CN111450076A - L emborexant soft capsule composition and preparation method thereof - Google Patents
L emborexant soft capsule composition and preparation method thereof Download PDFInfo
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- CN111450076A CN111450076A CN202010446368.6A CN202010446368A CN111450076A CN 111450076 A CN111450076 A CN 111450076A CN 202010446368 A CN202010446368 A CN 202010446368A CN 111450076 A CN111450076 A CN 111450076A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- 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
- A61K9/4816—Wall or shell material
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- 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
- A61K9/4816—Wall or shell material
- A61K9/4825—Proteins, e.g. gelatin
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- 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
- A61K9/4833—Encapsulating processes; Filling of capsules
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
Abstract
The invention discloses an L emborexant soft capsule composition and a preparation method thereof, wherein the soft capsule composition consists of liquid or semi-liquid content and a capsule shell, the content is a gelatinous composition consisting of L emborexant, gelatin and glycerol, and the capsule shell consists of the gelatin, the glycerol, water and an opacifier.
Description
One, the technical field
The invention relates to a soft capsule composition for an orexin receptor (orexin receptor) inhibitor L emborexant and a preparation method thereof, belonging to the technical field of pharmaceutical preparations.
Second, background Art
Insomnia is a common disease, and it is estimated that 10% to 30% of adults suffer from insomnia. This is a huge unmet medical need, however, since the development of safe, effective hypnotics is not easy, few new drugs are on the market in this field.
In 12 months 2019, new orexin receptor antagonist DAYVIGO tablets (common name: L emborexant) approved by FDA for treating insomnia of sanitary materials are sold on the market and are concerned by the industry.
L emborexant (leberexan), a dual inhibitor of the orexin receptors OX1 and OX2, was discovered and developed internally from defensive materials, which inhibits orexin by competitively binding to the orexin receptors of the 2-clock subtype (orexin receptor 1 and receptor 2.) in individuals with insomnia, the orexin system, which regulates sleep and wakefulness, may not function normally.
L emborexant (Leborasyn) is characterized by sleep onset and/or difficulty in sleep maintenance recent studies in the field of sleep disorders indicate that the cause of insomnia may not be the failure of the brain to "turn on" sleep-related circuits, but rather the failure to "turn off" wake-up promotion circuits.
Traditional medicines such as benzodiazepines and melatonin receptor antagonists can play a role in treating sleep, but most of the traditional medicines change the sleep structure and are accompanied by side effects such as residual effect, rebound insomnia, sleep disorder and the like. With the continuous and deep research on orexin receptors in the century, the orexin is found to play a vital role in the physiological function of sleep and can be used as a novel target point for treating insomnia. The orexin receptor antagonist only selectively blocks the orexin receptor, has no side effects of benzodiazepine drugs and the like, and has stronger pharmacological activity than the traditional hypnotic. The discovery of the compound provides a new approach for the research of treating insomnia, and also provides a selective treatment strategy for other orexin receptor-mediated pathologies such as drug addiction, obesity, depression, diet disorder and the like.
L emborexant (leberel) basic properties are as follows:
summary of Leibere Biochemical Properties
Prior art documents:
CN103153963B/WO2012039371, discloses the structure and preparation method of the compound, and shows that L emborexant is a poorly soluble molecule, which only achieves sufficient bioavailability in vivo when existing in an amorphous state.
CN107810006/WO2016063995 discloses an oral composition.
The soft capsule formulation is also called soft capsule, and is a preparation formed by sealing oil or non-water-soluble liquid or suspension without dissolving function to gelatin in a capsule shell, and the shape of the preparation is round, oval, fish-shaped, tubular and the like. The soft capsule is a new dosage form developed after tablet and injection, and its outer shell is made up by using gelatin through compression, and its capsule shell is filled with liquid medicine. It features its slower acting than injection, but faster acting than tablet, capsule and granule. Has high bioavailability, is more convenient to carry than oral liquid, can be made into slow release dosage forms such as enteric soft capsule and suppository by slightly changing capsule shell. Compared with other dosage forms, the soft capsule has the advantages of high bioavailability, accurate content, good uniformity, good appearance, and convenient administration. Therefore, soft capsules are becoming more and more popular with the market and patients.
The solid preparation needs to undergo the processes of disintegration, dissolution and absorption, which is quite unfavorable for the efficacy exertion of insoluble drugs, but the oral tablet can not accurately divide the dosage, unfortunately, L emborexant belongs to a water-insoluble drug, L emborexant is a tablet currently on the market, but L emborexant is almost insoluble in water, the dissolution rate is low after the tablet is prepared, the bioavailability of L emborexant is influenced, the individual difference is large, the curative effect is unstable, besides, L emborexant is easy to degrade under the action of light, the product quality is seriously influenced, the market specification indicates that the absorption of the solid preparation is greatly influenced by postprandial diet, and after L emborexant is orally taken after high-fat and high-calorie diet, the blood concentration reaches a peak value within about 3-5 hours, so that the urgent requirement of an insomnia patient for symptom relief is difficult to meet.
Factors that affect the bioavailability of a drug when administered orally include water solubility, drug absorption, dose strength, and first pass effect. Various salts or other derivatives of the drug may be prepared in order to obtain maximum water solubility. Various capsule dosage forms may also be formulated to maximize the bioavailability of the drug.
Therefore, developing a novel L emborexant oral preparation capable of rapidly exerting therapeutic effect, and increasing the in vitro dissolution rate of the medicine becomes a technical problem facing those skilled in the art for improving bioavailability and clinical efficacy.
However, to date, none of the prior art documents provide scientific evidence for the development of L emorexant soft capsule dosage forms.
Third, the invention
The invention aims to provide a soft capsule which comprises L emborexant with effective treatment amount as an active ingredient.
However, when conventional solvents are used to obtain clear solutions, the soft capsule system can be problematic, e.g., leakage of the soft capsule contents, migration of the drug, migration of the solvent, disqualification of the gelatin due to disintegration, failure to release the drug, etc. therefore, it is desirable to provide, first, liquid or semi-solid-liquid compositions suitable for formulating L emobrexant soft capsules that are stable and do not reduce the bioavailability of the active ingredient, or even significantly enhance the bioavailability of the active ingredient.
The invention has been completed through further research on the physicochemical properties of L emborexant, particularly through screening and composing of auxiliary materials such as matrix, cosolvent and the like in the soft capsule, and compared with the existing tablet, the blood concentration of the soft capsule after oral administration of the invention reaches the peak value rapidly, and the relative bioavailability is improved remarkably, and the effect can not be predicted by the technical personnel in the field.
Specifically, the invention is realized by the following technical scheme:
the invention mainly aims to provide an L emborexant soft capsule composition, which consists of a soft capsule rubber and a liquid or semi-liquid content pharmaceutical composition wrapped on the rubber, wherein the liquid or semi-liquid content pharmaceutical composition mainly comprises the following substances in percentage by weight:
Lemborexant 1％～10％
30 to 65 percent of gelatin
20 to 50 percent of glycerin
The soft capsule rubber mainly comprises the following substances in percentage by weight:
the L emborexant soft capsule does not use vegetable oil or fatty acid esters and polyethylene glycol substances as solvents, but uses gelatin and glycerin as L emborexant solvents, wherein the oil and fat components are unsaturated fatty acids which are easy to oxidize, the acid value and peroxide value of the oil and fat components are easy to exceed the standards, the product quality is influenced, the oil and fat components are harmful to human bodies, meanwhile, the oil and fat components have certain influence on product detection due to complex components, and the product quality monitoring is not facilitated, the gelatin and the glycerin are water-soluble matrixes and have better affinity with water, the capsule shells are easier to disperse and absorb after being broken, and the gelatin and the glycerin have long use history, have better stability relative to the oil and fat solvents, do not interfere with L emborexant detection, are favorable for monitoring and controlling the product quality, and have more reliable guarantee on the quality of the whole product.
The gelatin is a mixture of hydrolyzed gelatin and 80-120 bloom gelatin. The hydrolyzed gelatin is the product of collagen protein hydrolyzed by enzyme (acid or alkali), and is more easily absorbed by human body than collagen protein, and can exert its effect more effectively. Hydrolyzed gelatin is an enzymatic breakdown product of collagen, and actually hydrolyzed gelatin is more effective by oral administration. Hydrolyzed gelatin is well studied abroad in western european countries such as japan and germany, france, etc. And (3) after hydrolysis, the peptide bond is broken to become polypeptide, the molecular weight is reduced to 2000-10000, and the polypeptide can be dissolved in water at normal temperature. The 20% aqueous solution has a viscosity of about 50Pa/s at 25 deg.C, and the solution does not freeze again after cooling. The gelatin also uses a substance with gelatin gel strength of 80-120 bloom, and the gelatin and the substance are used in a reasonable proportion range, so that the prepared content can be directly absorbed.
The L emborexant soft capsule content also comprises glycerin which is an anti-water absorption component and can weaken the water absorption effect of the gelatin on the soft capsule shell, so that the hardening effect of the gelatin on the capsule shell is avoided.
The L emborexant soft capsule takes gelatin as a solvent of L emborexant, and simultaneously forms L emborexant liquid or contents of the semisolid-liquid soft capsule with glycerin which is a water absorption resistant component, L emborexant exists in the soft capsule in a solution form, the soft capsule is convenient to take, after a capsule shell is disintegrated, L emborexant can be directly absorbed, the absorption is not needed in a re-emulsification mode in a body, the dissolution speed is higher, and the soft capsule is more direct, rapid and effective.
The capsule shell is a special component of the soft capsule preparation, and effectively isolates the medicine from contacting with the outside, protects the medicine in the capsule shell and ensures that the medicine is more stable. However, the soft capsule product has a main problem that the capsule shell is aged along with the prolonging of the storage time, so that the disintegration time is prolonged, even the soft capsule is not disintegrated, and the drug release of the soft capsule is realized only after the capsule shell is disintegrated, so that the capsule shell has larger influence on the drug effect, and the improvement of the disintegration time of the capsule shell has direct influence on the drug quality. The soft capsule shell consists of gelatin, glycerin, opacifier and water.
Furthermore, the gelatin in the soft capsule shell has gel strength of one of 160-180 bloom, 200-220 bloom and 240-260 bloom.
Since L emorexant is sensitive to light and easily decomposed by light, which affects the quality of the product, the soft capsule shell of the present invention further comprises an opacifier to avoid the photodegradation of L emorexant drugs, wherein the opacifier can be any one known to those skilled in the art.
The invention also aims to provide a preparation method of the L emborexant soft capsule composition, which comprises the following specific technical scheme:
1) preparing contents by heating gelatin and glycerol in the prescription of the contents to 60 +/-5 ℃ until the gelatin and the glycerol are completely melted, cooling to 45 +/-5 ℃, adding L emborexant, and uniformly stirring to obtain a gel substance for later use;
2) preparing sol and capsule shell: heating water and glycerol to 80 + -5 deg.C, adding gelatin for melting, dissolving opacifier with glycerol, dispersing, adding into the glue solution, stirring, degassing, filtering to obtain glue solution, keeping the temperature at 60 + -5 deg.C, and standing for 24 hr;
3) filling capsules, and preparing soft capsules: installing a mold, debugging the soft capsule machine, pressing the heat-preservation gelatin solution into a gelatin box of the soft capsule machine by using an air compressor, controlling the temperature of the gelatin box to be 55 +/-5 ℃, controlling the rotating speed of the mold to be 2.6cm/min, and controlling the temperature of a spraying body to be 40-42 ℃; adding the liquid medicine of the content into a material storage compartment of the soft capsule machine, starting the machine, adjusting the loading amount, observing that the appearance of the soft capsule is round and neat without deformity and convex head, ensuring tight and neat locking degree and no protruding edge leakage phenomenon, and starting the machine for pressing;
4) drying, introducing the pressed soft capsule into opened shaping rotary cage, shaping with cold air (shaping temperature controlled at room temperature) until soft capsule skin is primarily hard, primarily drying, washing with anhydrous ethanol, drying to obtain semi-finished product, inspecting to obtain qualified finished product, and packaging with inner package, middle package, outer package, and warehousing.
The drying of the present invention is divided into two parts. The primary drying is rolling drying, the primary drying process is also the shaping and shaping process of the soft capsule, the temperature is controlled at 25 ℃, the humidity is about 45 percent, and the drying time is 100 minutes. And after the first-stage drying is finished, the second-stage flat drying is carried out, and the process is carried out under the conditions that the temperature is 21-24 ℃ and the humidity is 25%. Drying until the water content of the soft capsule is 11-14% and the hardness is 42-48 HA, collecting the sample, transferring the sample to a cool warehouse, and packaging.
In addition, the L emborexant soft capsule can effectively solve the defects of unbalanced dissolution and large individual difference after the tablet is taken (because the tablet is greatly influenced by absorption after high-fat and high-calorie meals, the unbalanced dissolution is caused and the blood peak time is long), can be directly absorbed and utilized, and has high bioavailability and stable curative effect.
Fourth, detailed description of the invention
The detailed description is merely illustrative or explanatory of the invention and should not be construed as limiting the invention in any way. Unless otherwise specified, the methods used in the following examples are all conventional methods.
EXAMPLE 1 preparation of 1L emborexant Soft Capsule
Prescription (2.5 mg/capsule):
the preparation process comprises the following steps:
1) preparing contents by heating gelatin and glycerol in the prescription of the contents to 60 +/-5 ℃ until the gelatin and the glycerol are completely melted, cooling to 45 +/-5 ℃, adding L emborexant, and uniformly stirring to obtain a gel substance for later use;
2) preparing sol and capsule shell: heating water and glycerol to 80 + -5 deg.C, adding gelatin for melting, dissolving opacifier with glycerol, dispersing, adding into the glue solution, stirring, degassing, filtering to obtain glue solution, keeping the temperature at 60 + -5 deg.C, and standing for 24 hr;
3) filling capsules, and preparing soft capsules: installing a mold, debugging the soft capsule machine, pressing the heat-preservation gelatin solution into a gelatin box of the soft capsule machine by using an air compressor, controlling the temperature of the gelatin box to be 55 +/-5 ℃, controlling the rotating speed of the mold to be 2.6cm/min, and controlling the temperature of a spraying body to be 40-42 ℃; adding the liquid medicine of the content into a material storage compartment of the soft capsule machine, starting the machine, adjusting the loading amount, observing that the appearance of the soft capsule is round and neat without deformity and convex head, ensuring tight and neat locking degree and no protruding edge leakage phenomenon, and starting the machine for pressing;
4) drying, introducing the pressed soft capsule into opened shaping rotary cage, shaping with cold air (shaping temperature controlled at room temperature) until soft capsule skin is primarily hard, primarily drying, washing with anhydrous ethanol, drying to obtain semi-finished product, inspecting to obtain qualified finished product, and packaging with inner package, middle package, outer package, and warehousing.
EXAMPLE 2 preparation of 2L emborexant Soft Capsule
Prescription (5.0 mg/capsule):
the preparation process comprises the following steps:
1) preparing contents by heating gelatin and glycerol in the prescription of the contents to 60 +/-5 ℃ until the gelatin and the glycerol are completely melted, cooling to 45 +/-5 ℃, adding L emborexant, and uniformly stirring to obtain a gel substance for later use;
2) preparing sol and capsule shell: heating water and glycerol to 80 + -5 deg.C, adding gelatin for melting, dissolving opacifier with glycerol, dispersing, adding into the glue solution, stirring, degassing, filtering to obtain glue solution, keeping the temperature at 60 + -5 deg.C, and standing for 24 hr;
3) filling capsules, and preparing soft capsules: installing a mold, debugging the soft capsule machine, pressing the heat-preservation gelatin solution into a gelatin box of the soft capsule machine by using an air compressor, controlling the temperature of the gelatin box to be 55 +/-5 ℃, controlling the rotating speed of the mold to be 2.6cm/min, and controlling the temperature of a spraying body to be 40-42 ℃; adding the liquid medicine of the content into a material storage compartment of the soft capsule machine, starting the machine, adjusting the loading amount, observing that the appearance of the soft capsule is round and neat without deformity and convex head, ensuring tight and neat locking degree and no protruding edge leakage phenomenon, and starting the machine for pressing;
4) drying, introducing the pressed soft capsule into opened shaping rotary cage, shaping with cold air (shaping temperature controlled at room temperature) until soft capsule skin is primarily hard, primarily drying, washing with anhydrous ethanol, drying to obtain semi-finished product, inspecting to obtain qualified finished product, and packaging with inner package, middle package, outer package, and warehousing.
EXAMPLE 3 preparation of 3L emborexant Soft Capsule
Prescription (10 mg/pill):
the preparation process comprises the following steps:
1) preparing contents by heating gelatin and glycerol in the prescription of the contents to 60 +/-5 ℃ until the gelatin and the glycerol are completely melted, cooling to 45 +/-5 ℃, adding L emborexant, and uniformly stirring to obtain a gel substance for later use;
2) preparing sol and capsule shell: heating water and glycerol to 80 + -5 deg.C, adding gelatin for melting, dissolving opacifier with glycerol, dispersing, adding into the glue solution, stirring, degassing, filtering to obtain glue solution, keeping the temperature at 60 + -5 deg.C, and standing for 24 hr;
3) filling capsules, and preparing soft capsules: installing a mold, debugging the soft capsule machine, pressing the heat-preservation gelatin solution into a gelatin box of the soft capsule machine by using an air compressor, controlling the temperature of the gelatin box to be 55 +/-5 ℃, controlling the rotating speed of the mold to be 2.6cm/min, and controlling the temperature of a spraying body to be 40-42 ℃; adding the liquid medicine of the content into a material storage compartment of the soft capsule machine, starting the machine, adjusting the loading amount, observing that the appearance of the soft capsule is round and neat without deformity and convex head, ensuring tight and neat locking degree and no protruding edge leakage phenomenon, and starting the machine for pressing;
4) drying, introducing the pressed soft capsule into opened shaping rotary cage, shaping with cold air (shaping temperature controlled at room temperature) until soft capsule skin is primarily hard, primarily drying, washing with anhydrous ethanol, drying to obtain semi-finished product, inspecting to obtain qualified finished product, and packaging with inner package, middle package, outer package, and warehousing.
EXAMPLE 4 preparation of 4L emborexant Soft Capsule
Prescription (50 mg/pill):
the preparation process comprises the following steps:
1) preparing contents by heating gelatin and glycerol in the prescription of the contents to 60 +/-5 ℃ until the gelatin and the glycerol are completely melted, cooling to 45 +/-5 ℃, adding L emborexant, and uniformly stirring to obtain a gel substance for later use;
2) preparing sol and capsule shell: heating water and glycerol to 80 + -5 deg.C, adding gelatin for melting, dissolving opacifier with glycerol, dispersing, adding into the glue solution, stirring, degassing, filtering to obtain glue solution, keeping the temperature at 60 + -5 deg.C, and standing for 24 hr;
3) filling capsules, and preparing soft capsules: installing a mold, debugging the soft capsule machine, pressing the heat-preservation gelatin solution into a gelatin box of the soft capsule machine by using an air compressor, controlling the temperature of the gelatin box to be 55 +/-5 ℃, controlling the rotating speed of the mold to be 2.6cm/min, and controlling the temperature of a spraying body to be 40-42 ℃; adding the liquid medicine of the content into a material storage compartment of the soft capsule machine, starting the machine, adjusting the loading amount, observing that the appearance of the soft capsule is round and neat without deformity and convex head, ensuring tight and neat locking degree and no protruding edge leakage phenomenon, and starting the machine for pressing;
4) drying, introducing the pressed soft capsule into opened shaping rotary cage, shaping with cold air (shaping temperature controlled at room temperature) until soft capsule skin is primarily hard, primarily drying, washing with anhydrous ethanol, drying to obtain semi-finished product, inspecting to obtain qualified finished product, and packaging with inner package, middle package, outer package, and warehousing.
EXAMPLE 5 preparation of 5L emborexant Soft Capsule
Prescription (2.5 mg/capsule):
the preparation process comprises the following steps:
1) preparing contents by heating gelatin and glycerol in the prescription of the contents to 60 +/-5 ℃ until the gelatin and the glycerol are completely melted, cooling to 45 +/-5 ℃, adding L emborexant, and uniformly stirring to obtain a gel substance for later use;
2) preparing sol and capsule shell: heating water and glycerol to 80 + -5 deg.C, adding gelatin for melting, dissolving opacifier with glycerol, dispersing, adding into the glue solution, stirring, degassing, filtering to obtain glue solution, keeping the temperature at 60 + -5 deg.C, and standing for 24 hr;
3) filling capsules, and preparing soft capsules: installing a mold, debugging the soft capsule machine, pressing the heat-preservation gelatin solution into a gelatin box of the soft capsule machine by using an air compressor, controlling the temperature of the gelatin box to be 55 +/-5 ℃, controlling the rotating speed of the mold to be 2.6cm/min, and controlling the temperature of a spraying body to be 40-42 ℃; adding the liquid medicine of the content into a material storage compartment of the soft capsule machine, starting the machine, adjusting the loading amount, observing that the appearance of the soft capsule is round and neat without deformity and convex head, ensuring tight and neat locking degree and no protruding edge leakage phenomenon, and starting the machine for pressing;
4) drying, introducing the pressed soft capsule into opened shaping rotary cage, shaping with cold air (shaping temperature controlled at room temperature) until soft capsule skin is primarily hard, primarily drying, washing with anhydrous ethanol, drying to obtain semi-finished product, inspecting to obtain qualified finished product, and packaging with inner package, middle package, outer package, and warehousing.
EXAMPLE 6 preparation of 6L emborexant Soft Capsule
Prescription (10 mg/pill):
the preparation process comprises the following steps:
1) preparing contents by heating gelatin and glycerol in the prescription of the contents to 60 +/-5 ℃ until the gelatin and the glycerol are completely melted, cooling to 45 +/-5 ℃, adding L emborexant, and uniformly stirring to obtain a gel substance for later use;
2) preparing sol and capsule shell: heating water and glycerol to 80 + -5 deg.C, adding gelatin for melting, dissolving opacifier with glycerol, dispersing, adding into the glue solution, stirring, degassing, filtering to obtain glue solution, keeping the temperature at 60 + -5 deg.C, and standing for 24 hr;
3) filling capsules, and preparing soft capsules: installing a mold, debugging the soft capsule machine, pressing the heat-preservation gelatin solution into a gelatin box of the soft capsule machine by using an air compressor, controlling the temperature of the gelatin box to be 55 +/-5 ℃, controlling the rotating speed of the mold to be 2.6cm/min, and controlling the temperature of a spraying body to be 40-42 ℃; adding the liquid medicine of the content into a material storage compartment of the soft capsule machine, starting the machine, adjusting the loading amount, observing that the appearance of the soft capsule is round and neat without deformity and convex head, ensuring tight and neat locking degree and no protruding edge leakage phenomenon, and starting the machine for pressing;
4) drying, introducing the pressed soft capsule into opened shaping rotary cage, shaping with cold air (shaping temperature controlled at room temperature) until soft capsule skin is primarily hard, primarily drying, washing with anhydrous ethanol, drying to obtain semi-finished product, inspecting to obtain qualified finished product, and packaging with inner package, middle package, outer package, and warehousing.
Example 7 stability study
First, influence factor test investigation
The influence of L emborexant content, related substances and disintegration on the L emborexant soft capsule is determined by preliminarily examining L emborexant soft capsules under three severe conditions of high temperature, high humidity and light for 10d, and sampling the 1L emborexant soft capsules under the following three conditions.
1 high temperature test
The method comprises spreading the soft capsule of example 1L emborexant in a sealed and clean opaque container, and storing at 40 deg.C for 10 days.
2 high humidity test
Example 1L emborexant soft capsules were spread in a clean container and the container was placed open in a desiccator containing saturated sodium chloride solution (RH 75% ± 1%), protected from light and stored at below 25 ℃ for 10 days.
3 light test
The method comprises the following steps of spreading 1L emborexant soft capsules of example 1 in a clean transparent container, sealing and placing in an illumination box, placing for 10d under the condition of illumination intensity of 4500L x +/-500L x, and detecting various index parameters of L emborexant soft capsules by taking samples under the three conditions of 5d and 10d, wherein the measurement results are shown in the following table:
l emborexant soft capsule influence factor test result
Second, accelerated test investigation
Example 1L emborexant soft capsules, packed with aluminium-plastic blisters made of PCTFE material, were placed in a constant temperature and humidity cabinet at 40 ℃ and 75% relative humidity as required for new drug applications, and were sampled at 1, 2, 3 and 6 months, respectively, for the following test results:
l emborexant Soft Capsule accelerated test results
The influence factors and accelerated tests of the invention show that the sample of the invention is stable.
Example 8 bioavailability comparison
The results show that the preparation of the invention remarkably improves the absorption and utilization in vivo, remarkably improves the bioavailability, and is remarkably superior to the prior published L emborexant tablet composition preparation, and the results are shown in the following table:
the above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
Claims (7)
1. An L emborexant soft capsule composition, which consists of a soft capsule rubber and a liquid or semi-liquid content pharmaceutical composition wrapped on the rubber, and is characterized in that the liquid or semi-liquid content pharmaceutical composition mainly comprises the following substances in percentage by weight:
Lemborexant 1％～10％
30 to 65 percent of gelatin
20 to 50 percent of glycerin
The soft capsule rubber mainly comprises the following substances in percentage by weight:
2. the L emborexant soft capsule composition of claim 1, wherein the gelatin in the liquid or semi-liquid content pharmaceutical composition is a mixture of hydrolyzed gelatin and 80-120 bloom gelatin, and the glycerol is one or both of anhydrous glycerol and 85% glycerol.
3. The L emborexant soft capsule composition of claim 1, wherein the gelatin in the soft capsule shell is one of 160-180 bloom gelatin, 200-220 bloom gelatin and 240-260 bloom gelatin.
4. The L emborexant soft capsule composition of claim 1, wherein the opacifier in the soft capsule shell is one or more of titanium dioxide, red iron oxide, black iron oxide and yellow iron oxide.
5. The L emborexant soft capsule composition of claim 1, wherein L emborexant is contained in an amount of 1.0-15 mg/capsule.
6. The L emborexant soft capsule composition of claim 5, wherein L emborexant is contained in an amount of 2.0-10 mg/capsule.
7. The method of preparing the L emorexant soft capsule composition of any of claims 1-6, comprising the steps of:
1) preparing contents by heating gelatin and glycerol in the prescription of the contents to 60 +/-5 ℃ to completely melt, cooling to 45 +/-5 ℃, adding L emborexant, and stirring uniformly to obtain a gel substance for later use;
2) preparing capsule skin: heating water and glycerol to 80 + -5 deg.C, adding gelatin for melting, dissolving opacifier with glycerol, dispersing, adding into the glue solution, stirring, degassing, filtering to obtain glue solution, keeping the temperature at 60 + -5 deg.C, and standing for 24 hr;
3) preparing the soft capsule: installing a mold, debugging the soft capsule machine, pressing the heat-preservation gelatin solution into a gelatin box of the soft capsule machine by using an air compressor, controlling the temperature of the gelatin box to be 55 +/-5 ℃, controlling the rotating speed of the mold to be 2.6cm/min, and controlling the temperature of a spraying body to be 40-42 ℃; adding the liquid medicine of the content into a material storage compartment of the soft capsule machine, starting the machine, adjusting the loading amount, observing that the appearance of the soft capsule is round and neat without deformity and convex head, ensuring tight and neat locking degree and no protruding edge leakage phenomenon, and starting the machine for pressing;
4) and (3) guiding the pressed soft capsules into an opened sizing rotating cage, sizing for about 1h by cold air (the sizing temperature is controlled to be 18-20 ℃) until the soft capsule skin is initially hardened, primarily drying, washing by absolute ethyl alcohol, drying to obtain a semi-finished product, inspecting to be qualified to obtain a finished product, and carrying out inner packaging, intermediate packaging, outer packaging and warehousing to obtain the soft capsule.
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| CN114983962A (en) * | 2021-03-02 | 2022-09-02 | 仙乐健康科技股份有限公司 | Soft capsule shell composition, soft capsule and preparation method and application thereof |
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| CN114983962A (en) * | 2021-03-02 | 2022-09-02 | 仙乐健康科技股份有限公司 | Soft capsule shell composition, soft capsule and preparation method and application thereof |
| CN114983962B (en) * | 2021-03-02 | 2024-03-15 | 仙乐健康科技股份有限公司 | Soft capsule shell composition, soft capsule, preparation method and application thereof |
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