±2.45 | 10.12±2.30 |
| Linaclotide group | 21 | 8.12±2.57 | 22.19±2.18 |
| Bifidobacterium group | 23 | 7.43±1.49 | 20.88±1.76 |
| Hard capsule group | 20 | 6.56±2.10 | 30.27±1.58 |
| Microcapsule group | 21 | 7.10±2.98 | 33.05±2.33 |
| Normal group | 20 | 30.44±2.01 | 29.76±2.87 |
Comparison with the Normal group P <0.01
(2) Determination of neuropeptide SP content in intestinal mucosal tissue: the small intestine mucous membrane tissues were obtained by laparotomy of each group of rats, the SP content thereof was measured by the radioimmunoassay, and the measurement results are shown in Table 2.
TABLE 2 variation of SP content in rat intestinal mucosal tissue
(1) P <0.01, compared to normal group; (2) p <0.01, compared to model group
Example 7
Microcapsules containing bifidobacterium hornii, bifidobacterium bovis and bifidobacterium lactis were prepared by the preparation method of example 4, and the efficacy was examined by animal experiments of example 6. The results are shown in Table 3.
TABLE 3 moisture content of feces before and after treatment with various bifidobacteria
| Group of | 1d before treatment | Post-treatment 7d |
| Model group | 8.13±2.41 | 10.70±1.15 |
| Bifidobacterium animal microcapsule group | 7.60±2.17 | 31.21±2.13 |
| Bifidobacterium adolescentis microcapsule group | 8.00±2.88 | 31.61±2.47 |
| Bifidobacterium breve microcapsule group | 7.72±2.11 | 30.83±2.21 |
| Bifidobacterium carotovorum microcapsule group | 7.69±1.97 | 28.56±2.55 |
| Bifidobacterium lactis microcapsule group | 7.99±2.81 | 28.98±1.67 |
Claims (7)
1. A linaclotide compound composition, which is characterized in that: the compound composition comprises linaclotide or a salt thereof and live bifidobacterium bacteria, wherein the weight part of the linaclotide or the salt thereof is 145-290, the weight part of the live bifidobacterium bacteria is 18000-25000, and the bifidobacterium is one or more selected from bifidobacterium adolescentis, bifidobacterium angulatum, bifidobacterium animalis, bifidobacterium breve and bifidobacterium lactis; the compound composition is linaclotide microcapsule; in the linaclotide microcapsule, the linaclotide or salt thereof is wrapped by a capsule wall material, and the live bifidobacteria are attached and inlaid on the surface of the capsule wall material;
the compound composition is prepared by a method comprising the following steps: 1) Weighing a prescription amount of linaclotide or salt thereof, dissolving the linaclotide or salt thereof in an aqueous solution of calcium chloride, and regulating the pH value of the solution to be 2-7 to obtain a solution A; 2) Weighing the viable bifidobacterium bacteria with the prescription amount, and dispersing the viable bifidobacterium bacteria in an aqueous solution of alginic acid or a salt thereof to obtain a solution B; 3) Atomizing the solution B; 4) Uniformly spraying the atomized solution B into the solution A, and standing for solidifying the solution; 5) After the solidification is completed, filtering and collecting a solidified substance; 6) Drying to obtain linaclotide microcapsule; the concentration of the calcium chloride in the solution A is 0.2-0.4M; the concentration of the aqueous solution of alginic acid or its salt is 0.5-5% by weight.
2. Use of the linaclotide compound composition according to claim 1, characterized in that: the application is used for preparing the medicine for treating and preventing constipation diseases.
3. An oral preparation of linaclotide, characterized in that: the oral formulation comprises the linaclotide compound composition of claim 1.
4. Use of the linaclotide oral formulation according to claim 3, characterized in that: the application is used for preparing the medicine for treating and preventing constipation diseases.
5. A process for the preparation of an oral formulation of linaclotide according to claim 3, characterized in that it comprises the following steps: 1) Weighing a prescription amount of linaclotide or salt thereof, dissolving the linaclotide or salt thereof in an aqueous solution of calcium chloride, and regulating the pH value of the solution to be 2-7 to obtain a solution A; 2) Weighing the viable bifidobacterium bacteria with the prescription amount, and dispersing the viable bifidobacterium bacteria in an aqueous solution of alginic acid or a salt thereof to obtain a solution B; 3) Atomizing the solution B; 4) Uniformly spraying the atomized solution B into the solution A, and standing for solidifying the solution; 5) After the solidification is completed, filtering and collecting a solidified substance; 6) Drying to obtain linaclotide microcapsule; the concentration of the calcium chloride in the solution A is 0.2-0.4M; the concentration of the aqueous solution of alginic acid or its salt is 0.5-5% by weight.
6. The method for preparing linaclotide microcapsule according to claim 5, characterized in that: in the step 6), the drying treatment is carried out by adopting a freeze drying process.
7. The method for preparing linaclotide microcapsule according to claim 6, characterized in that: the freeze-drying process comprises the following steps: 1) Pre-freezing, cooling to-40deg.C at a cooling rate of 0.1-0.5deg.C/min, and maintaining for 2-4 hr; 2) Primary drying at-2-2deg.C; 3) The secondary drying is carried out at a temperature of 20-30 ℃.
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| 拉克替醇和婴儿双歧杆菌对便秘大鼠AQP3及ICC的影响;丁一芮;《中国优秀硕士学位论文全文数据库 医药卫生科技辑》;20170228;第E064-74页 * |
| 氟哌噻吨美利曲辛联合双歧杆菌四联活菌治疗肠易激综合征的临床效果;李传;《临床医学》;20180630;第38卷(第6期);第104-105页 * |
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