CN108606961B

CN108606961B - Levolipoic acid and lysine salt soft capsule and preparation method thereof

Info

Publication number: CN108606961B
Application number: CN201810434498.0A
Authority: CN
Inventors: 包玉胜; 杨小萍; 张爱洁; 马冲; 陶莉; 袁晓丽; 郑慧娟
Original assignee: Nanjing Hairong Pharmaceutical Co ltd; Nanjing Heron Pharmaceutical Science and Technology Co Ltd
Current assignee: Nanjing Hairong Pharmaceutical Co ltd; Nanjing Heron Pharmaceutical Science and Technology Co Ltd
Priority date: 2018-05-09
Filing date: 2018-05-09
Publication date: 2020-12-04
Anticipated expiration: 2038-05-09
Also published as: CN108606961A

Abstract

The invention discloses a soft capsule of dextro lipoic acid lysine salt and a preparation method thereof, and the invention screens the content prescription and the capsule shell prescription of the dextro lipoic acid amino acid salt soft capsule. Gelatin in the capsule shell formula: water: glycerol: PEG400: titanium dioxide =1:1.2:0.5:0.2: 2.5%. Preferably, the content is PEG400 solution. When the prescription of the capsule shell is screened, PEG400 is creatively used, so that the water balance exists between the content and the capsule shell; meanwhile, because the levolipoic acid lysine salt is a photosensitive medicament, ring-opening polymerization is easy to occur under the condition of illumination to produce a dimer which is extremely difficult to dissolve, and the prepared content is still unstable under light, an opacifier such as titanium dioxide is added in the capsule shell formula to ensure the light stability of the content.

Description

Levolipoic acid and lysine salt soft capsule and preparation method thereof

Technical Field

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a lipoic acid lysine salt soft capsule and a preparation method thereof.

Background

Lipoic Acid (LA), a natural antioxidant soluble in both water and fat, has the chemical name 1, 2-dithiolane-3-pentanoic acid and the molecular formula C₈H₁₄O₂S₂. In 1950, the traditional Chinese medicine is separated and extracted from pig liver for the first time by Reed and the like in the United states, has wide distribution in the liver, heart and kidney of animals, is the strongest one of natural antioxidants, and is known as 'universal antioxidant'. From the chemical structural analysis of lipoic acid, the presence of the asymmetric center of carbon atom number 3 of dithiolane produces two corresponding R (dextrorotatory) and S (levorotatory) enantiomers, which have been shown to have different pharmacological activities and pharmacological properties.

In the field of DPN treatment, the medicine improves diabetic peripheral neuropathy symptoms by suppressing oxidative stress state in nerves, increasing blood flow of neurotrophic vessels, accelerating nerve conduction speed, increasing the activity of sodium-potassium ATPase of nerves and other mechanisms. The characteristic of the lipoic acid for improving the DPN is caused by the independent R-enantiomer, and the S-enantiomer has no biological activity, so that the lipoic acid can be resolved to prepare the pure R-lipoic acid. However, the R-lipoic acid has low melting point, is easy to polymerize under high temperature and acidic conditions, has poor stability, has higher melting point after reacting with lysine to generate salt, is more stable to store, and can achieve higher bioavailability by orally taking right lipoic acid lysine because the R-enantiomer can be preferentially absorbed by organisms and has higher concentration distribution in vivo when the S-enantiomer does not exist. However, the dextro-lipoic acid has the important defects of instability, low lipoic acid melting point (47-50 ℃), and polymerization at a low temperature, so that the curative effect and the safety of clinical treatment of the dextro-lipoic acid are influenced. Furthermore, the dextro-lipoic acid is insoluble in water, so the physicochemical property of the dextro-lipoic acid directly limits the application of the dextro-lipoic acid in preparing various medicinal preparations.

At present, preparations related to alpha-lipoic acid in markets at home and abroad mainly comprise injection, tablets, hard capsules and the like, the compliance of patients with the injection is poor, and the bioavailability of the tablets and the hard capsules is low. Chinese patent (CN105001195A) discloses a novel crystal form I of R (+) -lipoic acid-L-lysine salt, which is an innovative medicine developed by the applicant in earlier period, and no related preparation of the lipoic acid-L-lysine salt is on the market. Compared with lipoic acid, the right lipoic acid lysine has good stability and high bioavailability, but researches show that the right lipoic acid lysine is unstable under acidic, damp and hot, high temperature and illumination conditions, and is easy to polymerize particularly under the acidic and damp and hot conditions, so that the content is reduced, the exertion of the drug effect is influenced, and the potential safety problem of a polymer exists.

Disclosure of Invention

Aiming at the technical defects, the invention aims to prevent the main medicine of the lipoic acid lysine salt from polymerizing and improve the bioavailability in vivo through a preparation technology. It is worth noting that in the preparation process of the right lipoic acid lysine oral preparation, the main drug needs to be prevented from contacting with an acidic medium or combined with other polymers to avoid the open-chain polymerization reaction.

Chinese patent (CN105001195A) discloses a novel crystal form I of R (+) -lipoic acid-L-lysine salt. The chemical name of the R (+) -lipoic acid-L-lysine salt is R (+) -1, 2-dithiolane-3-pentanoic acid L (+) -2, 6-aminocaproic acid (1:1), and the structural formula is shown as follows.

The research of the new crystal form I of the R (+) -lipoic acid-L-lysine salt proves that the crystal form I has better physicochemical property, proper melting point and strong stability through comparative experiments.

Aiming at the novel crystal form I of the R (+) -lipoic acid-L-lysine salt, the subject group is further researched and developed in the follow-up process, and the crystal form is further prepared into a right lipoic acid lysine salt soft capsule with higher bioavailability by adopting a double-screw extrusion technology so as to better serve patients suffering from the diseases.

The invention aims to provide a lipoic acid lysine salt soft capsule and a preparation method thereof.

The soft capsule is a common solid preparation after a tablet, can quantitatively encapsulate medicine suspension, oily liquid, medicine solution, paste or pasty substance and even medicine powder by a capsule shell, and has the characteristics of good taste, convenient taking, accurate dosage, safe transportation, beautiful appearance and the like.

The capsule shell material of the soft capsule is mainly prepared from gelatin, but the gelatin has the obvious defect that the gelatin is easy to crosslink in the storage process to cause the hardening of the capsule shell, so that the disintegration time is prolonged and the disintegration degree is reduced.

The technical scheme for realizing the aim of the invention is as follows:

the invention provides a soft capsule of right lipoic acid lysine salt, which comprises a capsule shell and liquid or suspension which is arranged in the capsule shell and takes the right lipoic acid lysine salt as a raw material medicine;

the levolipoic acid lysine salt is a novel crystal form I of R (+) -lipoic acid-L-lysine salt, and the structural formula is shown as follows:

the capsule shell mainly comprises gelatin, water, glycerol, a plasticizer and an opacifier in a weight ratio of 1: 1-1.2: 0.4-0.6: 0.2-0.3: 2.5-3%;

as a preferable scheme of the soft capsule of the lipoic acid lysine salt, the main components of the content placed in the capsule shell are the lipoic acid lysine salt, a low-molecular-weight PEG matrix, a suspending agent, an antioxidant and a humectant.

As a preferable scheme of the lipoic acid lysine salt soft capsule, the plasticizer is PEG400, the opacifier is titanium dioxide, the capsule shell mainly comprises gelatin, water, glycerol, PEG400 and titanium dioxide in a weight ratio of gelatin: water: glycerol: PEG400: titanium dioxide ═ 1:1.2:0.5:0.2: 2.5%.

As a preferable scheme of the lipoic acid lysine salt soft capsule, low-molecular-weight PEG400 is used as a matrix, and the optimal ratio of API to PEG400 is 300mg to 1 mL.

As a preferable scheme of the lipoic acid lysine salt soft capsule, the suspending agent is selected from PEG4000 or PEG 6000.

As a preferable scheme of the lipoic acid lysine salt soft capsule, the antioxidant is selected from one or more of L-arginine, L-cysteine, butylated hydroxytoluene, butylated hydroxyanisole and vitamin E.

Still further, the antioxidant is preferably butylated hydroxytoluene.

As a preferable embodiment of the lipoic acid lysine salt soft capsule of the present invention, the humectant is selected from glycerin or propylene glycol.

The invention also provides a method for preparing the lipoic acid lysine salt soft capsule, which is characterized by comprising the following steps of:

(1) preparing contents: weighing the formula amounts of R (+) -lipoic acid-L-lysine salt, PEG400, PEG4000, butylated hydroxytoluene and water, oscillating until the components are mainly and completely dissolved, finally adding glycerol, and oscillating until the solution is bright yellow and clear;

(2) glue solution preparation: weighing gelatin, water, PEG400 and titanium dioxide in a prescription amount in a small beaker, swelling the gelatin for 24h, heating and melting in a 60 ℃ water bath kettle to form liquid, adding glycerol in a corresponding prescription amount, stirring uniformly, keeping in a 55 ℃ water bath to remove bubbles, and standing for later use;

(3) pressing the soft capsules: the glue solution obtained in the step (2) flows into a glue box through a glue tube, and the glue solution flows out of the glue box to a rotary drum; simultaneously adding the prepared contents in the step (1) into a hopper, adjusting the temperature of a spray body to 35-65 ℃ after the thickness of the rubber is adjusted to the thickness required by the process, carrying out pelleting and checking rubber crack, filling the contents after the determination, adjusting the filling amount to the process requirement, and then carrying out pelleting;

(4) drying soft capsule, shaping the pressed soft capsule in a rotary cage, and drying at 15-30 deg.C and humidity of 15-40% in a sealed space to obtain the final product.

Wherein the thickness of the rubber is 1.5-2.5 mm.

Compared with the prior art, the invention has the following remarkable advantages:

1. the invention takes a self-developed novel crystal form I of R (+) -lipoic acid-L-lysine salt as a main medicine, develops related preparations thereof, and finds that after dextro-lipoic acid reacts with amino acid to generate dextro-lipoic acid amino acid salt, the stability of the dextro-lipoic acid can be improved, thereby not only preventing the defect that the dextro-lipoic acid is easy to polymerize, but also preventing the problem that the dextro-lipoic acid is easy to decompose when meeting heat. The reason is that amino acid is an antioxidant used in the medicine, and the oxidation of the dextro-lipoic acid is prevented after the dextro-lipoic acid is prepared into amino acid salt. Meanwhile, due to the characteristics of amino acids: the salt generated by the amino acid reaction has higher melting point, so that the melting point of the medicinal substance is greatly improved after the dextro lipoic acid reacts with the amino acid to generate dextro lipoic acid amino acid salt, and the thermal stability of the medicinal substance is obviously improved. The amino acid is also the effective component of the medicine, and the pharmacodynamic action of the dextro lipoic amino acid salt is higher than that of the single dextro lipoic acid.

2. The invention screens the content prescription and the capsule shell prescription of the dextro lipoic amino acid salt soft capsule. Gelatin in the capsule shell formula: water: glycerol: PEG400: titanium dioxide ═ 1:1.2:0.5:0.2: 2.5%. Preferably, the content is PEG400 solution.

3. When the prescription of the capsule shell is screened, PEG400 is creatively used, so that the water balance exists between the content and the capsule shell; meanwhile, because the levolipoic acid lysine salt is a photosensitive medicament, ring-opening polymerization is easy to occur under the condition of illumination to produce a dimer which is extremely difficult to dissolve, and the prepared content is still unstable under light, an opacifier such as titanium dioxide is added in the capsule shell formula to ensure the light stability of the content.

Drawings

FIG. 1 is a graph of the stability data for the lysine salt of lipoic acid of the present invention under acidic conditions.

Fig. 2 is data on the stability of the lipoic acid lysine salt of the present invention under high temperature conditions.

FIG. 3 shows stability data of the homolipoic acid lysine salt of the present invention under humid heat conditions.

FIG. 4 stability data for L-lipoic acid lysine salt of the present invention under light conditions.

Detailed Description

The invention will be further elucidated with reference to the following description of an embodiment in conjunction with the accompanying drawing. It is to be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention, which is to be given the full breadth of the appended claims and any and all equivalent modifications thereof which may occur to those skilled in the art upon reading the present specification.

Chinese patent (CN105001195A) discloses a novel crystal form I of R (+) -lipoic acid-L-lysine salt. The chemical name of the R (+) -lipoic acid-L-lysine salt is R (+) -1, 2-dithiolane-3-pentanoic acid L (+) -2, 6-aminocaproic acid (1:1), and the structural formula is shown as follows:

in PXRD spectrum, the radiation source is CuKa₁And diffraction peaks at 2 theta values of 5.102, 7.589, 10.072, 12.549, 15.036, 16.688, 18.627, 19.356, 25.064 and 27.611, wherein the error range of the 2 theta values is +/-0.2. The melting point of the crystal form I of the R (+) -lipoic acid-L-lysine salt provided by the invention is 185-188 ℃.

Example 1

The stability data of the right lipoic acid lysine salt under the conditions of acidity, high temperature, damp heat and illumination are tested. Specifically, as shown in fig. 1-4, the product is unstable under acidic conditions, the content is obviously reduced after the product is placed for 1 hour, the content is reduced slightly after the product is placed continuously, the content is reduced mainly because the product is polymerized soon after the product is contacted with acid, and the content is not reduced obviously after the product is polymerized. Under the damp-heat condition, the content is gradually and obviously reduced along with the time, and the content is relatively less reduced when the lipoic acid is placed under the high-temperature and dry conditions, which indicates that the lipoic acid is unstable under the acidic, damp-heat, high-temperature and illumination conditions, and is easy to polymerize particularly under the acidic and damp-heat conditions.

EXAMPLE 2 selection of substrates

The common matrix of the soft capsule at present comprises soybean oil, sunflower seed oil, low molecular weight PEG such as PEG400, etc. Although the process for preparing the right lipoic acid lysine salt into the oil suspension by using the soybean oil or the sunflower oil as the matrix and the white beeswax as the suspending agent is simpler, the year of preparing the oil suspension is longer and the content of the right lipoic acid lysine salt is reduced quickly under the conditions of 24h stability, 40 ℃ and refrigeration in consideration of lower solubility of the right lipoic acid lysine salt in oil. Meanwhile, according to a preliminary test of solubility of the right lipoic acid lysine salt, the right lipoic acid lysine salt can be easily dissolved in PEG400, so that PEG with low molecular weight is selected, and PEG400 is preferably used as a matrix.

TABLE 1 substrate selection

Substrate	Solubility in water	Suspension property	Fluidity of the resin	Content of 30 days at 40 DEG C	Content of 30 days at 4 DEG C
						Oil	Difference (D)	In general	Is poor	55.17％	65.83％
PEG	Is preferably used	——	Is preferably used	87.92％	90.27％

EXAMPLE 3 selection of the amount of lysine salt of lipoic acid

The lipoic acid lysine salt is easy to dissolve in PEG with low molecular weight, and the optimal proportion of the API and the PEG is selected by considering the influence of the dosage on the dissolution rate, the fluidity, the stability and the like of the solution and the dosage of administration when the lipoic acid lysine salt is prepared into a preparation. The amount of the right lipoic acid lysine salt was chosen, taking 1mL of low molecular weight PEG400 as an example.

TABLE 2 screening of lipoic acid lysine salt dosage

API dosage (mg)	Rate of dissolution	Fluidity of the resin	Content of 30 days at 40 DEG C
				200	Is quicker	Is preferably used	88.13％
300	Is quicker	Is preferably used	86.36％
				400	Fast-acting toy	Good taste	80.27％
600	Fast-acting toy	Good taste	74.41％
				800	Slow	Difference (D)	67.94％
1000	Is slower	Is poor	60.68％
				1200	Very slow	Very poor	53.49％

As can be seen from the table, the optimal ratio of API to PEG400 is 300mg to 1mL, taking into account solubility, flowability, stability and dosage administered.

Although the right lipoic acid lysine salt can be quickly dissolved in the PEG400 to form a clear and transparent yellow solution, the high-temperature stability of the right lipoic acid lysine salt is not qualified, presumably because the molecular movement of the right lipoic acid lysine salt is accelerated under the high-temperature condition of the PEG400 solution, the intermolecular collision is increased to cause the right lipoic acid to be polymerized, the related substances are increased, and the content is reduced. In order to improve the stability, PEG4000 and PEG6000 are selected as suspending agents.

TABLE 3 screening of PEG with high degree of polymerization

PEG	Solubility in water	Fluidity of the resin	Content of 30 days at 40 DEG C	Content of 30 days at 4 DEG C
					PEG4000	Has no influence on	Becomes worse after cooling	94.42％	84.97％
PEG6000	Slightly become worse	Becomes worse after cooling	94.75％	79.36％

As can be seen from the table, the solubility of the dexlipoic acid lysine salt was not changed by the addition of PEG4000, but PEG6000 was deteriorated, so that it is preferable to add PEG4000 to improve the high temperature stability.

EXAMPLE 4 selection of antioxidants

Because the levolipoic acid lysine salt is unstable under acidic, damp-heat, high-temperature and illumination conditions, and particularly is easy to polymerize under the acidic and damp-heat conditions, the antioxidant is considered to be added to improve the stability of the content of the soft capsule. The antioxidant commonly used in soft capsules is water-soluble and oil-soluble antioxidant; in the soft capsule using PEG400 as dispersing medium, L-arginine, L-cysteine, butylated hydroxytoluene, butylated hydroxyanisole and vitamin E are further screened. Butylated hydroxytoluene is further preferred as an antioxidant because of its good solubility, 89.14% at 40 ℃ for 30 days and 90.41% at 40 ℃ for 30 days.

EXAMPLE 5 selection of humectant type and amount

PEG400 is preferably used as a dispersion medium in the invention, and PEG400 has strong water absorption, is easy to absorb water in a capsule shell to cause the capsule shell to be hardened, so glycerin or propylene glycol should be added into the content for improvement. The choice of glycerin as the humectant was best known from preliminary tests in which equal amounts of glycerin or propylene glycol were added to the contents.

The dosage of the glycerol in the formula is 50-200 mg, and the glycerol has good moisture retention, uniformity and stability; considering convenient and quantitative filling of the capsule, glycerin is selected to adjust the weight of the content, and the preferable dosage of the glycerin is 80-120 mg.

Example 6

Combining the factors discussed in examples 2-5, the contents of a dexlipoic acid lysine salt soft capsule are preferably as follows:

1. prescription

Novel crystal form I300 mg of R (+) -lipoic acid-L-lysine salt

PEG400 1100mg

PEG4000 50mg

Butylated hydroxytoluene 50mg

200mg of water

Glycerol 100mg

2. Content stability test

Weighing the R (+) -lipoic acid-L-lysine salt, PEG400, PEG4000, butylated hydroxytoluene and water according to the formula amount, oscillating until the components are mainly and completely dissolved, finally adding glycerol, and oscillating until the solution is bright yellow and clear. 12 parts of samples are prepared according to the method, are divided into 3 groups, and are lofted for 0-30 days respectively under high temperature (150 ℃), high light (4500 +/-5000 x) and high humidity (90% +/-5%).

The conclusion is as follows: the physical properties of the soft capsule contents are not changed under the high-temperature condition, and the content measurement is between 98 percent and 99.9 percent, thereby meeting the requirements; under the highlight condition, the liquid becomes dark in color at 15 days, the content is reduced to 90 percent, and the further optimization of the capsule shell prescription is considered subsequently; under high humidity conditions, the physical properties are not significantly changed, but the moisture absorption weight gain is significant, and thus the capsule should be stored under dry conditions.

EXAMPLE 7 screening of prescription for Capsule Shell

The capsule shell mainly comprises gelatin, a plasticizer and water, and the weight ratio of the gelatin to the plasticizer to the water is as follows: plasticizer: water (1-3): 1: (1 to 2)

If the amount of the plasticizer is too low or too high, the capsule wall is correspondingly too hard or too soft; the ratio of gelatin to water is proper between 2:1 and 1:1, when the ratio of gelatin to water is more than 2:1, the gelatin has poor water absorption and expansion effects, the viscosity of the gelatin solution is high, the flow is poor, and the prepared capsule shell is thick and uneven; when the ratio of gelatin to water is less than 1:1, the obtained gelatin solution is thin, and the prepared capsule shell has poor elasticity and is not dense and easy to produce oil.

Since moisture is easily gasified and lost during the preparation and storage of the soft capsule, the ratio of gelatin to plasticizer has a very important influence on the preparation and quality control of the soft capsule. Because the prescription of the soft capsule content contains PEG400 and the right lipoic acid lysine salt is unstable to light, moisture and heat, a proper amount of PEG400 is added in the prescription of the capsule shell besides glycerin to serve as a plasticizer and a small amount of titanium dioxide to serve as an opacifier.

1. Selection of the amount of glycerol

The elasticity and plasticity of the soft capsule shell depend on the amount of glycerin in the prescription. The disintegration and dissolution of the soft capsule are unqualified depending on the proportion of gelatin, glycerin and water in the prescription. The ratio of the gelatin to the plasticizer is preferably 3: 1-1: 1. The glue solution obtained by the proportion has moderate viscosity, good fluidity and elastic rubber.

The production is carried out by taking gelatin: when the water is 1:1, the prepared capsule shell is more suitable, but experiments show that the gelatin dosage is less, more water is evaporated during the preparation, the adjustment ratio is 1:1.2, the obtained glue solution has better fluidity, and the prepared capsule shell has better performance.

The glycerol dosage is particularly important for capsule shell molding, and the glycerol dosage is screened under the condition of keeping the gelatin and the water quantity unchanged. The glycerol dosage is 30-100% of the gelatin dosage, and the results are shown in the following table:

TABLE 4

Prescription number	1	2	3	4	5	6
							Amount of gelatin (g)	10	10	10	10	10	10
Amount of water (g)	12	12	12	12	12	12
							Amount of glycerin (% of gelatin amount)	30	40	50	60	80	100

2. Preparing rubber sheets:

weighing gelatin and water in corresponding amount according to the prescription in Table 4, adding gelatin into a small beaker, swelling for 24h, heating and melting in a 60 deg.C water bath kettle to form liquid, adding glycerol in corresponding amount, stirring, and keeping in 55 deg.C water bath to remove bubbles. Spreading the hot glue solution on a glass slide, cooling, ventilating and drying at room temperature for 12h, taking down the rubber, and cutting into rubber with the size of 2cm multiplied by 2cm for later use. The properties are given in the following table:

TABLE 5 rubber Performance test

According to the table, the rubber consumption is preferably 40-60%, preferably 50%, the obtained rubber liquid has good fluidity, and the prepared rubber has good formability, good elasticity, moderate strength and fast solubility.

3. Selection of the amount of titanium dioxide

Because the levolipoic acid lysine salt is a photosensitive drug, ring-opening polymerization is very easy to occur under the condition of illumination to produce a dimer which is very difficult to dissolve, and the prepared content is still unstable by light, an opacifier such as titanium dioxide should be added into the capsule shell formula. The dosage of the opacifier can be selected from 0.8%, 1.5%, 2%, 2.5%, 3% and 4% of the dosage of the gelatin, glue solutions are prepared according to corresponding proportions, the glue solutions are sequentially paved on a glass slide, the other surface of the glass slide is coated with a layer of the content of the right lipoic acid lysine salt, and the light transmittance of the glue film is observed under a light source. The results are shown in the table:

TABLE 6 rubber light transmittance test

In conclusion, if the prepared rubber can completely cover the content, a minimum of 2.5g to 3g of titanium dioxide is added to every 100g of gelatin, and more than 3g of titanium dioxide is added, although the gelatin can also completely cover the content of the gelatin, the excessive titanium dioxide is not completely dispersed and appears as particles, and the smoothness of the surface of the rubber is influenced. Preferably 2.5%.

4. PEG400 dosage selection

The addition of PEG400 serves to equilibrate the contents and water in the capsule shell, keeping the gelatin: water: glycerol: changing the addition amount of PEG400 to be 20%, 30%, 50%, 70% and 100% of the dosage of gelatin respectively when the titanium dioxide is unchanged at the ratio of 1:1.2:0.5: 2.5%, placing the capsule shell in an open air at room temperature for a period of time, wherein the oil outlet condition is serious when the capsule shell is placed continuously, and a small amount of oily liquid drops appear on 30% of the surface, but 20% does not appear. Finally, the capsule shell prescription is determined as follows: gelatin: water: glycerol: PEG400: titanium dioxide ═ 1:1.2:0.5:0.2: 2.5%.

Example 8

The preferred scheme of the preparation method of the lipoic acid and lysine salt soft capsule is as follows:

(1) preparing contents: weighing the R (+) -lipoic acid-L-lysine salt, PEG400, PEG4000, butylated hydroxytoluene and water in the formula amount of the embodiment 6, oscillating until the components are mainly and completely dissolved, finally adding glycerol, and oscillating until the solution is bright yellow and clear;

(2) glue solution preparation: weighing gelatin, water, PEG400 and titanium dioxide in the amount of the prescription in example 7 in a small beaker, swelling the gelatin for 24 hours, heating and melting in a water bath kettle at 60 ℃ to form liquid, adding glycerol in the amount corresponding to the prescription, uniformly stirring, keeping in a water bath at 55 ℃ to remove bubbles, and standing for later use;

(3) pressing the soft capsules: the glue solution obtained in the step (2) flows into a glue box through a glue tube, and the glue solution flows out of the glue box to a rotary drum; adding the prepared contents in the step (1) into a hopper, adjusting the temperature of a spray body to 35-65 ℃ after the thickness of the rubber is adjusted to the thickness (1.5-2.5 mm) required by the process, performing pelleting and checking a rubber crack, filling the contents after the temperature is determined, adjusting the filling amount to the process requirement, and performing capsule pelleting;

Claims

1. The soft capsule of the right lipoic acid lysine salt is characterized by comprising a capsule shell and liquid or suspension which is arranged in the capsule shell and takes the right lipoic acid lysine salt as a raw material medicine;

the capsule shell mainly comprises gelatin, water, glycerol, a plasticizer PEG400 and opacifier titanium dioxide, and the weight ratio of the gelatin to the opacifier titanium dioxide is 1:1.2:0.5:0.2: 2.5%;

the main components of the contents in the capsule shell are right lipoic acid lysine salt, low molecular weight PEG400 as a matrix, a suspending agent PEG4000, antioxidant butylated hydroxytoluene and humectant glycerin; the optimal ratio of the lipoic acid lysine salt to the PEG400 is 300mg to 1 mL;

the preparation method of the lipoic acid lysine salt soft capsule comprises the following steps:

(4) and (3) drying the soft capsules, namely putting the pressed soft capsules into a rotating cage for shaping, and then drying in a closed space with the temperature of 15-30 ℃ and the humidity of 15-40% to obtain the product, wherein the thickness of the rubber sheet is 1.5-2.5 mm.