WO2020238297A1

WO2020238297A1 - Soft capsule containing nadh or nadph, preparation method therefor and application thereof

Info

Publication number: WO2020238297A1
Application number: PCT/CN2020/076287
Authority: WO
Inventors: 陈建生
Original assignee: 泓博元生命科技（深圳）有限公司
Priority date: 2019-05-29
Filing date: 2020-02-22
Publication date: 2020-12-03
Also published as: CN110339179A

Abstract

A soft capsule containing NADH or NADPH, a preparation method and an application thereof in the field of medicine and health products. The content therein comprises NADH or NADPH and edible vegetable oil and/or edible glycol, wherein the mass of the edible vegetable oil and/or the edible glycol is 1-2 times that of NADH or NADPH. The content also comprises an antioxidant or/and liposoluble antacid.

Description

Soft capsule containing NADH or NADPH and its preparation method and application

Technical field

The invention belongs to the field of medical technology and health food technology, and particularly relates to a soft capsule containing NADH or NADPH, and a preparation method and application thereof.

Background technique

Nicotinamide-Adenine Dinucleotide (NADH)

And nicotinamide-adenine-phosphate-dinucleotide (NADPH)

It is a physiological substance in the human body and exists in all living cells including human cells. These substances are cofactors of many enzymes, and most of these enzymes can catalyze oxidation-reduction reactions.

NADH or NADPH participates in thousands of physiological and metabolic reactions in the human body, and plays an important role in gene repair, immunity enhancement, anti-oxidation, and sleep improvement. Adequate NADH or NADPH can make the body better protected and less healthy. Problems, prevention and control of diseases, and supplementation of NADH or NADPH in vitro is beneficial to promote various physiological functions of the body to maintain the best condition. However, NADH or NADPH is a biological form of hydrogen, which is extremely unstable. Light, acidic environment, or oxygen and moisture in the air will destroy the molecular structure of NADH or NADPH. For a long time, NADH or NADPH was mainly used in the form of infusion and tablets, and due to its chemical instability, the infusion needed to be prepared fresh, and it was difficult to ensure its activity during the preparation process. Although the preparation of tablets is simple, the preparation process requires Add more excipients, and the bioavailability is not high.

Therefore, how to solve the instability of NADH or NADPH and prepare an oral dosage form with stable properties, less impurities, and high bioavailability is the current research difficulty.

technical problem

The purpose of the present invention is to overcome the above-mentioned shortcomings of the prior art, and firstly provides a soft capsule containing NADH or NADPH.

Technical solutions

The present invention provides a soft capsule containing NADH or NADPH. The contents of the soft capsule include NADH or NADPH and edible vegetable oil or/and edible alcohol. The quality of the edible vegetable oil or/and edible alcohol is determined Said NADH or NADPH quality 1-2 times.

The present invention also provides a method for preparing the above-mentioned soft capsules containing NADH or NADPH, which includes the following steps:

Stir and melt the edible vegetable oil or/and edible alcohol, and after cooling, stir and mix NADH or NADPH with the edible vegetable oil or/and edible alcohol evenly, and obtain a raw material mixture after grinding and sieving;

Stir and mix the water and the capsule shell forming materials evenly, vacuum and degas to obtain a colorless glue;

When the viscosity of the glue liquid reaches 10000mPa.s or more by the viscometer, the glue liquid is cooled down;

Sieve the cooled glue;

The raw material mixture and the sieved glue are used to prepare soft capsules with a capsule making machine, which is shaped and dried.

The preparation method of the above-mentioned NADH or NADPH-containing soft capsule provided by the present invention has a simple preparation process and is easy to realize, and further improves the bioavailability and administration effect of NADH or NADPH.

The present invention also provides the application of the aforementioned soft capsules containing NADH or NADPH and the soft capsules prepared by the aforementioned preparation method in the field of medicine and/or health care products.

Beneficial effect

In the above-mentioned soft capsule with NADH or NADPH as the main active ingredient provided by the present invention, the content of NADH or NADPH in the soft capsule is mixed with edible vegetable oil or/and edible alcohol to form a protective film on the surface of NADH or NADPH, which is effective Reduces the influence of the external environment on NADH or NADPH, makes it difficult to be degraded by gastric acid, ensures that it is absorbed and utilized by the human body in the intestine, and significantly improves the water solubility and biological activity of NADH or NADPH, which is beneficial to the absorption of NADH or NADPH, and the effect is fast , High curative effect, easy to take, easy to store and preserve, has great application prospects.

The best mode of the invention

In order to make the objectives, technical solutions, and advantages of the present invention clearer, the following further describes the present invention in detail with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described here are only used to explain the present invention, but not to limit the present invention.

The present invention first provides a soft capsule containing NADH or NADPH. The contents of the soft capsule include NADH or NADPH, as well as edible vegetable oil or/and edible alcohol. The quality of the edible vegetable oil or/and edible alcohol can be 1-2 times the quality of NADH or NADPH.

The NADH or NADPH can be prepared by yeast fermentation, chemical synthesis or in vitro enzyme catalysis. It can also be prepared by whole-enzyme catalysis in vitro. This preparation method is a non-chemical synthesis method that can be achieved by an in vitro enzyme-catalyzed reaction. It mainly includes the following three steps: (1) cloning and expressing related enzymes; (2) Enzyme separation, purification or/and immobilization; (3) Enzymes are obtained after interacting with raw materials (ie, catalytic reactions) under normal temperature and pressure. The NADH or NADPH prepared by the in vitro holoenzyme catalysis method has the advantages of high purity, no organic solvent residue, no chirality problem, and the preparation is the same type as the body.

When edible vegetable oil or/and edible alcohol is mixed with NADH or NADPH, a protective film can be formed on the periphery of NADH or NADPH to form a coating effect on NADH or NADPH, so as to reduce the influence of external environment on NADH or NADPH and effectively avoid NADH Or the destruction of the molecular structure of NADPH reduces its activity and improves the chemical stability of NADH or NADPH.

Specifically, the edible vegetable oil includes but is not limited to at least one of linseed oil, olive oil, medium-chain triglycerides, coconut oil, or camellia seed oil. The edible alcohols include but are not limited to at least one of xylitol, maltitol or mannitol. These are the vegetable oils and sugar alcohol varieties commonly eaten by humans, with low cost, safety and no side effects, and are resistant to NADH or The effect of NADPH has no effect.

Further, the content in the soft capsule may also include antioxidants, the mass of which is 2-5 times the mass of NADH or NADPH. The antioxidant can be rosemary, which has the characteristics of good thermal stability, low production cost and natural non-toxicity. It has a strong inhibitory effect on the oxidation of various vegetable oils: on the one hand, it can prevent the oxidation of the protective film to ensure The protective effect of the protective film on NADH or NADPH; on the other hand, it is also conducive to the preservation and storage of soft capsules and improves the service life of soft capsules.

Furthermore, the contents of the soft capsule may also include a fat-soluble antacid, the quality of which is 2-10 times that of NADH or NADPH, which can weaken the digestive effect of the acidity in the stomach on the soft capsule when the soft capsule passes through the human stomach , To prevent NADH or NADPH from losing activity due to gastric acid. The fat-soluble antacid can be selected from fatty acid salts, such as sodium stearate, calcium stearate or zinc stearate, preferably calcium stearate.

The soft capsule containing NADH or NADPH of the present invention also includes a capsule shell molding material. The capsule shell molding material can be made of polymer materials, or alginate, or a combination of polymer materials and alginate. Conducive to the formation of the capsule shell. The amount of alginate used in combination is 0.5%-30% of the mass of the polymer material. The polymer material can be chitosan, cyclodextrin, or konjac glucomannan and its derivatives, and the konjac glucomannan and its derivatives can be konjac glucomannan, quaternary ammonium At least one of konjac glucomannan, carboxymethyl konjac glucomannan, or deacetyl konjac glucomannan. The alginate may be at least one of potassium alginate, sodium alginate or/and at least one of polyethylene glycol alginate. These are the raw materials for the preparation of capsules, which are safe and have no side effects. They can not only protect the raw materials, but also facilitate the formation of the capsule, and can also be used as a matrix to produce slow-release effects on drugs, and have antibacterial and antioxidant functions.

In the contents of the soft capsule containing NADH or NADPH of the present invention, by mixing NADH or NADPH with edible vegetable oil or/and edible alcohol, a protective film can be formed on the outer surface of NADH or NADPH, which can make NADH or NADPH in During the preparation process, the influence of light, air, moisture, processing, etc. on it is avoided, and the instability caused by the influence of the external environment on NADH or NADPH is effectively reduced. At the same time, supplemented with antioxidants on the basis of the above-mentioned protective film can avoid oxidation of the oily protective film. The added fat-soluble antacid can further resist gastric acid and other environmental erosion before the drug enters the intestine, so that the soft capsule can enter the human stomach. Afterwards, it is not easy to be degraded by gastric acid, which can avoid the influence of gastric acid to inactivate NADH or NADPH and reduce the curative effect, thereby improving the water solubility and biological activity of NADH or NADPH, and delaying the release of NADH or NADPH into the human body. Absorption, distribution and metabolism can ensure its smooth entry into the intestines and be absorbed and utilized by the human body. It has a fast effect and high curative effect. At the same time, NADH or NADPH has a protective film on the outer surface, which is also conducive to the preservation and storage of soft capsules, which has great application prospects.

S1 Stir and heat the edible vegetable oil or/and edible alcohol to 70-80°C to melt, then cool to 35-45°C, then stir and mix with NADH or NADPH according to the ratio for 30-60 Min, grind and sieve to obtain a raw material mixture.

In the S1 step, the edible vegetable oil or/and edible alcohol are stirred and heated to melt, which can remove impurities and precipitates in the vegetable oil and edible alcohol, and can make the vegetable oil and edible alcohol have a better dispersion effect, and stir and mix with NADH or NADPH After that, it can ensure the uniform formation of a protective film on the outer surface of NADH or NADPH.

Before step S1, the method of the present invention may further include the following steps:

S0 First mix NADH or NADPH with fat-soluble antacid according to the ratio and sieving to obtain mixture A, and then stir and mix said mixture A with edible vegetable oil or/and edible alcohol after heating, melting and cooling for 30-60Min After grinding and sieving, the raw material mixture is obtained.

In this step, NADH or NADPH is first mixed with fat-soluble antacid, so that NADH or NADPH can be uniformly attached to the antacid powder, which can resist the erosion of the external acidic environment and is also beneficial to edible vegetable oil or/and edible alcohol Formation of protective film.

In the present invention, in step S0 and/or step S1, antioxidants can also be added, and the antioxidants can be added when NADH or NADPH is stirred and mixed with vegetable oil or/and edible alcohol.

S2 After mixing and stirring the water and the capsule shell forming materials for 10-30 minutes, vacuumize and degas, with a vacuum degree of "-0.07MPa, to obtain a colorless glue solution.

In this step:

When a polymer material is used as the raw material for the capsule shell molding, the water and the polymer material can be mixed and stirred for 10-30 minutes, and then vacuumed and degassed with a vacuum degree of <-0.07MPa to obtain a colorless glue.

When alginate is used as the raw material for the capsule shell molding, the alginate and water can be heated to 75-80°C, and after melting, vacuumize and degas, with a vacuum degree of "-0.07MPa, to obtain a colorless glue solution.

When the raw material of the capsule shell is formed by using a combination of alginate and polymer materials, the alginate and water can be heated to 75-80°C, melted and then mixed with the polymer materials and stirred for 10-30 minutes, and then vacuum degassed. Vacuum degree "-0.07MPa, get colorless glue liquid.

S3 When the viscosity of the glue is detected by the viscometer to reach 10000mPa.s or more, the temperature of the glue is reduced to about 65°C.

S4 Pass the glue through a sieve and store at a temperature of 60±2°C.

In this step, if a colored soft capsule needs to be formed, the glue can be toned. Mix the food coloring with an appropriate amount of sodium alginate, grind it with a colloid mill, add the glue, and mix well. The amount of pigment added can be selected according to the desired capsule color and pigment depth.

When preparing the soft capsule of the present invention, an appropriate amount of light-shielding agent can be added to prevent light. The light-shielding agent is a common light-shielding agent known to those skilled in the art, such as titanium dioxide.

After mixing the glue, stir it for 40 minutes and keep it at 60±2℃ for later use.

S5 The mixed liquid in step S1 and the glue liquid in step S4 (or the glue liquid after color mixing) are prepared by a capsule machine to prepare soft capsules, which are shaped and dried, inspected and packaged.

The above soft capsules containing NADH or NADPH and the soft capsules prepared by the above preparation method can be widely used in the field of medicine and/or health care products, effectively solving the existing defects of NADH or NADPH that are intolerant to acid, easy to oxidize, and have low bioavailability. This not only guarantees the effective ingredients and curative effects of NADH or NADPH, but also brings convenience to users, and further prevents cross-infection.

Embodiments of the invention

The following examples further illustrate the preparation method of the soft capsules containing NADH or NADPH.

实施例Example 11 ：:

S1 Mix 50 parts of linseed oil, stir and heat to 80°C to melt, then stir and cool to about 40°C; then stir and mix 30 parts of NADH or NADPH with the cooled linseed oil for 60 minutes, grind, and pass through a 100 mesh sieve to obtain the raw material mixture liquid.

S2 Heat 3 parts of sodium alginate with water to 80°C, melt, and then mix with 10 parts of konjac glucomannan. After stirring for 30 minutes, vacuumize and degas with a vacuum degree of "-0.07MPa to obtain a colorless glue solution.

S4 Pass the glue through a 100-mesh sieve and store it at a temperature of 60±2°C.

In S5, mix 2 parts of food coloring with 1 part of sodium alginate and 5 parts of water, then grind with colloid, pour into glue liquid and mix evenly after grinding, and color glue liquid. After mixing the glue, stir it for 40 minutes and keep it at 60±2℃ for later use.

Furthermore, an appropriate amount of light-shielding agent commonly used in the market, such as titanium dioxide, is added to the glue solution after toning to avoid light.

In S6, the raw material mixture obtained in step S1 and the toned glue are used in a capsule making machine to prepare soft capsules.

S7 puts the soft capsule in an environment with a temperature of 25°C and a humidity of 30%, and uses a measuring ruler to detect the rubber thickness.

S8 will shape the soft capsules and dry them at a temperature of 25°C and a humidity of 30%.

S9 manually picks pills, removes special-shaped pills, large and small pills, bubble pills, deflated pills, etc. Then, after the soft capsules are dried, they are boxed, labeled, and boxed.

实施例Example 22 ：:

S1 Mix 20 parts of NADH or NADPH and 60 parts of antacid calcium stearate uniformly, and pass through a 100-mesh sieve to obtain mixture A.

S2 Stir and heat 40 parts of xylitol to 75°C to melt, and then stir and cool to about 40°C; then stir and mix the mixture A with the cooled xylitol for 40Min, grind, and pass through a 100 mesh sieve to obtain a raw material mixture.

S3 Mix 20 parts of chitosan with 20 parts of water, and after stirring for 30 minutes, vacuumize and degas, with a vacuum degree of "-0.07MPa, to obtain a colorless glue solution.

S4 When the viscosity of the glue is detected by a viscometer to reach more than 10000mPa.s, the temperature of the glue is reduced to about 65°C.

S5 Pass the glue through a 100-mesh sieve and store it at a temperature of 60±2°C.

S6 Mix 3 parts of pigment with 1 part of appropriate amount of sodium alginate and 5 parts of water, and then grind with colloid. After grinding, pour into the glue liquid and mix evenly, to color the glue liquid, and add an appropriate amount of light shielding agent to avoid light.

After mixing the S7 glue, stir it for 50 minutes, and keep it at 60±2℃ for later use.

S8 The raw material mixture obtained in step S2 and the toned glue are used in a capsule machine to prepare soft capsules.

S9 Put the soft capsule in an environment with a temperature of 20°C and a humidity of 25%, and measure the rubber thickness with a measuring ruler.

S10. Shape the soft capsule and dry it at a temperature of 20°C and a humidity of 25%.

S11 Manually pick pills, remove special-shaped pills, large and small pills, bubble pills, collapsed pills, etc., and then dry the soft capsules after picking the pills, pack them into boxes, label them, and pack them.

实施例Example 33 ：:

S1 Mix 40 parts of NADH or NADPH and 200 parts of antacid sodium stearate evenly, and pass through a 100-mesh sieve to obtain mixture A.

S2 Stir and heat 60 parts of medium chain triglycerides to 70°C to melt, and then stir and cool to about 40°C; then stir and mix mixture A and the cooled medium chain triglycerides for 40 minutes, grind, and pass through a 100 mesh sieve to obtain the raw material Mixture.

S3 Heat 10 parts of potassium alginate and 30 parts of water to 80℃, melt, and then mix with 40 parts of carboxymethyl konjac glucomannan, stir for 25 minutes, vacuum and degas, vacuum degree "-0.07MPa, get no Color glue liquid.

S4 When the viscosity of the glue is detected by the viscometer to reach more than 10000mPa.s, the temperature of the glue is reduced to about 65°C.

S6 Mix 1 part of pigment with 1 part of appropriate amount of sodium alginate and 5 parts of water, and then grind with colloid. After grinding, pour into the glue liquid and mix evenly, to color the glue liquid, and add an appropriate amount of light shielding agent to avoid light.

After mixing the S7 glue, stir it for 45min, keep it at 60±2℃ for later use.

S9 Put the soft capsule in an environment with a temperature of 30°C and a humidity of 30%, and measure the rubber thickness with a measuring ruler.

S10. Shape the soft capsule and dry it at a temperature of 30°C and a humidity of 30%.

实施例Example 44 ：:

S1 Stir and heat 100 parts of camellia seed oil to 75°C to melt, then stir and cool to about 40°C; then stir and mix 80 parts of NADH or NADPH with the cooled camellia seed oil for 45 minutes, then add 200 parts of rosemary, grind, and pass After a 100-mesh sieve, a raw material mixture is obtained.

S2 Heat 15 parts of sodium alginate and 15 parts of water to 80°C, melt, and then mix with 50 parts of cyclodextrin, stir for 30 minutes, vacuum and degas, vacuum degree "-0.07MPa, to obtain colorless glue liquid.

S3 When the viscosity of the glue liquid reaches 10000mPa.s or more by the viscometer, the glue liquid temperature is reduced to about 65°C.

S4 Pass the glue through a 100-mesh sieve and store it at a temperature of 60±2℃.

In S5, mix 2 parts of pigment with 2 parts of sodium alginate and 5 parts of water, then grind with colloid, pour into glue liquid and mix evenly after grinding, to color glue liquid, and add appropriate amount of light shielding agent to avoid light.

After mixing the S6 glue, stir it for 40 minutes and keep it at 60±2℃ for later use.

S7 The raw material mixture obtained in step S1 and the toned glue are used in a capsule making machine to prepare soft capsules.

S8 Put the soft capsule in an environment with a temperature of 25°C and a humidity of 30%, and measure the rubber thickness with a measuring ruler.

S9. Shape the soft capsule and dry it at a temperature of 25°C and a humidity of 30%.

S10 manually picks pills, removes special-shaped pills, large and small pills, bubble pills, deflated pills, etc. Then, after the soft capsules are dried, they are boxed, labeled, and boxed.

本发明的上述实施例所示仅为本发明较佳实施例之部分，并不能以此局限本发明，在不脱离本发明精髓的条件下，本领域技术人员所作的任何修改、等同替换和改进等，都属本发明的保护范围。The above-mentioned embodiments of the present invention are only part of the preferred embodiments of the present invention, and cannot be used to limit the present invention. Any modification, equivalent replacement and improvement made by those skilled in the art without departing from the essence of the present invention Etc., all belong to the protection scope of the present invention.

Claims

A soft capsule containing NADH or NADPH, characterized in that the contents in the soft capsule include NADH or NADPH and edible vegetable oil or/and edible alcohol, and the quality of the edible vegetable oil or/and edible alcohol is determined Said NADH or NADPH quality 1-2 times.
The soft capsule containing NADH or NADPH according to claim 1, wherein the edible vegetable oil includes but not limited to at least one of linseed oil, olive oil, medium-chain triglycerides, coconut oil or camellia seed oil Species; the edible alcohol includes but is not limited to at least one of xylitol, maltitol or mannitol.
The soft capsule containing NADH or NADPH according to claim 1, wherein the content in the soft capsule further comprises an antioxidant, and the quality of the antioxidant is 2-5 times the weight of the NADH or NADPH .
The soft capsule containing NADH or NADPH according to claim 3, wherein the antioxidant includes but not limited to rosemary.
The soft capsule containing NADH or NADPH according to any one of claims 1 to 4, wherein the content in the soft capsule further comprises a fat-soluble antacid, and the quality of the fat-soluble antacid is The quality of NADH or NADPH is 2-10 times.
The soft capsule containing NADH or NADPH according to claim 5, wherein the fat-soluble antacid is a fatty acid salt, and the fatty acid salt includes but is not limited to sodium stearate, calcium stearate or Zinc stearate.
The soft capsule containing NADH or NADPH according to claim 1, wherein the soft capsule includes a capsule shell molding material, and the capsule shell molding material includes a polymer material or/and alginate, wherein the high Molecular materials include but are not limited to chitosan, cyclodextrin or konjac glucomannan and their derivatives; the alginate includes but is not limited to at least one of potassium alginate, sodium alginate or/and polyethylene At least one of glycol alginate; the mass of the alginate is 0.5%-30% of the mass of the polymer material.
The soft capsule containing NADH or NADPH according to claim 7, wherein the konjac glucomannan and its derivatives are konjac glucomannan, quaternized konjac glucomannan, carboxymethyl konjac At least one of glucomannan or deacetyl konjac glucomannan.
A preparation method of soft capsules containing NADH or NADPH, which is characterized in that it comprises the following preparation steps:

Stir and melt the edible vegetable oil or/and edible alcohol, and after cooling, stir and mix NADH or NADPH with the edible vegetable oil or/and edible alcohol evenly, and obtain a raw material mixture after grinding and sieving;

Stir and mix the water and the capsule shell molding materials evenly, vacuum and degas to obtain a colorless glue;

When the viscosity of the glue liquid reaches 10000mPa.s or more by the viscometer, the glue liquid is cooled down;

Sieve the cooled glue;

The raw material mixture and the sieved glue are used to prepare soft capsules with a capsule making machine, which is shaped and dried.
The method for preparing NADH or NADPH-containing soft capsules according to claim 9, characterized in that, before the NADH or NADPH is mixed with edible vegetable oil or/and edible alcohol, the method further comprises the following steps:

Mix NADH or NADPH with fat-soluble antacids or/and antioxidants according to the ratio and mix them evenly and sieving to obtain mixture A, and then stir the mixture A with the edible vegetable oil or/and edible alcohol after heating, melting and cooling Mix for 30-60Min, grind and siev to obtain a raw material mixture.

11. Application of the soft capsule containing NADH or NADPH according to any one of claims 1-8 and the soft capsule prepared by the preparation method according to claim 9 or 10 in the field of medicine and/or health care products.