CN115105582A - Pharmaceutical composition containing linaclotide or linaclotide salt and preparation method thereof - Google Patents

Pharmaceutical composition containing linaclotide or linaclotide salt and preparation method thereof Download PDF

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Publication number
CN115105582A
CN115105582A CN202110287073.3A CN202110287073A CN115105582A CN 115105582 A CN115105582 A CN 115105582A CN 202110287073 A CN202110287073 A CN 202110287073A CN 115105582 A CN115105582 A CN 115105582A
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drug
pharmaceutical composition
linaclotide
percent
pellet
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王蕊瑞
范道兵
曾金
孙运栋
王小雷
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/501—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives

Abstract

The invention discloses a pharmaceutical composition containing linaclotide or a salt thereof and a preparation method thereof. The drug composition comprises drug-containing pellets consisting of blank pellet cores and drug-containing layers, wherein the drug-containing layers comprise active substance components, metal cations, protective amino acid and adhesive. The pharmaceutical composition prepared by the invention improves the stability of the pharmaceutical composition while ensuring the release of the drug, is beneficial to the production and storage of the drug, and further improves the safety of the drug.

Description

Pharmaceutical composition containing linaclotide or linaclotide salt and preparation method thereof
Technical Field
The invention belongs to the field of medicinal preparations, and particularly relates to a composition containing linaclotide or a salt thereof and a preparation method thereof.
Background
The chemical name of linaclotide is L-cysteinyl-L-glutamyl-L-tyrosyl-L-cysteinyl-L-asparaginyl-L-prolyl-L-alanyl-L-cysteinyl-L-threonyl-glycyl-L-cysteinyl-L-tyrosine loop (1-6), (2-10), (5-13) -tri (disulfide bond), polypeptide consisting of 14 amino acids. The chemical structural formula is as follows:
Figure BDA0002980908550000011
the polypeptide is generally the most active in a solution state, so the polypeptide drug is usually developed into a water-soluble preparation, but the polypeptide drug is easy to generate typical degradation phenomena such as aggregation, oxidation, hydrolysis and the like in an aqueous solution, is not particularly stable in general, and needs refrigeration or freezing storage to prolong the storage time.
Linaclotide (linaclotide) was developed by Ironwood, now co-developed and marketed by elankang (in areas other than asia, japan, etc.), anstailai (in japan, indonesia, korea, philippines, taiwan china and thailand), astrazene (in areas within china, hong kong and australia), is the first GC-C agonist worldwide for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) and Chronic Idiopathic Constipation (CIC).
The trade name of original research company on the market in China is Shu-ze
Figure BDA0002980908550000012
Its formulation patent CN200980140931.9 discloses a composition containing linaclotide, which comprises linaclotide and Ca 2+ Solid compositions of cations and leucine can achieve a shelf life of at least 18 months or at least 24 months under room temperature storage conditions (e.g., 25 ℃/RH 60% relative humidity).
Because the linaclotide is easily affected by moisture during the storage process to accelerate the degradation of the linaclotide, gelatin capsule shells are adopted for filling in the patent. The moisture content of gelatin capsule shells is generally high and when stored with a desiccant, although the desiccant can absorb a portion of the moisture content of the capsule shell, the moisture content of the capsule shell is maintained at a high level (10%), which adversely affects the stability of linaclotide, while excessive water loss from the gelatin capsule shell risks embrittlement and fragmentation.
The plant source capsule shell hydroxypropyl methylcellulose hollow capsule shell has low water content, and the physical stability of the capsule shell can be still maintained when the water content of the capsule shell is 1 percent according to literature reports. However, linaclotide is slightly less compatible with its major component HPMC.
Due to the problems in the prior art, the development of the linaclotide pharmaceutical composition with excellent dissolution rate and better stability effect is of great significance.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a pharmaceutical composition of linaclotide or a salt thereof with good stability and a preparation method thereof.
The drug composition containing linaclotide or pharmaceutically acceptable salts thereof comprises drug-containing pellets consisting of blank pellet cores and drug-containing layers, wherein the drug-containing layers comprise active substance components, metal cations, protective amino acids and adhesives, and the protective amino acids are selected from histidine, leucine, proline or valine; .
Further, the metal cation is selected from Ca 2+ 、Mg 2+ 、Zn 2+ ，Mn 2+ ，K + Or Na + (ii) a The binder is selected from Hypromellose (HPMC), Hyprolose (HPC), polyvinylpyrrolidone (PVP) or polyvinyl alcohol (PVA); the blank pellet core is selected from sucrose pellet core or microcrystalline cellulose pellet core.
Further, the blank pellet core is selected from microcrystalline cellulose pellet cores; the microcrystalline cellulose micro-pill accounts for 90-99 percent, preferably 94-99 percent of the drug-containing micro-pill in percentage by weight.
Furthermore, the particle size of the microcrystalline cellulose pellet core is 300-500 μm.
Furthermore, the linaclotide accounts for 0.05 to 0.50 percent, preferably 0.15 to 0.30 percent of the drug-containing pellets in percentage by weight;
further, the protecting amino acid is selected from histidine; the protective amino acid accounts for 0.3-5.0% of the drug-containing pellet, preferably 0.3-3.0%, more preferably 0.3-1.2%, and even more preferably 0.6-0.9% by weight.
Further, the metal cation is selected from Ca 2+ Preferably one or more of calcium chloride, calcium phosphate, calcium sulfate or calcium acetate; more preferably calcium chloride or its hydrate salt; the metal cation salt accounts for 0.5 to 5.0 percent of the drug-containing pellet, preferably 1.0 to 3.0 percent, more preferably 1.0 to 2.0 percent by weight.
Further, the binder is selected from hypromellose; the adhesive accounts for 0.1 to 4.0 percent of the drug-containing pellets, preferably 0.5 to 2.0 percent, more preferably 0.5 to 1.0 percent by weight.
Further, the metal cation in the composition: protection of amino acid: the molar ratio of the active substance components is 40-80: 20-100: 1; the preferred ratio is 50-70: 25-75: 1, more preferably 55-65: 25-50: 1, further preferably 55 to 65: 25-35: 1, most preferably 60: 30: 1.
in a preferred scheme of the invention, the drug-containing pellets comprise the following components in percentage by weight:
Figure BDA0002980908550000031
preferably, the first and second electrodes are formed of a metal,
Figure BDA0002980908550000032
more preferably still, the first and second liquid crystal compositions are,
Figure BDA0002980908550000033
it is further preferred that the first and second liquid crystal display panels,
Figure BDA0002980908550000034
it is still further preferred that the first and second substrates are,
Figure BDA0002980908550000041
most preferably, the first and second substrates are,
Figure BDA0002980908550000042
in the preferable scheme of the invention, the drug-containing pellets can be further coated with an inert coating and then filled in a hydroxypropyl methylcellulose hollow capsule shell with lower water content, so that the stability of the product is further improved. The coating layer comprises a film forming material and an anti-sticking agent; the film forming material is selected from polyvinyl alcohol; the antisticking agent is selected from one or more of talcum powder and titanium dioxide.
Further, the mass ratio of the film forming material to the anti-sticking agent is 1: 1.
the invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps:
1) providing an acidic aqueous solution comprising:
contains linaclotide or pharmaceutically acceptable salt;
metal cations and protected amino acids;
(iii) optionally, a pharmaceutically acceptable binder;
2) spraying the acidic aqueous solution on the blank pellet core by a fluidized bed coating and medicine application method to obtain a medicine-containing pellet;
3) optionally, coating the drug-containing pellets to obtain coated pellets;
4) the drug-containing pellets or the coated pellets are filled in the hard capsule shell.
The hard capsule shell can be selected from a gelatin hollow capsule shell or a hydroxypropyl methylcellulose hollow capsule shell.
The capsule can be filled in an HDPE bottle together with a certain proportion of a drying agent, and 6M related substances under accelerated conditions (40 ℃/RH 75%) show that the total impurity increase is less than or equal to 2.0%, andhas better stability than a reference preparation, namely, luezhu
Figure BDA0002980908550000043
。
The capsule can be packaged in a PTP bubble cap mode, is sealed in a composite membrane bag together with a certain weight of drying agent, and has an acceleration condition (40 ℃/RH 75%) of 6M related substances, wherein the total impurity increase is less than or equal to 2.0%, and the stability of the capsule is better than that of a reference preparation namely Yizeshu
Figure BDA0002980908550000052
。
Compared with the prior art, the invention has the following advantages and beneficial effects:
1. the preparation method is simple and convenient, is simple to operate, and is easy for industrial amplification production;
2. the pharmaceutical composition has good stability, and related substances grow slowly, so that the production and storage of products are facilitated;
3. the pharmaceutical composition prepared by the invention has good effect of improving constipation, can obviously shorten defecation time, promote the movement of small intestine and increase the defecation quantity and weight.
Drawings
FIG. 1 is a comparison of in vitro dissolution profiles of the capsules of the present invention and reference formulations.
Detailed Description
In order to better explain the present invention, the present invention will be further described with reference to the following specific examples, but the scope of the present invention is not limited to the examples.
Examples 1 to 8: preparation of linaclotide drug-containing micro-pill
The prescription of the specific embodiment: the prescription is detailed in the following table 1:
TABLE 1 formulation composition of linaclotide-containing pellets
Figure BDA0002980908550000051
Figure BDA0002980908550000061
The preparation scheme is as follows:
(1) preparation of coating solution: coating liquids were prepared according to the recipe of the above examples, and the specific preparation method is as follows:
preparing hydrochloric acid with pH1.75; adding a proper amount of hydrochloric acid into 1L of purified water, and controlling the ph range to be 1.5-2.0.
Weighing a proper amount of hydrochloric acid aqueous solution, adding a prescription amount of inorganic salt containing metal cations, and stirring until the inorganic salt is dissolved;
adding amino acid in the amount of the prescription, and stirring until the amino acid is dissolved;
thirdly, adding the adhesive in the prescription amount, stirring until the adhesive is dissolved, and adjusting the pH value to be 1.5-2.0.
Fourthly, adding the linaclotide with the prescription amount and stirring until the linaclotide is completely dissolved.
Fifthly, sieving the solution with a 80-mesh sieve for later use.
(2) Preparing pellets by coating and feeding on a fluidized bed:
and (3) putting the microcrystalline cellulose pellet cores into a Mini Glatt pellet coating machine, setting the air inlet temperature to be 60-70 ℃, preheating the pellet cores to be more than 40 ℃, and respectively spraying the linaclotide-containing coating liquid prepared according to the different embodiments onto blank pellet cores to prepare the drug-containing pellets containing linaclotide.
Examples 9 to 10: preparation of coated pellets
The drug-containing pellets prepared in example 2 and example 5 were further coated with a water-soluble coating solution containing 50% PVA and 50% talc by using a fluidized bed, and the coating weight was increased by 3% to obtain coated pellets.
TABLE 2 formulation composition of linaclotide-containing coated pellets
Figure BDA0002980908550000062
Experimental example 1: stability study of pellets
In order to quickly evaluate the influence of the types and the dosage of amino acids and the dosage of metal ions on the stability of products, the pellets containing linaclotide prepared in the above examples 1-9 and the reference preparation pellets (batch number: W50128) were placed in an environment of 40 ℃/RH 75% for 30 days, and the influence of the prescription composition on the stability of the pellets was evaluated by examining the change of related substances of the pellets of different prescriptions by an HPLC liquid phase method. The stability results are shown in Table 3.
Table 3: pellet stability (40 ℃/RH 75-30 d) related substance investigation result
Figure BDA0002980908550000071
According to the stability test result, the preparation containing leucine in the prescription has the degradation degree of Cys 1-ketone greater than that of pellets consisting of other amino acids. Example 6, example 7 micropellets prepared hydrolysing impurity ASP 7 The degree of degradation was greater, with the pellets prepared in example 3, example 5, example 6, example 8 showing relatively better stability in the prediction, and the stability after coating (example 9, example 10) was slightly better than for the uncoated pellets.
Experimental example 2: study on stability of self-made capsules
The drug-containing pellets prepared in the above examples 2, 5, 6 and 8 were filled in 2# gelatin empty capsules in a loading of 290 μ g; the coated pellets prepared in example 9 and example 10 were filled into # 2 hypromellose empty capsules according to a loading of 290 μ g, and the stability of the two packaging forms was examined:
the packaging form I is as follows: respectively filling 7 granules/bottle with 1g of silica gel column desiccant, and filling into High Density Polyethylene (HDPE) bottles.
And a second packaging form: PTP package is 7 granules/plate, contains 1g of bagged desiccant, and is sealed by a composite film bag.
Examination conditions and time: the mixture was placed at 40 ℃/RH 75% at 6M.
The results show that the stability of HDPE bottles is slightly better than that of blister packaging, and the capsules filled with hypromellose empty capsules are stableThe qualitative was slightly better. The stability of examples 9 and 10 was better than that of uncoated examples 2 and 5, and was mainly shown in ASP 7 And Cys 1-one degradation was reduced. See in particular table 4 below:
table 4: investigation result of capsule stability-related substances
Figure BDA0002980908550000081
Experimental example 3: investigation of dissolution rate of linaclotide capsules
The drug-containing pellets prepared in the above examples 2, 5 and 6 were filled into # 2 gelatin empty capsules according to the loading of 290 μ g, and dissolution of the capsules of the above 3 examples and the reference preparation capsules in phosphate buffered saline ph4.5 was examined, respectively.
The dissolution method comprises the following steps:
a dissolution device: basket method;
rotating speed: 100 rpm;
medium: 0.05M sodium dihydrogen phosphate, 500 ml/cup, temperature 37 + -0.5 deg.C;
sampling time points are as follows: 5min, 10min, 15min and 30 min;
the results show that: the dissolution speed of the product is not obviously influenced by different types and dosage of the amino acid.
The specific results are shown in figure 1.
Experimental example 4: research on experimental treatment effect of linaclotide on mouse constipation model
Since linaclotide is administered orally with a major action zone in the intestinal tract, and hardly absorbed by blood, an animal model was established and the influence of the capsule and the reference preparation of example 5 on pharmacodynamics was examined, respectively.
The purpose is as follows: the experimental therapeutic effect of linaclotide (self-made preparation) on constipation in mice was evaluated.
The method comprises the following steps: 60 ICR mice were randomized into 6 groups of 10 mice per group by weight: blank control group, model group, linaclotide (commercially available preparation) 200. mu.g/kg group, linaclotide (self-made preparation) 400. mu.g/kg group, linaclotide (self-made preparation) 200. mu.g/kg group, linaclotide (self-made preparation) 100. mu.g/kg group. After fasting for 16-24h, the blank control group is given with a solvent, and the other groups are fed with 10mg/kg compound diphenoxylate for molding. And performing intragastric administration on the prepared Chinese ink 30min after the model building, performing intragastric administration on the test object with the corresponding concentration according to the administration volume of 10ml/kg for each group, performing single administration, and stopping water and not fasting after the administration.
Mice were raised in a single cage, and the first black stool discharge time, the number of stools within 5 hours, and the stool weight were recorded and statistically compared with SPSS.
As a result: compared with the defecation time 74.50 +/-4.63 min of the blank control group, the defecation time of the model group is prolonged to 129.30 +/-18.54. After the administration of the drugs, defecation times of the linaclotide (commercially available preparation) group at 200. mu.g/kg, linaclotide (self-made preparation) group at 400. mu.g/kg, linaclotide (self-made preparation) group at 200. mu.g/kg and linaclotide (self-made preparation) group at 100. mu.g/kg were 112.20 + -12.24, 92.20 + -8.40, 94.90 + -10.94 and 99.60 + -9.03 min, respectively, and were all shortened as compared with the model group.
Compared with the blank control group, the number of the feces is 16.10 +/-1.43, the number of the feces in the model group is obviously reduced to 2.50 +/-0.69 (P < 0.001). After the drugs were administered, the numbers of feces in the linaclotide (commercially available preparation) 200 μ g/kg group, linaclotide (self-made preparation) 400 μ g/kg group, linaclotide (self-made preparation) 200 μ g/kg group and linaclotide (self-made preparation) 100 μ g/kg group were 3.90 ± 0.59, 5.40 ± 0.70(P <0.05), 5.60 ± 0.91 (P <0.05) and 4.40 ± 1.09, respectively, which were more than the model group.
Compared with the blank control group, the weight of the feces is 0.3417 +/-0.0163 g, and the weight of the feces in the model group is obviously reduced to 0.0689 +/-0.0180 g (P is less than 0.001). After the administration of the drugs, the fecal weights of linaclotide (commercially available preparation) 200 μ g/kg group, linaclotide (self-made preparation) 400 μ g/kg group, linaclotide (self-made preparation) 200 μ g/kg group and linaclotide (self-made preparation) 100 μ g/kg group were 0.1438 ± 0.0384(P <0.05), 0.1776 ± 0.0120 (P <0.001), 0.1535 ± 0.0183(P <0.01) and 0.1165 ± 0.0215g, respectively, each group of fecal weights being higher than the model group.

Claims (12)

1. A drug composition containing linaclotide or a pharmaceutically acceptable salt thereof is characterized by comprising drug-containing pellets consisting of a blank pellet core and a drug-containing layer, wherein the drug-containing layer comprises an active substance component, metal cations, a protective amino acid and a binder, and the protective amino acid is selected from histidine, leucine, proline or valine.
2. The pharmaceutical composition of claim 1, wherein the metal cation is selected from the group consisting of Ca 2+ 、Mg 2+ 、Zn 2+ ，Mn 2 + ，K + Or Na + (ii) a The binder is selected from hypromellose, hyprolose, polyvidone or polyvinyl alcohol; the blank pellet core is selected from sucrose pellet core or microcrystalline cellulose pellet core.
3. The pharmaceutical composition of claim 2, wherein the blank pellet core is selected from the group consisting of a microcrystalline cellulose pellet core; the microcrystalline cellulose micro-pill accounts for 90-99 percent of the drug-containing micro-pill, preferably 94-99 percent.
4. The pharmaceutical composition according to claim 3, wherein the particle size of the microcrystalline cellulose pellet core is 300-500 μm.
5. The pharmaceutical composition of claim 1, wherein the protecting amino acid is selected from the group consisting of histidine; the protective amino acid accounts for 0.3-5.0% of the drug-containing pellet, preferably 0.3-3.0%, more preferably 0.3-1.2% by weight.
6. The pharmaceutical composition of claim 2, wherein the metal cation is selected from the group consisting of Ca 2+ Preferably one or more of calcium chloride, calcium phosphate, calcium sulfate or calcium acetate; more preferably calcium chloride or a hydrate salt thereof; the metal cation salt accounts for 0.5 to 5.0 percent of the drug-containing pellet, preferably 1.0 to 3.0 percent of the drug-containing pellet, and more preferably 1.0 to 2.0 percent of the drug-containing pellet.
7. The pharmaceutical composition of claim 2, wherein the binder is selected from the group consisting of hypromellose; the adhesive accounts for 0.1 to 4.0 percent of the drug-containing pellets, preferably 0.5 to 2.0 percent, more preferably 0.5 to 1.0 percent by weight.
8. The pharmaceutical composition of claim 2, wherein the ratio of metal cation: protection of amino acids: the molar ratio of active substance components is 40-80: 20-100: 1; the preferred ratio is 50-70: 25-75: 1; more preferably 55 to 65: 25-50: 1.
9. the pharmaceutical composition according to any one of claims 1 to 8, wherein the composition of the drug-containing pellet is as follows by weight percent:
Figure FDA0002980908540000021
preferably, the first and second electrodes are formed of a metal,
Figure FDA0002980908540000022
more preferably still, the first and second liquid crystal compositions are,
Figure FDA0002980908540000023
it is further preferred that the first and second liquid crystal compositions,
Figure FDA0002980908540000024
Figure FDA0002980908540000031
10. the pharmaceutical composition according to any one of claims 1 to 9, wherein the drug-containing pellets are further coated, the coating layer comprising a film-forming material and an anti-sticking agent; the film forming material is selected from polyvinyl alcohol; the antisticking agent is selected from one or more of talcum powder, titanium dioxide and silicon dioxide.
11. The pharmaceutical composition of claim 10, wherein the mass ratio of the film-forming material to the anti-sticking agent is 1: 1.
12. a process for the preparation of a pharmaceutical composition according to any one of claims 1 to 11, comprising the steps of:
1) providing an acidic aqueous solution comprising:
contains linaclotide or pharmaceutically acceptable salt;
metal cations and protected amino acids;
(iii) optionally, a pharmaceutically acceptable binder;
2) spraying the acidic aqueous solution on the blank pellet core by a fluidized bed coating and medicine application method to obtain a medicine-containing pellet;
3) optionally, coating the drug-containing pellets to obtain coated pellets;
4) the drug-containing pellets or the coated pellets are filled in the hard capsule shell.
CN202110287073.3A 2021-03-17 2021-03-17 Pharmaceutical composition containing linaclotide or linaclotide salt and preparation method thereof Pending CN115105582A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116672309A (en) * 2023-07-26 2023-09-01 北京普诺旺康医药科技有限公司 dry suspension pharmaceutical composition

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116672309A (en) * 2023-07-26 2023-09-01 北京普诺旺康医药科技有限公司 dry suspension pharmaceutical composition

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