CN117679367A - Perilla Wo Leisheng oral emulsion and preparation method thereof - Google Patents

Abstract

The invention relates to the technical field of preparation of pharmaceutical preparations, in particular to a Perilla Wo Leisheng oral emulsion and a preparation method thereof. The oral emulsion is composed of a main medicine suvorexant, an auxiliary material solubilizer, an emulsifying agent, an antioxidant and a flavoring agent. The preparation process is simple, and is beneficial to industrial production; the prepared suvorexant oral emulsion has good sleep-aiding effect and high bioavailability; the emulsion formed is stable, is little affected by digestion, and can promote the absorption of medicines; the oral emulsion is convenient to take, and the compliance of patients in taking medicine is improved.

Description

Perilla Wo Leisheng oral emulsion and preparation method thereof

Technical Field

The invention relates to the technical field of preparation of pharmaceutical preparations, in particular to a Perilla Wo Leisheng oral emulsion and a preparation method thereof.

Background

Suvorexant (Suvorexant) is a novel hypnotic agent, the first orexin receptor antagonist approved for the treatment of insomnia, whose pharmacological mechanism of action is a dual orexin OX1R and OX2R receptor inhibitor, for the treatment of sleep onset or sleep maintenance difficulties. The recommended dosage of Suvorexant is 10mg taken 30min before sleeping every night, and the maximum dosage is 20mg every day, so that the Suvorexant is effective and well-tolerated in treating insomnia. Common adverse effects are sleepiness, headache and dry mouth. Orexin is also called hypothalamic secretin, and has effect in promoting wakefulness. Orexin receptor antagonists capable of competitively blocking the binding of orexin to orexin receptors are useful in the treatment of insomnia and sleep disorders. Suvorexant blocks both orexin A and orexin B receptors. Can significantly improve sleep onset and sleep maintenance (including the last third of night). Unlike other hypnotics, general hypnotics are taken on demand (i.e., only when needed, treat symptoms without root cause), but Suvorexant is a therapeutic drug that needs to be taken for a long period of time.

Suvorexant was developed by MerkSharp & Dohme, MSD for the treatment of insomnia, approved by the united states Food and Drug Administration (FDA) at 13, 8, 2014, and later approved by the japan pharmaceutical and medical device integrated agency (PMDA) at 26, 9, 2014.

The chemical name of suvorexant is 5-chloro-2- [ (5R) -5-methyl-4- [ 5-methyl-2- (2H-1, 2, 3-triazol-2-yl) benzoyl ] -1, 4-diazepan-1-yl ] -1, 3-benzoxazole; the structural formula is as follows:

suvorexant is insoluble in water, resulting in low bioavailability of Suvorexant tablets, and according to FDA published information, the main excretion route of Su Wo Leisha tablets after oral administration is through feces (66% of recovered dose in feces), 23% of the dose is excreted through urine, thus the bioavailability of human body is estimated to be lower than 10%.

The suvorexant tablet also has the condition that the proportion of the side effects to sleepiness is increased along with the increase of the dosage, and the normal life of patients is affected.

Therefore, there is an urgent need for improving suvorexant tablets to improve their oral bioavailability and to meet the expected therapeutic effect with lower specifications.

The emulsion is a liquid preparation, and the active component is dissolved in the ester auxiliary materials, thereby bypassing the dissolution process and having high dissolution rate. The components of the emulsion may solubilize the drug directly after digestion, or indirectly by forming micelles with phospholipids, bile acids in the digestive system.

Disclosure of Invention

Aiming at the defects existing in the prior art, the invention provides the Su Wo Leisheng oral emulsion and the preparation process thereof, and the dosage form reduces the taking specification and reduces the probability of side effects of somnolence.

In order to solve the technical problems, the invention adopts the following technical scheme:

an oral emulsion of Su Wo Leisheng comprises the following main drugs and auxiliary materials in percentage by weight: 0.1 to 0.4 percent of Suvorexant, 60 to 80 percent of solubilizer, 18 to 40 percent of emulsifier, 0.01 to 2 percent of antioxidant, 0.01 to 0.05 percent of flavoring agent, and the sum of the weight percentages of the five components is 100 percent.

Preferably, the oral emulsion comprises main medicines and auxiliary materials in percentage by weight: 0.1 to 0.2 percent of Suvorexant, 74 to 80 percent of solubilizer, 19 to 25 percent of emulsifier, 0.01 to 1 percent of antioxidant, 0.025 to 0.05 percent of flavoring agent, and the sum of the weight percentages of the five components is 100 percent.

More preferably, the oral emulsion comprises the following main medicines and auxiliary materials in percentage by weight: 0.1% of Suvorexant, 79.99% of solubilizer, 19.7% of emulsifier, 0.2% of antioxidant and 0.01% of flavoring agent.

The solubilizer is fatty acid ester, and is one or two selected from fatty acid glyceride and propylene glycol fatty acid ester; preferred fatty acid glycerides are caprylic capric acid mono-di-glycerides, mono-linoleic acid glycerides; the preferred propylene glycol fatty acid ester is propylene glycol monocaprylate; more preferably, the solubilizer is a mixture of caprylic/capric monodiglycerol ester and propylene glycol monocaprylate in a mass ratio of (1-3) 1.

The emulsifier is nonionic surfactant, and is selected from one or more of polyoxyethylene monolaurate, polyoxyethylene lauryl ether, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene stearyl ether and polyoxyethylene monooleate; preferred emulsifiers are polyoxyethylated castor oil, polyoxyethylated hydrogenated castor oil or mixtures of both; a more preferred emulsifier is polyoxyethylene hydrogenated castor oil; the most preferred emulsifier is polyoxyethylene (40) hydrogenated castor oil.

The antioxidant is tert-butyl p-hydroxy anisole, dibutyl hydroxy toluene or a mixture of the two, and the preferable antioxidant is the mixture of tert-butyl p-hydroxy anisole and dibutyl hydroxy toluene with the mass ratio of 1:1.

The flavoring agent is selected from one or two of sweetener and flavoring agent, preferably sweetener, more preferably sucralose.

The invention also provides a preparation method of the suvorexant oral emulsion, which comprises the following steps:

(1) Mixing the solubilizer and the emulsifier in the formula amount, heating to 60 ℃, and uniformly stirring to obtain a solution 1;

(2) Adding antioxidant with the formula amount into the solution 1, and stirring and dissolving to obtain a solution 2;

(3) Adding the flavoring agent with the formula amount into the solution 2, and stirring and dissolving to obtain a solution 3;

(4) Adding the active ingredient suvorexant with the formula amount into the solution 3, stirring and dissolving to obtain the emulsion.

Compared with the prior art, the invention has the following beneficial effects:

the suvorexant oral emulsion has good sleep aiding effect and high bioavailability (more than 25 percent); the oral emulsion has low administration specification, and reduces the probability of side effects of somnolence; the emulsion formed is stable, is little affected by digestion, and can promote the absorption of medicines; the oral emulsion is convenient to take, and the compliance of patients in taking medicine is improved; the preparation process is simple, and is beneficial to industrial production.

Detailed Description

For the purpose of making the invention and its summary more apparent, the applicant further describes the invention in connection with examples, but the scope of the invention is not limited to these examples. It will be appreciated by those skilled in the art that equivalent substitutions for technical features of the present invention are still within the scope of the present invention.

All reagents of the following examples were commercially available and analytically pure; the auxiliary materials are all commercial auxiliary materials, the details are shown in table 1, and the medicinal and injection standards or pharmacopoeia standards are met.

Table 1: auxiliary material related information

Example 1:

an oral emulsion of su Wo Leisheng, the formulation of which is shown in table 2 below:

TABLE 2

The preparation method of the suvorexant oral emulsion of the embodiment comprises the following steps:

(1) Mixing the solubilizer and the emulsifier, heating to 60 ℃, and uniformly stirring to obtain a solution 1;

(2) Adding an antioxidant into the solution 1, stirring and dissolving to obtain a solution 2;

(3) Adding a flavoring agent into the solution 2, stirring and dissolving to obtain a solution 3;

(4) Adding active ingredient suvorexant into solution 3, stirring and dissolving to obtain the emulsion.

Example 2:

an oral emulsion of su Wo Leisheng, the formulation of which is shown in table 3 below:

TABLE 3 Table 3

The preparation method of the suvorexant oral emulsion of the present embodiment is the same as that of example 1.

Example 3:

an oral emulsion of su Wo Leisheng, the formulation of which is shown in table 4 below:

TABLE 4 Table 4

The preparation method of the suvorexant oral emulsion of the present embodiment is the same as that of example 1.

Example 4:

an oral emulsion of su Wo Leisheng, the formulation of which is shown in table 5 below:

TABLE 5

The preparation method of the suvorexant oral emulsion of the present embodiment is the same as that of example 1.

Example 5:

an oral emulsion of su Wo Leisheng, the formulation of which is shown in table 6 below:

TABLE 6

The preparation method of the suvorexant oral emulsion of the present embodiment is the same as that of example 1.

Example 6: emulsion stability investigation of Suvorexant oral emulsion

2000mL of Suvorexant oral emulsion sample was prepared according to example 5, and the sample was dispensed into 10mL brown penicillin bottles, capped and sealed, and intermediate acceleration test (30 ℃ + -2 ℃, 65% + -5% RH) was carried out according to the non-sterile drug microorganism limitation standard of the fourth edition of the general rule 1107 of the Chinese pharmacopoeia 2020, and relevant substances were measured by HPLC, and the detection results are shown in Table 7.

Table 7: sample stability test results of Suvorexant oral emulsion of example 5

As is clear from Table 7, the oral emulsion of the present invention was stable for at least 12 months under intermediate acceleration conditions, and had good quality stability.

Example 7: bioavailability investigation of Suvorexant oral emulsion

Test drug: suvorexant.

Experimental animals: the suvorexant plasma kinetics study used healthy Beagle dogs as experimental animals.

The animal experiments are grouped in a random number table mode, and the grouping is carried out according to gender layering.

The number of the experimental animals meets 6 data at each sampling point to determine the number of the experimental animals, and the male and female animals are adopted for half, so that the male and female differences of in-vivo dynamics can be conveniently analyzed.

Administration preparation: the injectable preparation for stomach is the Suvorexant oral emulsion of example 5, the injectable preparation for intravenous injection is a solution prepared by taking physiological saline and N, N-dimethylformamide as mixed solvents.

Dosage and mode of administration: the dogs were subjected to bioavailability studies by single gastric lavage administration of 5mg/kg (as suvorexant), intravenous injection of 5mg/kg (as suvorexant), and gastric lavage administration of 5ml/kg and intravenous injection of 1 ml/kg. Fasted before administration is not less than 12 hours, and the medicine is taken after administration for 3 hours.

The research method comprises the following steps: after single-dose gastric lavage administration and single-dose intravenous administration of healthy Beagle dogs, plasma samples were collected and analyzed for suvorexant concentration in the plasma samples by a validated LC-MS method. The measured plasma drug concentration-time data of each experimental animal is used for calculating the main pharmacokinetic parameters of the test drug Suvorexant by adopting a statistical moment method of WinNonlin7.0 software.

Healthy Beagle dogs are administrated by stomach-inserting and gastric tube-inserting mode, blood is taken from the vein of the forelimb according to preset time, and the blood volume is about 1ml at each time point. Setting the blood sampling time point of the single gastric lavage administration of the dogs as 0.25h, 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 48h and 72h before administration; intravenous administration was consistent with the single lavage blood sampling time point. And (3) collecting a whole blood sample, anticoagulating heparin sodium, centrifuging to obtain plasma, and freezing at-70 ℃ in a refrigerator until LC-MS quantitative analysis is performed.

Test results: the plasma drug concentration data of each animal after the intragastric administration and intravenous administration were fitted using winnonlin7.0 drug generation software, and the drug generation parameters were calculated by a non-compartmental model statistical moment method, and the results are shown in table 8 below. After calculation of AUC after administration by gavage (5 mg/kg) and intravenous administration (5 mg/kg), the absolute bioavailability of the Suvorax emulsion after administration by gavage to dogs was calculated to be about 25.9%.

Table 8: pharmacokinetic data of suvorexant

Claims (10)

1. An oral emulsion of Perilla Wo Leisheng is characterized by comprising the following components in percentage by weight: 0.1 to 0.4 percent of Suvorexant, 60 to 80 percent of solubilizer, 18 to 40 percent of emulsifier, 0.01 to 2 percent of antioxidant, 0.01 to 0.05 percent of flavoring agent, and the sum of the weight percentages of the five components is 100 percent.

2. The suvorexant oral emulsion according to claim 1, comprising the following components in weight percent: 0.1 to 0.2 percent of Suvorexant, 74 to 80 percent of solubilizer, 19 to 25 percent of emulsifier, 0.01 to 1 percent of antioxidant, 0.025 to 0.05 percent of flavoring agent, and the sum of the weight percentages of the five components is 100 percent.

3. The suvorexant oral emulsion according to claim 2, comprising the following components in weight percent: 0.1% of Suvorexant, 79.99% of solubilizer, 19.7% of emulsifier, 0.2% of antioxidant and 0.01% of flavoring agent.

4. A suvorexant oral emulsion according to claim 1,2 or 3, wherein said solubilising agent is selected from one or both of a fatty acid glyceride, a propylene glycol fatty acid ester.

5. The suvorexant oral emulsion according to claim 4, wherein said fatty acid glycerides are caprylic capric acid mono-di-glycerides or mono-linoleic acid glycerides; the propylene glycol fatty acid ester is propylene glycol monocaprylate; the preferable solubilizer is a mixture of caprylic/capric acid mono/diglyceride and propylene glycol mono caprylate in a mass ratio of (1-3): 1.

6. A suvorexant oral emulsion according to claim 1,2 or 3, wherein said emulsifier is selected from one or more of polyoxyethylene monolaurate, polyoxyethylene lauryl ether, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene stearyl ether, polyoxyethylene monooleate.

7. The suvorexant oral emulsion according to claim 6, wherein the emulsifier is polyoxyethylated castor oil, polyoxyethylated hydrogenated castor oil, or a mixture of both; the preferred emulsifier is polyoxyethylene hydrogenated castor oil; a more preferred emulsifier is polyoxyethylene (40) hydrogenated castor oil.

8. A suvorexant oral emulsion according to claim 1,2 or 3, wherein said antioxidant is t-butyl parahydroxyanisole, dibutyl hydroxytoluene or a mixture of both; the preferred antioxidant is a mixture of tert-butyl p-hydroxy anisole and dibutyl hydroxy toluene in a mass ratio of 1:1.

9. A suvorexant oral emulsion according to claim 1,2 or 3, wherein said flavoring agent is selected from one or both of a sweetener, a flavoring agent, preferably a sweetener, more preferably sucralose.

10. A process for the preparation of an oral emulsion of suvorexant as claimed in any one of claims 1 to 9, comprising the steps of:

(1) Mixing the solubilizer and the emulsifier in the formula amount, heating to 60 ℃, and uniformly stirring to obtain a solution 1;

(2) Adding antioxidant with the formula amount into the solution 1, and stirring and dissolving to obtain a solution 2;

(3) Adding the flavoring agent with the formula amount into the solution 2, and stirring and dissolving to obtain a solution 3;

(4) Adding the active ingredient suvorexant with the formula amount into the solution 3, stirring and dissolving to obtain the emulsion.