CN111450185B - Simotang soft capsule and preparation method thereof - Google Patents

Simotang soft capsule and preparation method thereof Download PDF

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CN111450185B
CN111450185B CN202010406821.0A CN202010406821A CN111450185B CN 111450185 B CN111450185 B CN 111450185B CN 202010406821 A CN202010406821 A CN 202010406821A CN 111450185 B CN111450185 B CN 111450185B
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soft capsule
parts
water
weight
content
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CN111450185A (en
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刘令安
刘正清
杨华
谭泽云
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HUNAN HANSEN PHARMACEUTICAL CO Ltd
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HUNAN HANSEN PHARMACEUTICAL CO Ltd
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Abstract

The invention relates to Simotang soft capsules and a preparation method thereof. On one hand, the soft capsule preparation provided by the invention is prepared from four medicinal materials of costustoot, bitter orange, betel nut and combined spicebush root, and comprises an inner hollow substance prepared from the four medicinal materials and a soft capsule shell wrapping the inner hollow substance, wherein the weight ratio of the four medicinal materials of costustoot, bitter orange, betel nut and combined spicebush root is 100: (50-150): (50-150): (50-150). Also provides a preparation method of the soft capsule. The soft capsule has the effects of guiding qi downward, lowering adverse qi, removing food retention and relieving pain, and can be used for treating infantile dyspepsia with symptoms of abdominal distention, abdominal pain, crying uneasiness, anorexia, diarrhea or constipation; it can also be used for the middle-aged and the elderly with syndrome of qi stagnation and food stagnation, manifested by abdominal distention, abdominal pain, and constipation; can also be used for promoting the recovery of gastrointestinal function after abdominal operation. The soft capsule of the present invention exhibits excellent effects as described in the specification.

Description

Simotang soft capsule and preparation method thereof
Technical Field
The invention belongs to the technical field of traditional Chinese medicines, relates to a medicament for treating digestive tract diseases, and particularly relates to a Simotang preparation which is a soft capsule and has one or more effects of more convenience in use, better physical or chemical stability and the like compared with the existing oral liquid.
Background
The four-grinding decoction is a traditional formula for regulating qi and lowering adverse qi, and consists of 4 medicines of bitter orange, costustoot, combined spicebush root and betel nut. Originally developed by hansen pharmaceutical products of Hunan province, Inc.
In the formula of Simo decoction, Zhi Qiao is good at regulating qi, relieving distension and removing stuffiness; mu Xiang regulates middle energizer and relieves pain, so it is good at moving qi stagnation of spleen, stomach and large intestine; radix Linderae can relieve pain and dispel cold; bing Lang is good at moving qi, resolving food stagnation and breaking stagnation. The four medicines are combined to play the effects of harmonizing stomach, descending adverse qi, guiding qi downward and removing food retention. It can be used for treating infantile dyspepsia with symptoms of abdominal distention, abdominal pain, cry restlessness, anorexia, diarrhea or constipation; middle-aged and elderly people with stagnation of qi, food stagnation, abdominal distention, abdominal pain, and constipation; and promoting the recovery of gastrointestinal functions after abdominal operation and after delivery.
Modern pharmacological research shows that the bitter orange can increase the gastrointestinal contraction rhythm and has the effects of calming, easing pain, resisting ulcer and the like; the costustoot can promote gastric secretion, gastrointestinal peristalsis and gallbladder contraction; radix Linderae has effects of exciting and inhibiting bidirectional regulation of gastrointestinal smooth muscle, promoting secretion of digestive juice, relieving pain, and resisting bacteria; betel nut can expel parasites and simulate choline, and has the function of promoting gastrointestinal peristalsis and secretion.
The quality standard of the Simotang oral liquid is recorded on page 264 and 265 of the spleen and stomach book of internal medicine in the national Chinese patent standards compilation (national standard part of local standard of Chinese patent medicine) issued by the State drug administration, and the standard numbers are as follows: WS-10040(ZD-0040) -2002, 10ml of oral liquid prepared by the standard is subpackaged for each branch, the 10ml of liquid medicine is prepared by 375mg of four medicinal materials of costustoot, bitter orange, betel nut and combined spicebush root respectively, and the oral liquid is taken by 3 times by 60ml for an adult per day. The shelf life of the Simotang oral liquid is 2 years, and only the Simotang oral liquid preparation is clinically applied up to now.
Chinese patent application No. 200610038224.7 discloses a dripping pill of Simotang and its preparation method, chinese patent application No. 94110842.2 discloses a Simotang oral liquid and its preparation method, chinese patent application No. 200410046986.2(CN1778369A) discloses a method for preparing granules, capsules and soft capsules of Simotang, especially in example 1 of the chinese patent application No. 200410046986.2, a method for preparing soft capsules is described, which comprises extracting volatile components from medicinal materials to obtain volatile oil, then extracting with water to obtain dry extract, mixing the volatile oil and dry extract powder with PEG400 to obtain a mixture, and then wrapping the mixture with soft capsule skin made of gelatin. However, the inventor finds that the soft capsule prepared by the 2004-year inventive technology has the technical problems of unstable capsule shell and the like, which is probably one of the reasons that the soft capsule preparation of Simotang has not been successfully developed and marketed.
Therefore, it would be highly desirable to those skilled in the art to prepare a simething preparation that is convenient to administer and has one or more beneficial effects, such as a simething soft capsule having one or more beneficial effects.
Disclosure of Invention
The present invention is directed to a Simpolo preparation that is convenient to administer and has one or more beneficial effects, such as a Soft Capsule Simpolo having one or more beneficial effects. It has been surprisingly found that one or more aspects of the benefits can be obtained by formulation process improvements to the terrazzo contents. The present invention has been completed based on such findings.
Therefore, the invention provides a soft capsule preparation which is prepared from four medicinal materials including costustoot, bitter orange, areca and combined spicebush root.
The soft capsule preparation comprises a content prepared from four medicinal materials and a soft capsule skin wrapping the content.
The soft capsule preparation according to the invention is prepared from the following four medicinal materials in parts by weight of 100: (50-150): (50-150): (50-150).
The soft capsule preparation according to the invention is prepared from the following four medicinal materials in parts by weight of 100: (75-125): (75-125): (75-125).
The soft capsule preparation according to the invention is prepared from the following four medicinal materials in parts by weight of 100: 100: 100: 100.
The soft capsule preparation according to the present invention, wherein the extracts prepared from the four medicinal materials are mixed with an auxiliary material to prepare the content.
The soft capsule preparation according to the invention, wherein the extracts of the four medicinal materials comprise volatile oil obtained by water extraction of the four medicinal materials and water extract obtained by water extraction of medicine dregs.
The soft capsule preparation comprises volatile oil obtained by extracting the four medicinal materials with water and extract obtained by extracting dregs of a decoction with water and precipitating the dregs of a decoction with alcohol.
The soft capsule preparation according to the present invention, wherein the extracts of the four herbs include extracts obtained by extracting the four herbs with alcohol (e.g. ethanol with a concentration of more than 95%).
The soft capsule preparation of the invention has 0.1-0.5 g, such as 0.2-0.4 g, such as 0.4-0.4 g, such as about 0.375g of medicinal wood fragrance in each capsule.
The soft capsule preparation according to the present invention, wherein the adjuvant mixed with the extracts prepared from the four medicinal materials comprises polyethylene glycol, such as polyethylene glycol 400.
According to the soft capsule preparation, 6000 to 8000 parts by weight of polyethylene glycol 400 is added in 3750 parts by weight of each added costustoot. Or the amount of the polyethylene glycol added in each soft capsule is 0.9-1.2 g.
The soft capsule preparation according to the present invention further contains tartaric acid. In one embodiment, 40-50 parts by weight of tartaric acid is added per 3750 parts by weight of costus root. In one embodiment, the tartaric acid is added before the extract is completely freed of extraction solvent.
The soft capsule preparation according to the present invention further comprises lysine. In one embodiment, 70-80 parts by weight of lysine is added per 3750 parts by weight of costus root. In one embodiment, the lysine is added before the extract is completely stripped of extraction solvent.
The soft capsule preparation according to the present invention, wherein the gelatin solution for formulating the soft capsule shell comprises gelatin, glycerin, water. In one embodiment, the weight ratio of gelatin, glycerin and water is 100: 40-60: 90-120 parts.
The soft capsule preparation according to the present invention is prepared as follows:
the main medicine prescription is as follows: 3750 parts of elecampane, 2812-4688 parts of fructus aurantii, 2812-4688 parts of betel nut and 2812-4688 parts of combined spicebush root
The preparation method comprises the following steps:
(1) putting the four medicines into an extraction tank, adding 4-6 times of water, extracting for 3-5 hours by a distillation method, and collecting volatile oil; standby;
(2) extracting the medicine residues twice with water, adding 6-8 times of water by weight of the medicinal materials for decocting and extracting for 1-2 hours for the first time, adding 5-7 times of water by weight of the medicinal materials for decocting and extracting for 1-1.5 hours for the second time, combining the decoctions, adding 40-50 parts by weight of tartaric acid and 70-80 parts by weight of lysine for dissolving, concentrating under reduced pressure to obtain a clear paste with a relative density of 1.2-1.3 (60 ℃), vacuum drying at 60-70 ℃ to obtain a dry paste, drying, crushing and sieving with a 80-mesh sieve to obtain a dry paste powder for later use;
(3) adding the dry extract powder and the volatile oil into 6000-8000 parts by weight of polyethylene glycol 400, and uniformly mixing by using a colloid mill to obtain the content of the soft capsule for later use;
(4) the content of the obtained soft capsule is wrapped with a soft capsule shell to prepare a soft capsule (for example:
(41) gelatin, glycerol and water are mixed according to the weight ratio of 100: 40-60: preparing a gelatin solution according to a proportion of 90-120, and preparing the gelatin solution into an adhesive tape for later use;
(42) selecting a mold with a proper size on a dynamic rotary capsule rolling machine at the room temperature of 20-25 ℃ and the relative humidity of 35-45%, and pressing the content of the soft capsule into the soft capsule by using an adhesive tape.
The soft capsule preparation according to the present invention is prepared as follows:
the main medicine prescription is as follows: 3750 parts of elecampane, 2812-4688 parts of fructus aurantii, 2812-4688 parts of betel nut and 2812-4688 parts of combined spicebush root
The preparation method comprises the following steps:
(1) putting the four medicines into an extraction tank, adding 4-6 times of water, extracting for 3-5 hours by a distillation method, collecting volatile oil for later use, and filtering to obtain medicine residues;
(2) extracting the medicine residues twice with water, adding 8-12 times of water by weight of the medicinal materials for decocting for 1-2 hours for the first time, adding 6-10 times of water by weight of the medicinal materials for decocting for 0.5-1 hour for the second time, combining the decoctions, concentrating under reduced pressure to obtain a clear paste with a relative density of 1.0-1.2 (60 ℃), adding ethanol until the ethanol content reaches 75%, refrigerating for 10-12 hours, filtering, recovering ethanol from the filtrate until no ethanol smell exists, adding 10-12L of water, stirring, refrigerating for 12 hours, filtering, adding 40-50 parts by weight of tartaric acid and 70-80 parts by weight of lysine into the filtrate for dissolving, concentrating to obtain a dry extract with a relative density of 1.25-1.30 (60 ℃), drying under vacuum at 60-70 ℃ to obtain a dry paste, drying, crushing, and sieving by a sieve with 80 meshes to obtain a dry paste powder for later use;
(3) adding the dry extract powder and the volatile oil into 6000-8000 parts by weight of polyethylene glycol 400, and uniformly mixing by using a colloid mill to obtain the content of the soft capsule for later use;
(4) the content of the obtained soft capsule is wrapped with a soft capsule shell to prepare a soft capsule (for example:
(41) gelatin, glycerol and water are mixed according to the weight ratio of 100: 40-60: preparing a gelatin solution according to a proportion of 90-120, and preparing the gelatin solution into an adhesive tape for later use;
(42) selecting a mold with a proper size on a dynamic rotary capsule rolling machine at the room temperature of 20-25 ℃ and the relative humidity of 35-45%, and pressing the content of the soft capsule into the soft capsule by using an adhesive tape.
The soft capsule preparation according to the present invention is prepared as follows:
the main medicine prescription is as follows: 3750 parts of elecampane, 2812-4688 parts of fructus aurantii, 2812-4688 parts of betel nut and 2812-4688 parts of combined spicebush root
The preparation method comprises the following steps:
(1) placing the four medicines in an extraction tank, performing reflux extraction twice by using ethanol (95%), soaking for 2-3 hours before the first extraction, adding 7-9 times of ethanol for the first extraction for 2-3 hours, adding 5-7 times of ethanol for the second extraction for 1-2 hours, combining the extracting solutions, and filtering to obtain a filtrate;
(2) adding 40-50 parts by weight of tartaric acid and 70-80 parts by weight of lysine into the filtrate for dissolving, recovering ethanol under reduced pressure below 55 ℃, concentrating into thick paste, drying in vacuum at 60-70 ℃ to obtain dry paste, drying, crushing and sieving with a 80-mesh sieve to obtain dry paste powder for later use;
(3) adding the thick paste into 6000-8000 parts by weight of polyethylene glycol 400, and uniformly mixing by using a colloid mill to obtain a soft capsule content for later use;
(4) the content of the obtained soft capsule is wrapped with a soft capsule shell to prepare a soft capsule (for example:
(41) gelatin, glycerol and water are mixed according to the weight ratio of 100: 40-60: preparing a gelatin solution according to a proportion of 90-120, and preparing the gelatin solution into an adhesive tape for later use;
(42) selecting a mold with a proper size on a dynamic rotary capsule rolling machine at the room temperature of 20-25 ℃ and the relative humidity of 35-45%, and pressing the content of the soft capsule into the soft capsule by using an adhesive tape.
Further, the second aspect of the present invention provides a method for preparing a soft capsule preparation, which comprises the steps of preparing contents from four medicinal materials of costustoot, bitter orange, betel nut and combined spicebush root, and then wrapping the contents by using a soft capsule shell to obtain a soft capsule.
According to the second aspect of the invention, the weight ratio of the four medicinal materials of costustoot, bitter orange, betel nut and combined spicebush root is 100: (50-150): (50-150): (50-150).
According to the second aspect of the invention, the weight ratio of the four medicinal materials of costustoot, bitter orange, betel nut and combined spicebush root is 100: (75-125): (75-125): (75-125).
According to the second aspect of the invention, the weight ratio of the four medicinal materials of costustoot, bitter orange, betel nut and combined spicebush root is 100: 100: 100: 100.
the method according to the second aspect of the present invention, wherein the content is prepared by mixing the extracts prepared from the four medicinal materials with an auxiliary material.
According to the method of the second aspect of the present invention, the extracts of the four herbs comprise volatile oil obtained by extracting the four herbs with water and water extract obtained by extracting the herb residue with water.
The method according to the second aspect of the present invention, wherein the extracts of the four herbs comprise volatile oils obtained by water extraction of the four herbs and extracts obtained by water extraction and alcohol precipitation of the herb residues.
The method according to the second aspect of the present invention, wherein the extracts of the four herbs comprise extracts obtained by extracting the four herbs with alcohol (e.g. ethanol with a concentration of greater than 95%).
According to the method of the second aspect of the present invention, each granule is equivalent to 0.1-0.5 g, such as 0.2-0.4 g, such as 0.4-0.4 g, such as about 0.375g of medicated wood fragrance.
The method according to the second aspect of the present invention, wherein the adjuvant mixed with the extracts prepared from the four medicinal materials comprises polyethylene glycol, such as polyethylene glycol 400.
According to the method of the second aspect of the invention, 6000 to 8000 parts by weight of polyethylene glycol 400 is added per 3750 parts by weight of costustoot. Or the amount of the polyethylene glycol added in each soft capsule is 0.9-1.2 g.
According to the method of the second aspect of the invention, the content further comprises tartaric acid. In one embodiment, 40-50 parts by weight of tartaric acid is added per 3750 parts by weight of costus root. In one embodiment, the tartaric acid is added before the extract is completely freed of extraction solvent.
According to the method of the second aspect of the present invention, the content further comprises lysine. In one embodiment, 70-80 parts by weight of lysine is added per 3750 parts by weight of costus root. In one embodiment, the lysine is added before the extract is completely stripped of extraction solvent. The inventors have surprisingly found that the addition of appropriate amounts of tartaric acid and lysine to the contents of a soft capsule can significantly improve not only the physical stability characterized by the disintegration time of the soft capsule, but also the chemical stability characterized by synephrine and N-methyltyramine.
The method according to the second aspect of the present invention, wherein the gelatin solution for formulating the soft capsule shell comprises gelatin, glycerin, water. In one embodiment, the weight ratio of gelatin, glycerin and water is 100: 40-60: 90-120 parts.
The method according to the second aspect of the invention, comprising the steps of:
the main medicine prescription is as follows: 3750 parts of elecampane, 2812-4688 parts of fructus aurantii, 2812-4688 parts of betel nut and 2812-4688 parts of combined spicebush root
The preparation method comprises the following steps:
(1) putting the four medicines into an extraction tank, adding 4-6 times of water, extracting for 3-5 hours by a distillation method, and collecting volatile oil; standby;
(2) extracting the medicine residues twice with water, adding 6-8 times of water by weight of the medicinal materials for decocting and extracting for 1-2 hours for the first time, adding 5-7 times of water by weight of the medicinal materials for decocting and extracting for 1-1.5 hours for the second time, combining the decoctions, adding 40-50 parts by weight of tartaric acid and 70-80 parts by weight of lysine for dissolving, concentrating under reduced pressure to obtain a clear paste with a relative density of 1.2-1.3 (60 ℃), vacuum drying at 60-70 ℃ to obtain a dry paste, drying, crushing and sieving with a 80-mesh sieve to obtain a dry paste powder for later use;
(3) adding the dry extract powder and the volatile oil into 6000-8000 parts by weight of polyethylene glycol 400, and uniformly mixing by using a colloid mill to obtain the content of the soft capsule for later use;
(4) the content of the obtained soft capsule is wrapped with a soft capsule shell to prepare a soft capsule (for example:
(41) gelatin, glycerol and water are mixed according to the weight ratio of 100: 40-60: preparing a gelatin solution according to a proportion of 90-120, and preparing the gelatin solution into an adhesive tape for later use;
(42) selecting a mold with a proper size on a dynamic rotary capsule rolling machine at the room temperature of 20-25 ℃ and the relative humidity of 35-45%, and pressing the content of the soft capsule into the soft capsule by using an adhesive tape.
The method according to the second aspect of the invention, comprising the steps of:
the main medicine prescription is as follows: 3750 parts of elecampane, 2812-4688 parts of fructus aurantii, 2812-4688 parts of betel nut and 2812-4688 parts of combined spicebush root
The preparation method comprises the following steps:
(1) putting the four medicines into an extraction tank, adding 4-6 times of water, extracting for 3-5 hours by a distillation method, collecting volatile oil for later use, and filtering to obtain medicine residues;
(2) extracting the medicine residues twice with water, adding 8-12 times of water by weight of the medicinal materials for decocting for 1-2 hours for the first time, adding 6-10 times of water by weight of the medicinal materials for decocting for 0.5-1 hour for the second time, combining the decoctions, concentrating under reduced pressure to obtain a clear paste with a relative density of 1.0-1.2 (60 ℃), adding ethanol until the ethanol content reaches 75%, refrigerating for 10-12 hours, filtering, recovering ethanol from the filtrate until no ethanol smell exists, adding 10-12L of water, stirring, refrigerating for 12 hours, filtering, adding 40-50 parts by weight of tartaric acid and 70-80 parts by weight of lysine into the filtrate for dissolving, concentrating to obtain a dry extract with a relative density of 1.25-1.30 (60 ℃), drying under vacuum at 60-70 ℃ to obtain a dry paste, drying, crushing, and sieving by a sieve with 80 meshes to obtain a dry paste powder for later use;
(3) adding the dry extract powder and the volatile oil into 6000-8000 parts by weight of polyethylene glycol 400, and uniformly mixing by using a colloid mill to obtain the content of the soft capsule for later use;
(4) the content of the obtained soft capsule is wrapped with a soft capsule shell to prepare a soft capsule (for example:
(41) gelatin, glycerol and water are mixed according to the weight ratio of 100: 40-60: preparing a gelatin solution according to a proportion of 90-120, and preparing the gelatin solution into an adhesive tape for later use;
(42) selecting a mold with a proper size on a dynamic rotary capsule rolling machine at the room temperature of 20-25 ℃ and the relative humidity of 35-45%, and pressing the content of the soft capsule into the soft capsule by using an adhesive tape.
The method according to the second aspect of the invention, comprising the steps of:
the main medicine prescription is as follows: 3750 parts of elecampane, 2812-4688 parts of fructus aurantii, 2812-4688 parts of betel nut and 2812-4688 parts of combined spicebush root
The preparation method comprises the following steps:
(1) placing the four medicines in an extraction tank, performing reflux extraction twice by using ethanol (95%), soaking for 2-3 hours before the first extraction, adding 7-9 times of ethanol for the first extraction for 2-3 hours, adding 5-7 times of ethanol for the second extraction for 1-2 hours, combining the extracting solutions, and filtering to obtain a filtrate;
(2) adding 40-50 parts by weight of tartaric acid and 70-80 parts by weight of lysine into the filtrate for dissolving, recovering ethanol under reduced pressure below 55 ℃, concentrating into thick paste, drying in vacuum at 60-70 ℃ to obtain dry paste, drying, crushing and sieving with a 80-mesh sieve to obtain dry paste powder for later use;
(3) adding the thick paste into 6000-8000 parts by weight of polyethylene glycol 400, and uniformly mixing by using a colloid mill to obtain a soft capsule content for later use;
(4) the content of the obtained soft capsule is wrapped with a soft capsule shell to prepare a soft capsule (for example:
(41) gelatin, glycerol and water are mixed according to the weight ratio of 100: 40-60: preparing a gelatin solution according to a proportion of 90-120, and preparing the gelatin solution into an adhesive tape for later use;
(42) selecting a mold with a proper size on a dynamic rotary capsule rolling machine at the room temperature of 20-25 ℃ and the relative humidity of 35-45%, and pressing the content of the soft capsule into the soft capsule by using an adhesive tape.
Further, the third aspect of the present invention provides a use of the soft capsule preparation of the first aspect of the present invention or the soft capsule preparation prepared by the method of the second aspect of the present invention for preparing a medicament for:
guiding qi downward, lowering adverse qi, removing food stagnation and relieving pain;
infantile dyspepsia with symptoms of abdominal distention, abdominal pain, cry restlessness, anorexia, diarrhea or constipation;
the middle-aged and the elderly suffer from qi stagnation, food stagnation syndrome, abdominal distention, abdominal pain, and constipation; and/or
Promote the recovery of the gastrointestinal function after the abdominal operation.
Any embodiment according to any aspect of the invention, wherein the tablet has a formulation as described in any one of the embodiments of the invention.
According to any embodiment of any aspect of the invention, wherein the tablet has the formulation and manufacturing method as described in any one of the embodiments of the invention.
In the above-described steps of the preparation method of the present invention, although the specific steps described therein are distinguished in some detail or in language description from the steps described in the preparation examples of the detailed embodiments below, those skilled in the art can fully summarize the above-described method steps in light of the detailed disclosure throughout the present disclosure.
Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict. The invention is further described below.
All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.
Since the basic process of the soft capsule preparation is well known to those skilled in the art, the preparation process of the Simotang preparation as the soft capsule preparation of the present invention may not be particularly limited. In addition, Simotang preparation such as oral liquid has been the basis of folk and clinical application for hundreds of years. It is believed that Simo Tang comes from Ji Sheng Fang, which regulates qi to descend adverse qi, and relieves food stagnation to stop pain. The four-grinding decoction can be used for treating infantile milk food stagnation syndrome, abdominal distention, crying uneasiness, anorexia, diarrhea or constipation; can also be used for treating qi stagnation and food stagnation of the middle aged and the elderly with symptoms of abdominal distention, abdominal pain, and constipation; and can promote the recovery of gastrointestinal function after abdominal operation. Modern medical research shows that the costustoot can obviously enhance the peristalsis amplitude and muscle tension, promote gastric emptying and intestinal propulsion, and resist intestinal muscle spasm caused by acetylcholine and histamine; arecae semen can excite M-choline receptor, increase glandular secretion, promote digestive juice secretion, and excite smooth muscle; the combined spicebush root plays a key role in the formula, not only can enhance the pharmacological action of other medicines in the formula, but also can excite the gastrointestinal smooth muscle to enhance the intestinal tract contraction. Therefore, Simotang can achieve good effect in treating constipation. In particular, Hansen has been used in clinical applications
Figure BDA0002491639530000081
The four grinding soup oral liquid [ function indication ] is as follows: direct qi downward, remove food retention and alleviate pain. Can be used for treating infantile dyspepsia with symptoms of abdominal distention, abdominal pain, cry, anorexia, diarrhea or constipation; the middle-aged and the elderly suffer from qi stagnation and food stagnation, with symptoms of abdominal distention, abdominal pain, and constipation; and promoting the recovery of gastrointestinal function after abdominal operation. Therefore, the traditional Chinese medicine composition of the invention also has the [ functional indications ]. However,the essence of the present invention lies in that the Chinese medicinal composition of the present invention has particularly good pharmaceutical properties under specific formulation conditions, particularly excellent stability, and thus the present invention does not need to specifically limit the functional indications of the Chinese medicinal composition of the present invention.
The traditional Chinese medicine composition is used for guiding qi downward, lowering adverse qi, removing food retention and relieving pain. The traditional Chinese medicine composition is used for treating milk food stagnation symptoms of the infants, such as abdominal distension, abdominal pain, crying uneasiness, anorexia, diarrhea or constipation; the traditional Chinese medicine composition is used for treating qi stagnation and food retention syndromes of middle-aged and old people, with symptoms of abdominal fullness and distention, abdominal pain and constipation; the traditional Chinese medicine composition is used for promoting the recovery of gastrointestinal functions after abdominal operations.
In the present invention, the term "total herbs" refers to the sum of four herbs.
The inventor finds that the traditional Chinese medicine composition has excellent characteristics.
Detailed Description
The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible. The following examples further illustrate the invention without limiting it.
The following preparation steps are given for the purpose of illustration and are based on the comparative nature of the respective examples and the person skilled in the art is fully enabled to generalize from the prior knowledge the process of the invention for preparing the products of the invention. In the following experiments, the herbs were cut into 0.2-5cm size in advance with a herbal medicine cutting machine. The weight of the content of each soft capsule in the following examples is within the range of 0.9-1.2 g, so that each soft capsule is prepared into the soft capsule equivalent to 0.375g of wood fragrance containing the medicinal material, or the soft capsule is wrapped by 0.2-1.5 times of the wood fragrance containing the medicinal material.
Example 1: preparing Simotang soft capsule
The main medicine prescription is as follows: 3750g of costustoot, 3750g of bitter orange, 3750g of areca nut and 3750g of combined spicebush root
The preparation method comprises the following steps:
(1) placing the four medicines in an extraction tank, adding 5 times of water, extracting for 4 hours by a distillation method, and collecting volatile oil; standby;
(2) extracting the dregs of a decoction twice with water, adding 7 times of water by weight of the medicinal materials for decocting and extracting for 1.5 hours for the first time, adding 6 times of water by weight of the medicinal materials for decocting and extracting for 1.25 hours for the second time, merging the decoction, adding 45g of tartaric acid and 75g of lysine for dissolving, concentrating under reduced pressure to obtain clear paste with the relative density of 1.25(60 ℃), drying in vacuum at 60-70 ℃ to obtain dry paste, drying, crushing and sieving with a 80-mesh sieve to obtain dry paste powder for later use;
(3) adding the dry extract powder and volatile oil into 7000g of polyethylene glycol 400, and mixing with colloid mill to obtain soft capsule content;
(4) gelatin, glycerol and water are mixed according to the weight ratio of 100: 50: 105, preparing a gelatin solution according to the proportion to prepare an adhesive tape for later use;
(5) and (3) selecting a mold with a proper size on a dynamic rotary capsule rolling machine at the room temperature of 20-25 ℃ and the relative humidity of 35-45%, and pressing the content of the soft capsule into soft capsules with adhesive tapes, wherein each soft capsule is equivalent to 0.375g of wood fragrance containing the medicinal material.
Example 2: preparing Simotang soft capsule
The main medicine prescription is as follows: 3750g of costustoot, 3750g of bitter orange, 3750g of areca nut and 3750g of combined spicebush root
The preparation method comprises the following steps:
(1) placing the four medicines in an extraction tank, adding 4 times of water, extracting for 5 hours by a distillation method, and collecting volatile oil; standby;
(2) extracting the dregs of a decoction twice with water, adding 8 times of water by weight of the medicinal materials for decocting and extracting for 1 hour for the first time, adding 5 times of water by weight of the medicinal materials for decocting and extracting for 1.5 hours for the second time, merging decoction, adding 40g of tartaric acid and 80g of lysine for dissolving, concentrating under reduced pressure to obtain clear paste with the relative density of 1.3(60 ℃), drying in vacuum at 60-70 ℃ to obtain dry paste, drying, crushing and sieving by a sieve of 80 meshes to obtain dry paste powder for later use;
(3) adding the dry extract powder and volatile oil into 6000g of polyethylene glycol 400, and mixing with colloid mill to obtain soft capsule content;
(4) gelatin, glycerol and water are mixed according to the weight ratio of 100: 40: preparing gelatin solution according to the proportion of 120, and preparing the gelatin solution into an adhesive tape for later use;
(5) and (3) selecting a mold with a proper size on a dynamic rotary capsule rolling machine at the room temperature of 20-25 ℃ and the relative humidity of 35-45%, and pressing the content of the soft capsule into soft capsules with adhesive tapes, wherein each soft capsule is equivalent to 0.375g of wood fragrance containing the medicinal material.
Example 3: preparing Simotang soft capsule
The main medicine prescription is as follows: 3750g of costustoot, 3750g of bitter orange, 3750g of areca nut and 3750g of combined spicebush root
The preparation method comprises the following steps:
(1) placing the four medicines in an extraction tank, adding 6 times of water, extracting for 3 hours by a distillation method, and collecting volatile oil; standby;
(2) extracting the dregs of a decoction twice with water, adding 6 times of water by weight of the medicinal materials for decocting and extracting for 2 hours for the first time, adding 7 times of water by weight of the medicinal materials for decocting and extracting for 1 hour for the second time, mixing the decoctions, adding 50g of tartaric acid and 70g of lysine for dissolving, concentrating under reduced pressure to obtain a clear paste with the relative density of 1.2(60 ℃), drying in vacuum at 60-70 ℃ to obtain a dry paste, drying, crushing and sieving with a 80-mesh sieve to obtain a dry paste powder for later use;
(3) adding the dry extract powder and volatile oil into 8000g of polyethylene glycol 400, and mixing with colloid mill to obtain soft capsule content;
(4) gelatin, glycerol and water are mixed according to the weight ratio of 100: 60: 90, preparing gelatin solution to prepare adhesive tape for later use;
(5) and (3) selecting a mold with a proper size on a dynamic rotary capsule rolling machine at the room temperature of 20-25 ℃ and the relative humidity of 35-45%, and pressing the content of the soft capsule into soft capsules with adhesive tapes, wherein each soft capsule is equivalent to 0.375g of wood fragrance containing the medicinal material.
Example 4: preparing Simotang soft capsule
The main medicine prescription is as follows: 3750g of costustoot, 2812g of bitter orange, 4688g of betel nut and 2812g of combined spicebush root
The preparation method comprises the following steps:
(1) placing the four medicines in an extraction tank, adding 5 times of water, extracting for 4 hours by a distillation method, and collecting volatile oil; standby;
(2) extracting the dregs of a decoction twice with water, adding 7 times of water by weight of the medicinal materials for decocting and extracting for 1.5 hours for the first time, adding 6 times of water by weight of the medicinal materials for decocting and extracting for 1.25 hours for the second time, merging the decoction, adding 45g of tartaric acid and 75g of lysine for dissolving, concentrating under reduced pressure to obtain clear paste with the relative density of 1.25(60 ℃), drying in vacuum at 60-70 ℃ to obtain dry paste, drying, crushing and sieving with a 80-mesh sieve to obtain dry paste powder for later use;
(3) adding the dry extract powder and volatile oil into 7000g of polyethylene glycol 400, and mixing with colloid mill to obtain soft capsule content;
(4) gelatin, glycerol and water are mixed according to the weight ratio of 100: 50: 105, preparing a gelatin solution according to the proportion to prepare an adhesive tape for later use;
(5) and (3) selecting a mold with a proper size on a dynamic rotary capsule rolling machine at the room temperature of 20-25 ℃ and the relative humidity of 35-45%, and pressing the content of the soft capsule into soft capsules with adhesive tapes, wherein each soft capsule is equivalent to 0.375g of wood fragrance containing the medicinal material.
Example 5: preparing Simotang soft capsule
The main medicine prescription is as follows: 3750g of costustoot, 4688g of bitter orange, 2812g of betel nut and 4688g of combined spicebush root
The preparation method comprises the following steps:
(1) placing the four medicines in an extraction tank, adding 5 times of water, extracting for 4 hours by a distillation method, and collecting volatile oil; standby;
(2) extracting the dregs of a decoction twice with water, adding 7 times of water by weight of the medicinal materials for decocting and extracting for 1.5 hours for the first time, adding 6 times of water by weight of the medicinal materials for decocting and extracting for 1.25 hours for the second time, merging the decoction, adding 45g of tartaric acid and 75g of lysine for dissolving, concentrating under reduced pressure to obtain clear paste with the relative density of 1.25(60 ℃), drying in vacuum at 60-70 ℃ to obtain dry paste, drying, crushing and sieving with a 80-mesh sieve to obtain dry paste powder for later use;
(3) adding the dry extract powder and volatile oil into 7000g of polyethylene glycol 400, and mixing with colloid mill to obtain soft capsule content;
(4) gelatin, glycerol and water are mixed according to the weight ratio of 100: 50: 105, preparing a gelatin solution according to the proportion to prepare an adhesive tape for later use;
(5) and (3) selecting a mold with a proper size on a dynamic rotary capsule rolling machine at the room temperature of 20-25 ℃ and the relative humidity of 35-45%, and pressing the content of the soft capsule into soft capsules with adhesive tapes, wherein each soft capsule is equivalent to 0.375g of wood fragrance containing the medicinal material.
Example 6: preparing Simotang soft capsule
The main medicine prescription is as follows: 3750g of costustoot, 3750g of bitter orange, 3750g of areca nut and 3750g of combined spicebush root
The preparation method comprises the following steps:
(1) placing the four medicines in an extraction tank, adding 5 times of water, extracting for 4 hr by distillation, collecting volatile oil, and filtering to obtain residue;
(2) extracting the residue with water twice, adding 10 times of water by weight of the medicinal materials for the first time, decocting for 1.5 hours, adding 8 times of water by weight of the medicinal materials for the second time, decocting for 0.75 hours, mixing decoctions, concentrating under reduced pressure to obtain a fluid extract with a relative density of 1.1(60 ℃), adding ethanol until the ethanol content reaches 75%, refrigerating for 11 hours, filtering, recovering ethanol from the filtrate until no ethanol smell exists, adding 11L of water, stirring, refrigerating for 12 hours, filtering, adding 45g of tartaric acid and 75g of lysine into the filtrate for dissolving, concentrating to obtain an extract with a relative density of 1.28(60 ℃), vacuum drying at 65 ℃ to obtain a dry extract, drying, pulverizing, and sieving with a 80-mesh sieve to obtain a dry extract powder for later use;
(3) adding the dry extract powder and volatile oil into 7000g of polyethylene glycol 400, and mixing with colloid mill to obtain soft capsule content;
(4) gelatin, glycerol and water are mixed according to the weight ratio of 100: 50: preparing gelatin solution according to the proportion of 100, and preparing the gelatin solution into an adhesive tape for later use;
(5) and (3) selecting a mold with a proper size on a dynamic rotary capsule rolling machine at the room temperature of 20-25 ℃ and the relative humidity of 35-45%, and pressing the content of the soft capsule into soft capsules with adhesive tapes, wherein each soft capsule is equivalent to 0.375g of wood fragrance containing the medicinal material.
Practice ofExample 7: preparing Simotang soft capsule
The main medicine prescription is as follows: 3750g of costustoot, 2812g of bitter orange, 4688g of betel nut and 2812g of combined spicebush root
The preparation method comprises the following steps:
(1) placing the four medicines in an extraction tank, adding 4 times of water, extracting for 5 hr by distillation, collecting volatile oil, and filtering to obtain residue;
(2) extracting the residue with water twice, adding 12 times of water by weight of the medicinal materials for the first time, decocting for 1 hr, adding 10 times of water by weight of the medicinal materials for the second time, decocting for 0.5 hr, mixing decoctions, concentrating under reduced pressure to obtain fluid extract with relative density of 1.0(60 deg.C), adding ethanol until ethanol content reaches 75%, refrigerating for 12 hr, filtering, recovering ethanol from the filtrate until no ethanol smell exists, adding 10L of water, stirring, refrigerating for 12 hr, filtering, adding 40g tartaric acid and 80g lysine into the filtrate for dissolving, concentrating to obtain extract with relative density of 1.25(60 deg.C), vacuum drying at 70 deg.C to obtain dry extract, drying, pulverizing, and sieving with 80 mesh sieve to obtain dry extract powder;
(3) adding the dry extract powder and volatile oil into 6000g of polyethylene glycol 400, and mixing with colloid mill to obtain soft capsule content;
(4) gelatin, glycerol and water are mixed according to the weight ratio of 100: 40: preparing gelatin solution according to the proportion of 120, and preparing the gelatin solution into an adhesive tape for later use;
(5) and (3) selecting a mold with a proper size on a dynamic rotary capsule rolling machine at the room temperature of 20-25 ℃ and the relative humidity of 35-45%, and pressing the content of the soft capsule into soft capsules with adhesive tapes, wherein each soft capsule is equivalent to 0.375g of wood fragrance containing the medicinal material.
Example 8: preparing Simotang soft capsule
The main medicine prescription is as follows: 3750g of costustoot, 4688g of bitter orange, 2812g of betel nut and 4688g of combined spicebush root
The preparation method comprises the following steps:
(1) placing the four medicines in an extraction tank, adding 6 times of water, extracting for 3 hr by distillation, collecting volatile oil, and filtering to obtain residue;
(2) extracting the residue with water twice, adding 8 times of water by weight of the medicinal materials for the first time, decocting for 2 hours, adding 6 times of water by weight of the medicinal materials for the second time, decocting for 1 hour, mixing decoctions, concentrating under reduced pressure to obtain fluid extract with relative density of 1.2(60 deg.C), adding ethanol until ethanol content reaches 75%, refrigerating for 10 hours, filtering, recovering ethanol from filtrate until no ethanol smell exists, adding 12L of water, stirring, refrigerating for 12 hours, filtering, adding 50g tartaric acid and 70g lysine into the filtrate for dissolving, concentrating to obtain extract with relative density of 1.30(60 deg.C), vacuum drying at 60 deg.C to obtain dry extract, drying, pulverizing, and sieving with 80 mesh sieve to obtain dry extract powder;
(3) adding the dry extract powder and volatile oil into 8000g of polyethylene glycol 400, and mixing with colloid mill to obtain soft capsule content;
(4) gelatin, glycerol and water are mixed according to the weight ratio of 100: 60: 90, preparing gelatin solution to prepare adhesive tape for later use;
(5) and (3) selecting a mold with a proper size on a dynamic rotary capsule rolling machine at the room temperature of 20-25 ℃ and the relative humidity of 35-45%, and pressing the content of the soft capsule into soft capsules with adhesive tapes, wherein each soft capsule is equivalent to 0.375g of wood fragrance containing the medicinal material.
Example 9: preparing Simotang soft capsule
The main medicine prescription is as follows: 3750g of costustoot, 3750g of bitter orange, 3750g of areca nut and 3750g of combined spicebush root
The preparation method comprises the following steps:
(1) placing the four medicines in an extraction tank, performing reflux extraction twice with ethanol (98%), soaking for 2.5 hours before the first extraction, adding 8 times of ethanol for the first extraction for 2.5 hours, adding 6 times of ethanol for the second extraction for 1.5 hours, mixing the extractive solutions, and filtering to obtain filtrate;
(2) adding 45g tartaric acid and 75g lysine into the filtrate for dissolving, recovering ethanol under reduced pressure below 55 deg.C and concentrating to obtain soft extract, vacuum drying at 65 deg.C to obtain dry extract, drying, pulverizing, and sieving with 80 mesh sieve to obtain dry extract powder;
(3) adding the soft extract into 7000g polyethylene glycol 400, and mixing with colloid mill to obtain soft capsule content;
(4) gelatin, glycerol and water are mixed according to the weight ratio of 100: 50: 105, preparing a gelatin solution according to the proportion to prepare an adhesive tape for later use;
(5) and (3) selecting a mold with a proper size on a dynamic rotary capsule rolling machine at the room temperature of 20-25 ℃ and the relative humidity of 35-45%, and pressing the content of the soft capsule into soft capsules with adhesive tapes, wherein each soft capsule is equivalent to 0.375g of wood fragrance containing the medicinal material.
Example 10: preparing Simotang soft capsule
The main medicine prescription is as follows: 3750g of costustoot, 4688g of bitter orange, 2812g of betel nut and 4688g of combined spicebush root
The preparation method comprises the following steps:
(1) placing the four medicines in an extraction tank, performing reflux extraction twice with ethanol (95%), soaking for 2 hours before the first extraction, adding 9 times of ethanol for 2 hours, adding 7 times of ethanol for the second extraction, extracting for 1 hour, mixing the extractive solutions, and filtering to obtain filtrate;
(2) dissolving filtrate in 40g tartaric acid and 80g lysine, recovering ethanol under reduced pressure below 55 deg.C, concentrating into soft extract, vacuum drying at 70 deg.C to obtain dry extract, drying, pulverizing, and sieving with 80 mesh sieve to obtain dry extract powder;
(3) adding the soft extract into 6000g polyethylene glycol 400, and mixing with colloid mill to obtain soft capsule content;
(4) gelatin, glycerol and water are mixed according to the weight ratio of 100: 58: 95, preparing gelatin solution according to the proportion to prepare an adhesive tape for later use;
(5) and (3) selecting a mold with a proper size on a dynamic rotary capsule rolling machine at the room temperature of 20-25 ℃ and the relative humidity of 35-45%, and pressing the content of the soft capsule into soft capsules with adhesive tapes, wherein each soft capsule is equivalent to 0.375g of wood fragrance containing the medicinal material.
Example 11: preparing Simotang soft capsule
The main medicine prescription is as follows: 3750g of costustoot, 2812g of bitter orange, 4688g of betel nut and 2812g of combined spicebush root
The preparation method comprises the following steps:
(1) placing the four medicines in an extraction tank, reflux-extracting with ethanol (99%) twice, soaking for 3 hr before the first extraction, adding 7 times of ethanol for 3 hr, adding 5 times of ethanol for the second extraction for 2 hr, mixing extractive solutions, and filtering to obtain filtrate;
(2) dissolving filtrate in 50g tartaric acid and 70g lysine, recovering ethanol under reduced pressure below 55 deg.C, concentrating into soft extract, vacuum drying at 60 deg.C to obtain dry extract, drying, pulverizing, and sieving with 80 mesh sieve to obtain dry extract powder;
(3) adding the soft extract into 8000g polyethylene glycol 400, and mixing with colloid mill to obtain soft capsule content;
(4) preparing gelatin solution from gelatin, glycerol and water at a weight ratio of 100: 42: 115, and making into adhesive tape;
(5) and (3) selecting a mold with a proper size on a dynamic rotary capsule rolling machine at the room temperature of 20-25 ℃ and the relative humidity of 35-45%, and pressing the content of the soft capsule into soft capsules with adhesive tapes, wherein each soft capsule is equivalent to 0.375g of wood fragrance containing the medicinal material.
Example 21: preparing Simotang soft capsule
Referring to the formulation and preparation method of examples 1-11, respectively, 11 soft capsules were obtained except that no tartaric acid was added.
Example 22: preparing Simotang soft capsule
Referring to the formulation and preparation method of examples 1-11, respectively, except that no lysine was added, 11 soft capsules were obtained.
Example 23: preparing Simotang soft capsule
11 kinds of soft capsules were obtained by referring to the formulation and the production method of examples 1 to 11, respectively, except that neither tartaric acid nor lysine was added.
Example 24: preparation of Simotang Soft Capsule (#369)
Cutting qualified medicinal materials into pieces of 0.2-5cm, weighing 3.75 kg of radix aucklandiae, radix Linderae, fructus Aurantii, and Arecae semen, placing in a multifunctional extraction tank, distilling with water vapor to collect volatile components about 80L, and rectifying to obtain volatile oil about 15 ml; extracting the residue with water twice, adding water 90L each time, boiling to extract 1 water, concentrating the extractive solution to relative density of 1.26 (measured at 60 deg.C), vacuum drying at 60-70 deg.C to obtain dry extract 210 g, pulverizing the dry extract, and sieving with 80 mesh sieve; adding the obtained dry extract powder and volatile oil into 1000 g polyethylene glycol 400(PEG400), mixing with colloid mill, adding 6000g polyethylene glycol 400(PEG400) to obtain transparent capsule core, and collecting gelatin solution (gelatin 100 parts, glycerol 50 parts, and water 105 parts). Controlling the room temperature to be 20-25 ℃ and the relative temperature to be 35-45%, and pressing the mixture into soft capsules by a soft capsule machine, wherein each soft capsule is equivalent to 1.5 g of the medicinal materials.
Example 25: preparing Simotang soft capsule
Referring to the formula and the preparation method of the examples 1-11 respectively, 11 soft capsules are obtained except that the medicinal material fructus aurantii is not added.
Example 26: preparing Simotang soft capsule
Referring to the 11 formulations and preparation methods of example 23, respectively, except that fructus Aurantii was not added, 11 soft capsules were obtained.
Test example 1: stability inspection method
The prepared various soft capsules are packaged by a simulated commercially available blister, then are placed for 6 months under the conditions of the temperature of 40 +/-2 ℃ and the relative humidity of 75 +/-5 percent, and various performances and changes thereof at 0 month and 6 months are measured, wherein the treatment method for stability investigation can be simply referred to as treatment of 40-6 months.
Test example 2: disintegration time and disintegration time
The soft capsules prepared by the present invention were measured in artificial gastric juice according to the method described in "0921 disintegration time limit inspection method" of the four parts of the chinese pharmacopoeia 2015 edition.
All the soft capsules prepared in examples 1 to 11 and 21 to 26 were measured for disintegration time within three days after their preparation (equivalent to 0 month for stability test), and all the soft capsules were disintegrated within 23 to 39min, that is, the disintegration time was less than 40min, for example, the soft capsules of examples 1, 6 and 9 were disintegrated within 31.2min, 35.3min and 26.7min, respectively. These results indicate that the soft capsules of the present invention have good disintegration properties. According to the disintegration time limit inspection method, 6 soft capsules are measured for each batch of samples, the respective disintegration time of the 6 soft capsules tested for each batch of samples is counted, and the average disintegration time of the batch of samples is calculated (t0), and the result shows that the average disintegration time of all the soft capsules prepared in examples 1 to 11 and examples 21 to 26 is within the range of 20 to 34min, for example, the average disintegration time of the soft capsules of examples 1, 6 and 9 is 28.4min, 32.1min and 22.5min respectively.
The term "disintegration time" is not intended to be different from the meaning of "disintegration time".
From the stability examination method, the change in disintegration time was known. For each batch of soft capsules, their average disintegration time (t6) after the treatment of 40 ℃ to 6 months was measured, and the rate of increase in disintegration time was calculated according to the following formula:
the disintegration time increase rate (%) [ (t6-t0) ÷ t0 ]. times 100%
As a result:
the increase rates of the disintegration times of all the soft capsules obtained in the thirteen examples of examples 1 to 11, 25 and 26 are within the range of 19 to 33%, for example, the increase rates of the disintegration times of the soft capsules of the batches of examples 1, 6 and 9 are respectively 24.6%, 21.7% and 28.2%, which shows that the disintegration times of the soft capsules are prolonged, but still within the normal legal range of less than 60 min;
the increase rates of the disintegration time of all the soft capsules obtained in examples 21 to 24 were within the range of 142 to 171%, for example, the increase rates of the disintegration time of the soft capsules of the batches obtained in example 21 with reference to examples 1, 6 and 9 were 157.7%, 164.3% and 149.4%, respectively, and the increase rate of the disintegration time of the soft capsule obtained in example 24 was 163.1%, indicating that the disintegration times of these soft capsules were significantly prolonged and most exceeded 60 min.
The above results show that:
examples 1 to 11 the soft capsules containing both tartaric acid and lysine had excellent stability in disintegration time; but instead of the other end of the tube
When tartaric acid and lysine were not added or only one of them was added (examples 21 to 24), the stability of disintegration time was significantly deteriorated and the disintegration time limit exceeded;
example 25 shows that the stability of disintegration time is substantially the same as that of examples 1 to 11 when fructus Aurantii is not added to examples 1 to 11;
example 26 shows that the stability of disintegration time is substantially the same as in examples 1 to 11 when bitter orange is not added and tartaric acid and lysine are not added in example 23.
These results show that: the soft capsule prepared from the four medicinal materials has poor stability of disintegration time, and the stability of the disintegration time can be obviously improved when tartaric acid and lysine are simultaneously added into the soft capsule, and the results of examples 25 to 26 show that the problem of the disintegration stability in an environment system of the soft capsule is directly related to the medicinal material of fructus aurantii, and chemical substances in the fructus aurantii can generate adverse effects on the stability of a capsule shell.
Test example 3: determination of alkaloid content
Synephrine (synephrine) and N-methyltyramine (N-methyltyramine) are known to be typical active substances of fructus aurantii, and these alkaloids can excite gastrointestinal smooth muscle, and increase the rhythmicity of gastrointestinal movement and contraction. The detection of these alkaloids is therefore of interest.
This experimental example 3 provides the following method for detecting the typical alkaloids synephrine and N-methyltyramine in bitter orange using HPLC:
measured by high performance liquid chromatography (specification of 0512 in the four-part general regulation of 2015 edition of Chinese pharmacopoeia).
Chromatographic conditions and systematic adaptability test: strong cation exchange bonded silica gel is used as a filling agent (SCX-strong cation exchange resin column, Agilent SCX column, 4.6 multiplied by 250mm, 5 μm); methanol-phosphoric acid solution (2 → 1000, concentrated ammonia solution to adjust pH to 3.8) (65: 35) is used as mobile phase, and detection wavelength is 215 nm. The number of theoretical plates should not be less than 3000 calculated by synephrine peak.
Preparation of control solutions: accurately weighing appropriate amount of synephrine reference substance and N-methyltyramine reference substance, and adding methanol to obtain a mixed solution containing synephrine 25 μ g and N-methyltyramine 10 μ g per 1 ml. Synephrine and N-methyltyramine controls were both commercially available and had greater than 98% purity.
Preparation of a test solution: mixing the soft capsule contents, weighing 10g, adding 50% ethanol 45ml into 50ml measuring flask, ultrasonic treating for 30min, fixing volume to scale, shaking, filtering, and collecting the filtrate.
The determination method comprises the following steps: precisely absorbing 20 μ l of each of the reference solution and the sample solution, injecting into a liquid chromatograph, recording chromatogram to 50min, and calculating content of synephrine and N-methyltyramine in the soft capsule content by peak area according to external standard method.
In the HPLC method, the retention time of synephrine is about 13.4min, the retention time of N-methyltyramine is about 25.6min, the separation degree between the synephrine and the N-methyltyramine is greater than 3, the separation degree between the synephrine and other peaks adjacent to the synephrine is also greater than 3, and other methodological parameters of the determination method also meet the general specification of drug analysis.
Taking all the soft capsules prepared in the examples 1-11 and 21-24, measuring the content of synephrine and N-methyltyramine in the content of the soft capsules within three days after the preparation of the soft capsules (equivalent to 0 month of stability study), and the results show that the content of the soft capsules obtained from every 375mg of fructus aurantii is in the range of 124-141 mug synephrine (namely, the concentration of the synephrine in the content can be characterized as 124-141 mug/375 mg) and the concentration of the N-methyltyramine in the content is in the range of 47-58 mug/375 mg (namely, the concentration of the N-methyltyramine in the content can be characterized as 47-58 mug/375 mg), for example, the content of the synephrine in the soft capsule in the example 1 is 133.3 mug/375 mg, and the content of the N-methyltyramine is 52.6 mug/375 mg; despite the different extraction processes, there was no significant difference in the contents of both synephrine and N-methyltyramine; these month 0 levels can be designated as C0.
In addition, the content of synephrine and N-methyltyramine in the soft capsule contents obtained in examples 1-11 and 21-24 when the soft capsule contents are not wrapped by gelatin tape (i.e. the soft capsule contents are not in contact with gelatin) shows that the content of synephrine and N-methyltyramine in the contents is in the range of 122-140 mug/375 mg and the content of N-methyltyramine in the contents is in the range of 49-58 mug/375 mg, and the content of synephrine and the content of N-methyltyramine in the contents before and after the contents are wrapped by gelatin tape are basically the same; these month 0 levels can be designated as C0.
In addition, for each batch of soft capsules, after they had been left to stand for 40 ℃ to 6 months, the contents of both synephrine and N-methyltyramine were measured as described above (the content at 6 months is designated as C6), and the residual rates of synephrine and N-methyltyramine were calculated as follows:
synephrine residual rate (%) - [ C6 (synephrine) ÷ C0 (synephrine) ] × 100%,
n-methyltyramine residual rate (%) [ C6 (N-methyltyramine) ÷ C0 (N-methyltyramine) ] × 100%;
as a result:
the synephrine residue rate and the N-methyl tyramine residue rate of all the soft capsules obtained in the eleven examples 1 to 11 are respectively 97 to 99 percent and 97 to 100 percent, for example, the synephrine residue rate of the soft capsules of the batches 1, 6 and 9 is respectively 98.7 percent, 97.3 percent and 98.3 percent, and the N-methyl tyramine residue rate of the soft capsules of the batches 1, 6 and 9 is respectively 98.2 percent, 99.6 percent and 97.4 percent, which shows that the soft capsules are very excellent in the stability of synephrine and N-methyl tyramine;
the soft capsules obtained in the four examples 21 to 24 all had synephrine residue rates of 83 to 87% and N-methyl tyramine residue rates of 85 to 88%, for example, the soft capsules obtained in the example 21 in the reference examples 1, 6 and 9 had synephrine residue rates of 85.3%, 84.4% and 86.1%, respectively, the soft capsules obtained in the example 21 in the reference examples 1, 6 and 9 had N-methyl tyramine residue rates of 86.5%, 87.2% and 85.7%, and the soft capsules obtained in the example 24 had synephrine residue rates of 85.2% and N-methyl tyramine residue rates of 86.4%, respectively, indicating that these soft capsules were not satisfactory in synephrine and N-methyl tyramine stability;
the above results show that:
examples 1 to 11 soft capsules containing contents to which tartaric acid and lysine were added simultaneously, in which synephrine and N-methyltyramine were excellent in stability; but instead of the other end of the tube
When tartaric acid and lysine were not added or only one was added (examples 21-24), synephrine and N-methyltyramine were significantly less stable;
these results show that: the soft capsules prepared from the four medicinal materials have poor stability of synephrine and N-methyltyramine, and the stability of the synephrine and the N-methyltyramine can be obviously improved when tartaric acid and lysine are simultaneously added into the soft capsules.
In addition, for the contents used for preparing each batch of soft capsules, they were directly packaged in glass bottles without being wrapped with gelatin tape, and their contents of both synephrine and N-methyltyramine (the content at 6 months is denoted as C6) were measured after they had undergone a treatment for 40 to 6 months as above, respectively, and the residual rates of synephrine and N-methyltyramine of these contents of soft capsules not contacted with gelatin were calculated as follows:
synephrine residual rate (%) - [ C6 (synephrine) ÷ C0 (synephrine) ] × 100%,
n-methyltyramine residual rate (%) [ C6 (N-methyltyramine) ÷ C0 (N-methyltyramine) ] × 100%;
as a result:
the contents of all the soft capsules obtained in examples 1 to 11 and examples 21 to 24, which were not in contact with gelatin, had a synephrine residue rate in the range of 98 to 100% and an N-methyltyramine residue rate in the range of 97 to 99%, for example, the contents of example 1 had synephrine and N-methyltyramine residue rates of 99.4% and 98.6%, respectively, indicating that these contents of the soft capsules which were not in contact with gelatin were excellent in the stability of synephrine and N-methyltyramine;
these results show that: the chemical substances of the bitter orange have certain adverse interaction with the soft capsule shell, the interaction can directly deteriorate the chemical stability of synephrine and N-methyltyramine, and on the other hand, the performance of the soft capsule shell is also deteriorated, so that the disintegration time is remarkably prolonged. In this sense, it is meaningful to add tartaric acid and lysine to the contents of the soft Simon capsules at the same time when preparing the soft Simon capsules.
Test example 4: quality detection of Simotang soft capsule
Various indexes of the soft capsules of the embodiments 1 to 11 of the invention after 0 month and 40 to 6 months are determined by referring to the quality standard WS-10040(ZD-0040) -2002 of Simotang oral liquid. The result shows that the identification results of 0 month and 6 months both meet the standard specification, and the relative content of naringin in 6 months to 0 month is 96-100%, which shows that the soft capsules have excellent stability.
In addition, the content of norisoboldine and arecoline in the soft capsules of examples 1 to 11 of the present invention after 0 month and 40 ℃ to 6 months was measured by the HPLC method of test example 3, and as a result, the relative content of norisoboldine in 6 months to 0 month was 97 to 100%, and the relative content of arecoline in 6 months to 0 month was 97 to 99%, indicating that these soft capsules had excellent stability in terms of both norisoboldine and arecoline. In the soft capsules of examples 21 to 24, the content of norisoboldine and arecoline does not change significantly in 0 month and 40 to 6 months, and the relative content in 6 months is respectively in the range of 96 to 99% and 97 to 100%.
Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications and improvements can be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.

Claims (15)

1. A soft capsule preparation is prepared from four medicinal materials including costustoot, bitter orange, betel nut and combined spicebush root by the weight ratio of 100: 50-150: 50-150: 50-150 and a soft capsule skin wrapping the content; the content is prepared by mixing extracts prepared from four medicinal materials with an auxiliary material polyethylene glycol 400, and the content also contains tartaric acid and lysine; the soft capsule shell is made of a gelatin solution containing gelatin, glycerin and water;
the extract is selected from:
extracting the volatile oil from the four medicinal materials by water and extracting the water extract from the dregs of a decoction by water,
extracting the volatile oil from the four medicinal materials by water, extracting the dregs of a decoction by water, precipitating the extract by alcohol,
extracting the four medicinal materials by alcohol to obtain extracts;
the weight of polyethylene glycol 400 is 6000-8000 parts, tartaric acid is 40-50 parts, lysine is 70-80 parts, and tartaric acid and lysine are added before the extract is completely removed of the extraction solvent, wherein each part of costus root is 3750 parts.
2. The soft capsule preparation according to claim 1, wherein the weight ratio of the four medicinal materials of costustoot, bitter orange, betel nut and combined spicebush root is 100: 75-125: 75-125: 75-125.
3. The soft capsule preparation according to claim 1, wherein the weight ratio of the four medicinal materials of costustoot, bitter orange, betel nut and combined spicebush root is 100: 100: 100: 100.
4. the soft capsule formulation according to claim 1, wherein the extracts of the four herbs comprise extracts obtained by extracting the four herbs with ethanol having a concentration of more than 95%.
5. The soft capsule preparation according to claim 1, wherein each capsule is equivalent to 0.1 to 0.5g of a wood fragrance containing a medicinal material.
6. The soft capsule preparation according to claim 1, wherein each capsule is equivalent to 0.2 to 0.4g of a wood fragrance as a medicinal material.
7. The soft capsule preparation according to claim 1, which is equivalent to 0.375g of wood fragrance containing a medicinal material per capsule.
8. The soft capsule formulation according to claim 1, wherein the weight ratio of gelatin, glycerol and water is 100: 40-60: 90-120 parts.
9. The soft capsule preparation according to claim 1, which is prepared in the following manner:
the main medicine prescription is as follows: 3750 parts of elecampane, 2812-4688 parts of fructus aurantii, 2812-4688 parts of betel nut and 2812-4688 parts of combined spicebush root
The preparation method comprises the following steps:
(1) putting the four medicines into an extraction tank, adding 4-6 times of water, extracting for 3-5 hours by a distillation method, and collecting volatile oil; standby;
(2) extracting the medicine residues twice with water, adding 6-8 times of water by weight of the medicinal materials for decocting and extracting for 1-2 hours for the first time, adding 5-7 times of water by weight of the medicinal materials for decocting and extracting for 1-1.5 hours for the second time, combining the decoctions, adding 40-50 parts by weight of tartaric acid and 70-80 parts by weight of lysine for dissolving, concentrating under reduced pressure to obtain a clear paste with a relative density of 1.2-1.3 at 60 ℃, vacuum drying at 60-70 ℃ to obtain a dry paste, drying, crushing and sieving with a 80-mesh sieve to obtain a dry paste powder for later use;
(3) adding the dry extract powder and the volatile oil into 6000-8000 parts by weight of polyethylene glycol 400, and uniformly mixing by using a colloid mill to obtain the content of the soft capsule for later use;
(4) wrapping the content of the soft capsule with soft capsule skin to obtain soft capsule:
(41) gelatin, glycerol and water are mixed according to the weight ratio of 100: 40-60: preparing a gelatin solution according to a proportion of 90-120, and preparing the gelatin solution into an adhesive tape for later use;
(42) selecting a mold with a proper size on a dynamic rotary capsule rolling machine at the room temperature of 20-25 ℃ and the relative humidity of 35-45%, and pressing the content of the soft capsule into the soft capsule by using an adhesive tape.
10. The soft capsule preparation according to claim 1, which is prepared in the following manner:
the main medicine prescription is as follows: 3750 parts of elecampane, 2812-4688 parts of fructus aurantii, 2812-4688 parts of betel nut and 2812-4688 parts of combined spicebush root
The preparation method comprises the following steps:
(1) putting the four medicines into an extraction tank, adding 4-6 times of water, extracting for 3-5 hours by a distillation method, collecting volatile oil for later use, and filtering to obtain medicine residues;
(2) extracting the dregs of a decoction twice with water, adding 8-12 times of water by weight of the medicinal materials for decocting for 1-2 hours for the first time, adding 6-10 times of water by weight of the medicinal materials for decocting for 0.5-1 hour for the second time, combining the decoctions, concentrating under reduced pressure to obtain a fluid extract with a relative density of 1.0-1.2 at 60 ℃, adding ethanol until the ethanol content reaches 75%, refrigerating for 10-12 hours, filtering, recovering ethanol from the filtrate until no ethanol smell exists, adding 10-12L of water, stirring, refrigerating for 12 hours, filtering, adding 40-50 parts by weight of tartaric acid and 70-80 parts by weight of lysine into the filtrate for dissolving, concentrating to obtain an extract with a relative density of 1.25-1.30 at 60 ℃, vacuum drying at 60-70 ℃ to obtain a dry extract, drying and crushing to obtain a dry extract powder for later use, and sieving by using a sieve with 80 meshes;
(3) adding the dry extract powder and the volatile oil into 6000-8000 parts by weight of polyethylene glycol 400, and uniformly mixing by using a colloid mill to obtain the content of the soft capsule for later use;
(4) wrapping the content of the soft capsule with soft capsule skin to obtain soft capsule:
(41) gelatin, glycerol and water are mixed according to the weight ratio of 100: 40-60: preparing a gelatin solution according to a proportion of 90-120, and preparing the gelatin solution into an adhesive tape for later use;
(42) selecting a mold with a proper size on a dynamic rotary capsule rolling machine at the room temperature of 20-25 ℃ and the relative humidity of 35-45%, and pressing the content of the soft capsule into the soft capsule by using an adhesive tape.
11. The soft capsule preparation according to claim 1, which is prepared in the following manner:
the main medicine prescription is as follows: 3750 parts of elecampane, 2812-4688 parts of fructus aurantii, 2812-4688 parts of betel nut and 2812-4688 parts of combined spicebush root
The preparation method comprises the following steps:
(1) placing the four medicines into an extraction tank, performing reflux extraction twice by using 95% ethanol, soaking for 2-3 hours before the first extraction, adding 7-9 times of ethanol for the first extraction for 2-3 hours, adding 5-7 times of ethanol for the second extraction for 1-2 hours, combining the extracting solutions, and filtering to obtain a filtrate;
(2) adding 40-50 parts by weight of tartaric acid and 70-80 parts by weight of lysine into the filtrate for dissolving, recovering ethanol under reduced pressure below 55 ℃, concentrating into thick paste, drying in vacuum at 60-70 ℃ to obtain dry paste, drying, crushing and sieving with a 80-mesh sieve to obtain dry paste powder for later use;
(3) adding the thick paste into 6000-8000 parts by weight of polyethylene glycol 400, and uniformly mixing by using a colloid mill to obtain a soft capsule content for later use;
(4) wrapping the content of the soft capsule with soft capsule skin to obtain soft capsule:
(41) gelatin, glycerol and water are mixed according to the weight ratio of 100: 40-60: preparing a gelatin solution according to a proportion of 90-120, and preparing the gelatin solution into an adhesive tape for later use;
(42) selecting a mold with a proper size on a dynamic rotary capsule rolling machine at the room temperature of 20-25 ℃ and the relative humidity of 35-45%, and pressing the content of the soft capsule into the soft capsule by using an adhesive tape.
12. A method for preparing a soft capsule formulation comprising the steps of:
the main medicine prescription is as follows: 3750 parts of elecampane, 2812-4688 parts of fructus aurantii, 2812-4688 parts of betel nut and 2812-4688 parts of combined spicebush root
The preparation method comprises the following steps:
(1) putting the four medicines into an extraction tank, adding 4-6 times of water, extracting for 3-5 hours by a distillation method, and collecting volatile oil; standby;
(2) extracting the medicine residues twice with water, adding 6-8 times of water by weight of the medicinal materials for decocting and extracting for 1-2 hours for the first time, adding 5-7 times of water by weight of the medicinal materials for decocting and extracting for 1-1.5 hours for the second time, combining the decoctions, adding 40-50 parts by weight of tartaric acid and 70-80 parts by weight of lysine for dissolving, concentrating under reduced pressure to obtain a clear paste with a relative density of 1.2-1.3 at 60 ℃, vacuum drying at 60-70 ℃ to obtain a dry paste, drying, crushing and sieving with a 80-mesh sieve to obtain a dry paste powder for later use;
(3) adding the dry extract powder and the volatile oil into 6000-8000 parts by weight of polyethylene glycol 400, and uniformly mixing by using a colloid mill to obtain the content of the soft capsule for later use;
(4) wrapping the content of the soft capsule with soft capsule skin to obtain soft capsule:
(41) gelatin, glycerol and water are mixed according to the weight ratio of 100: 40-60: preparing a gelatin solution according to a proportion of 90-120, and preparing the gelatin solution into an adhesive tape for later use;
(42) selecting a mold with a proper size on a dynamic rotary capsule rolling machine at the room temperature of 20-25 ℃ and the relative humidity of 35-45%, and pressing the content of the soft capsule into the soft capsule by using an adhesive tape.
13. A method for preparing a soft capsule formulation comprising the steps of:
the main medicine prescription is as follows: 3750 parts of elecampane, 2812-4688 parts of fructus aurantii, 2812-4688 parts of betel nut and 2812-4688 parts of combined spicebush root
The preparation method comprises the following steps:
(1) putting the four medicines into an extraction tank, adding 4-6 times of water, extracting for 3-5 hours by a distillation method, collecting volatile oil for later use, and filtering to obtain medicine residues;
(2) extracting the dregs of a decoction twice with water, adding 8-12 times of water by weight of the medicinal materials for decocting for 1-2 hours for the first time, adding 6-10 times of water by weight of the medicinal materials for decocting for 0.5-1 hour for the second time, combining the decoctions, concentrating under reduced pressure to obtain a fluid extract with a relative density of 1.0-1.2 at 60 ℃, adding ethanol until the ethanol content reaches 75%, refrigerating for 10-12 hours, filtering, recovering ethanol from the filtrate until no ethanol smell exists, adding 10-12L of water, stirring, refrigerating for 12 hours, filtering, adding 40-50 parts by weight of tartaric acid and 70-80 parts by weight of lysine into the filtrate for dissolving, concentrating to obtain an extract with a relative density of 1.25-1.30 at 60 ℃, vacuum drying at 60-70 ℃ to obtain a dry extract, drying and crushing to obtain a dry extract powder for later use, and sieving by using a sieve with 80 meshes;
(3) adding the dry extract powder and the volatile oil into 6000-8000 parts by weight of polyethylene glycol 400, and uniformly mixing by using a colloid mill to obtain the content of the soft capsule for later use;
(4) wrapping the content of the soft capsule with soft capsule skin to obtain soft capsule:
(41) gelatin, glycerol and water are mixed according to the weight ratio of 100: 40-60: preparing a gelatin solution according to a proportion of 90-120, and preparing the gelatin solution into an adhesive tape for later use;
(42) selecting a mold with a proper size on a dynamic rotary capsule rolling machine at the room temperature of 20-25 ℃ and the relative humidity of 35-45%, and pressing the content of the soft capsule into the soft capsule by using an adhesive tape.
14. A method for preparing a soft capsule formulation comprising the steps of:
the main medicine prescription is as follows: 3750 parts of elecampane, 2812-4688 parts of fructus aurantii, 2812-4688 parts of betel nut and 2812-4688 parts of combined spicebush root
The preparation method comprises the following steps:
(1) placing the four medicines into an extraction tank, performing reflux extraction twice by using 95% ethanol, soaking for 2-3 hours before the first extraction, adding 7-9 times of ethanol for the first extraction for 2-3 hours, adding 5-7 times of ethanol for the second extraction for 1-2 hours, combining the extracting solutions, and filtering to obtain a filtrate;
(2) adding 40-50 parts by weight of tartaric acid and 70-80 parts by weight of lysine into the filtrate for dissolving, recovering ethanol under reduced pressure below 55 ℃, concentrating into thick paste, drying in vacuum at 60-70 ℃ to obtain dry paste, drying, crushing and sieving with a 80-mesh sieve to obtain dry paste powder for later use;
(3) adding the thick paste into 6000-8000 parts by weight of polyethylene glycol 400, and uniformly mixing by using a colloid mill to obtain a soft capsule content for later use;
(4) wrapping the content of the soft capsule with soft capsule skin to obtain soft capsule:
(41) gelatin, glycerol and water are mixed according to the weight ratio of 100: 40-60: preparing a gelatin solution according to a proportion of 90-120, and preparing the gelatin solution into an adhesive tape for later use;
(42) selecting a mold with a proper size on a dynamic rotary capsule rolling machine at the room temperature of 20-25 ℃ and the relative humidity of 35-45%, and pressing the content of the soft capsule into the soft capsule by using an adhesive tape.
15. Use of the soft capsule formulation of any one of claims 1 to 11 for the preparation of a medicament for:
guiding qi downward, lowering adverse qi, removing food stagnation and relieving pain;
infantile dyspepsia with symptoms of abdominal distention, abdominal pain, cry restlessness, anorexia, diarrhea or constipation;
the middle-aged and the elderly suffer from qi stagnation, food stagnation syndrome, abdominal distention, abdominal pain, and constipation; and/or
Promote the recovery of the gastrointestinal function after the abdominal operation.
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