CN105456530B - Preparation method of quick-release and slow-release traumatic injury bone-growing tablet - Google Patents

Abstract

A preparation method of a quick-release-slow-release traumatic injury bone-growing tablet is characterized in that: preparing a sustained-release tablet core according to the prescription amount, and sequentially coating an isolation layer, a stomach rapid-release layer and a common film coat. The quick-release and slow-release traumatic injury osteogenesis tablet quick-release layer prepared by the method of the invention finishes medicine release within 10 minutes, and the slow-release tablet core slowly and stably releases medicine within 24 hours, thereby achieving the purpose of quick-release and slow design. The quick-release and slow-release traumatic bone regeneration tablet has stable process and good reproducibility, and is suitable for industrial mass production.

Description

Preparation method of quick-release and slow-release traumatic injury bone-growing tablet

Technical Field

The invention relates to a preparation method of a traditional Chinese medicine, in particular to a preparation method of a quick-release and slow-release traumatic injury bone regeneration tablet.

Background

The prescription for traumatic injury and bone generation mainly comprises blood circulation promoting and blood stasis removing medicines, wherein the Zhangu and glabrous sarcandra herb are monarch medicines in the prescription. The bone-invigorating and pain-relieving powder has light bone-invigorating taste, has the functions of promoting blood circulation, removing blood stasis, strengthening tendons and bones, dredging collaterals and relieving pain, can remove blood stasis and relieve pain, can be used for setting bones and treating wounds, and is a common folk medicine; the glabrous sarcandra herb is a common medicinal material for treating fracture by Zhuang doctors, and has the effects of resisting bacteria and diminishing inflammation, dispelling wind and removing dampness, promoting blood circulation and removing meridian obstruction, and connecting tendons and bones. The Chinese and minister drugs in the prescription use the salvia miltiorrhiza to activate blood and remove stasis, cool blood and relieve swelling; corydalis tuber has the functions of promoting qi circulation, relieving pain, promoting blood circulation and removing blood stasis, so as to strengthen and assist the main drug in treating fracture. While native copper, eucommia bark and achyranthes root tonify liver and kidney, strengthen tendons and bones, benefit essence and marrow, and reunite bones and tendons.

The dosage of the medicines formed by the prescription is 83.6 percent of the total amount of the prescription, and the active ingredients of the medicines are clearly researched, so the medicine is the main material basis of the traumatic injury bone-growing tablet for treating the fracture and is also the temporary medicine for treating the early and severe fracture.

Patent 200910178242.9 provides a Chinese medicinal preparation in the form of granule for treating traumatic injury and promoting bone growth, and its preparation method, which comprises the following steps: percolating Saviae Miltiorrhizae radix and rhizoma corydalis with 60% ethanol, and concentrating the percolate under reduced pressure to obtain paste. Extracting the residue with five kinds of Chinese medicinal materials including Zhangu, precipitating with ethanol, and concentrating under reduced pressure to obtain ointment. Mixing the extracts, adding dextrin, and granulating. The process basically retains the medication characteristics of the original decoction, and neglects the compliance, safety and effectiveness of clinical medication.

The common traumatic injury bone-growing tablet is prepared by changing traumatic injury bone-growing granules into dosage forms, and the technical key points of the common traumatic injury bone-growing tablet are basically consistent with those of granules, so the following problems of the granules are not solved.

1. The 60 percent ethanol percolation extraction of the salvia miltiorrhiza and the corydalis tuber does not meet the requirements of physicochemical properties of active ingredients of the salvia miltiorrhiza and the corydalis tuber for treating fracture, and has low extraction rate and poor selectivity.

2. The Zhangu and glabrous sarcandra herb mainly contain flavonoids, and are decocted with native copper, so that precipitates are easily generated due to the existence of copper and iron ions, and the extraction rate of the flavonoids is reduced.

3. The medicine is taken once a day, the relative dose is larger, and clinical potential safety hazards exist due to the difference of the age, sex, region and the like of clinical patients, so that liver damage is easily caused.

Disclosure of Invention

The invention aims to provide a preparation method of a quick-release and slow-release traumatic injury osteogenesis tablet, wherein the quick-release layer of the quick-release and slow-release traumatic injury osteogenesis tablet prepared by the method finishes medicine release within 10 minutes, and the slow-release tablet core slowly and stably releases medicine within 24 hours, thereby achieving the purpose of quick-release and slow design. The quick-release and slow-release traumatic bone regeneration tablet has stable process and good reproducibility, and is suitable for industrial mass production.

The technical scheme is as follows:

a preparation method of a quick-release-slow-release traumatic injury bone-growing tablet is characterized in that: the method comprises the following process steps:

1. preparing a sustained-release tablet core:

mixing Saviae Miltiorrhizae radix, rhizoma corydalis, Zhangu and herba Pileae Scriptae extract, sustained release material, acidifying agent, and other adjuvants, adding binding liquid, granulating by wet method, drying, grading, adding adjuvant, and mixing; and tabletting the mixed materials on a tabletting machine.

2. Wrapping and isolating layer

Weighing coating materials, anti-sticking agents, coloring agents and other auxiliary materials according to the prescription, adding solvents, uniformly mixing to obtain coating liquid of the isolation layer, and coating the tablet core.

3. Coated quick-release gastric soluble layer

Weighing auxiliary materials such as achyranthes bidentata, eucommia ulmoides, native copper extracts, coating materials and the like according to the prescription amount, adding a solvent, and uniformly mixing to obtain the gastric instant layer coating solution.

4. Coated gastric soluble film coat

Weighing coating materials, an anti-sticking agent, a coloring agent and other auxiliary materials according to the prescription amount, adding a solvent, uniformly mixing to obtain gastric-soluble film coating liquid, and coating to obtain the gastric-soluble film coating.

In summary, the following can be found: the invention relates to a preparation method of a quick-release and slow-release traumatic injury bone-growing tablet, which comprises the steps of preparing a slow-release tablet core according to a traumatic injury bone-growing tablet prescription, and sequentially coating an isolation layer, a stomach quick-release layer and a common film coat.

Because the interaction exists between the iron ions, copper ions and other metal ions in the native copper and phenolic acids and flavonoid compounds in medicinal materials such as salvia miltiorrhiza, glabrous sarcandra herb, war bone and the like in the prescription, the invention is also characterized in that a gastric solubility isolating layer is arranged between the sustained-release tablet core and the quick-release layer. The isolating layer has the function of effectively preventing the metal ions from generating precipitation or complexation reaction with the total flavonoids and the total phenolic acids of the pharmacological active substances, so that the effect of reducing the native copper and other medicinal flavors is exerted. The literature indicates that the main active components of the native copper, namely copper ions and iron ions, are mainly absorbed at the duodenum part, and the absorption of the active components of the native copper is basically finished after the medicament enters the small intestine, so that the absorption of the medicament of the tablet core cannot be influenced.

The third characteristic of the invention is that the quick release layer is an external gastric soluble film coat because the extracts of eucommia bark and achyranthes root in the prescription are unstable. The film coat can effectively prevent phenolic compounds in the extract from interacting with the atmosphere, and particularly, when the concentration of metal ions is relatively high, reactions such as oxidation, hydrolysis and the like are easy to occur, so that moisture absorption and deterioration are easy to cause, the curative effect of the medicine is damaged, and the effective period of the medicine is shortened.

Because the salvia miltiorrhiza, the corydalis tuber, the war bone and the glabrous sarcandra herb extract in the prescription are equivalent to monarch and minister drugs, the effect of promoting blood circulation to remove blood stasis, dredging collaterals and relieving pain and reuniting bones and muscles is achieved, the formula is equivalent to a temporary medicine, the drug property is strong, the dosage of crude drugs is large, the crude drugs accounts for more than 80% of the crude drug quantity of the whole formula, the extract is released in the stomach in a short time, strong stimulation to gastric mucosa can be caused, even the drug concentration in the body in a short time is overhigh, transient or repeated liver huge load can be caused, and drug damage can be brought to patients with liver and kidney insufficiency. Therefore, the fourth characteristic of the invention is that the root of red rooted saliva, corydalis tuber, war bone and sarcandra which are the temporary symptoms in the prescription are extracted and separated scientifically, the non-active ingredients are removed to the maximum extent, the extraction process is researched again, the total mass of the extract is reduced by 60 percent compared with the total mass of the original process, and the active ingredient tanshinone II is_AThe extraction transfer rate of salvianolic acid B and total flavone is up to more than 80%. The sustained-release tablet core prepared from the extract is taken once a day, 2 tablets are taken once, and the sustained-release tablet core realizes the slow drug release within 24 hours and maintains relatively stable drug concentration.

The preparation method of the invention is different from the bone fracture growing tablets (Shenyang Shungding pharmaceutical Co., Ltd.) on the market. The traumatic injury bone-growing tablet is basically prepared by the most traditional Chinese medicine tablet preparation method, and the method is not different from traumatic injury bone-growing granules and traumatic injury bone-growing capsules in extraction and medicine release forms, so the inherent problems of the original preparation form are not solved, 5 tablets are taken once a day, which is equivalent to 2.5g of extract, the medicine concentration in the body is easily overhigh in a short time, the metabolic load of the liver and the kidney to the medicine is steeply increased, poisoning and adverse reaction are very easy to occur, and the method is particularly suitable for children and old people.

The preparation method of the quick-release and slow-release traumatic injury bone-growing tablet only uses a common tablet press and a coating machine in the preparation process. The sustained-release tablet core is prepared by using a conventional tablet press, and an isolation layer, a stomach quick-release layer and a stomach-soluble film coat are sequentially coated on a coating machine.

The quick-release and slow-release traumatic injury osteogenesis tablet quick-release layer prepared by the method of the invention finishes medicine release within 10 minutes, and the slow-release tablet core slowly and stably releases medicine within 24 hours, thereby achieving the purpose of quick-release and slow design. The quick-release and slow-release traumatic bone regeneration tablet has stable process and good reproducibility, and is suitable for industrial mass production.

Drawings

Figure 1 is a graph of the drug release profile for a mass produced sample (product lot No. 20140604).

Detailed Description

A preparation method of a quick-release-slow-release traumatic injury bone-growing tablet comprises the following process steps:

1. preparing extracts of Saviae Miltiorrhizae radix, rhizoma corydalis, ZUOGU and herba Pileae Scriptae;

pulverizing 1200g of salvia miltiorrhiza, 1200g of rhizoma corydalis, 1600g of glabrous sarcandra herb and 1600g of war bone into coarse powder, sequentially performing ultrasonic extraction with 90%, 70% and 40% ethanol at 50 ℃ for 1.0 hour each time, combining liquid medicines, recovering ethanol under reduced pressure, concentrating the mixture to obtain an extract with the relative density of 1.10(60 ℃), uniformly dispersing the extract in a colloid mill at high speed, and performing spray drying to obtain 300-320 g of traumatic injury extract A for later use;

2. preparing extracts of eucommia ulmoides and achyranthes bidentata;

pulverizing 400g of eucommia ulmoides and 400g of achyranthes bidentata into coarse powder, adding 60% and 30% ethanol, performing ultrasonic extraction at 50 ℃ for 1.0 hour respectively, combining extracting solutions, performing reduced pressure recovery, performing low-temperature (0 ℃) high-speed (8000r/min) centrifugation, adding a centrifugate onto a treated AB-8 macroporous resin column, eluting with water, 30% and 60% ethanol solutions in sequence, performing reduced pressure recovery of the ethanol solution, concentrating to obtain an extract with a relative density of 1.10(60 ℃), and performing spray drying to obtain fine powder;

3. decocting 300g of Pyritum in water, concentrating, drying, and pulverizing;

4. and (3) uniformly mixing the eucommia ulmoides and achyranthes bidentata extracts prepared in the step (2) and the native copper extract prepared in the step (3) to obtain 80-90 g of traumatic injury extract.

5. Preparing a sustained-release tablet core:

putting 300g g of traumatic injury extract A prepared in the step 1, 10g of hydroxypropyl methylcellulose SHK10M 20g and 200g of fumaric acid into a one-step granulator (PGL-A40 type, Baokang drying machinery, Inc., Changzhou), uniformly mixing, preheating to 50 ℃, adding 90g of 30% isopropanol (adhesive), according to the requirements of post operation specifications, steam pressure of 0.4-0.6 Mpa and compressed air of 0.6Mpa, ensuring the material temperature to be 55 +/-5 ℃, finally enabling the water content of the material to be less than 2.5% (wt), granulating, adding 100g of magnesium stearate, uniformly mixing, putting on a tablet press, adopting a phi 14 x 8mm oval punching tablet, and controlling the tablet hardness to be 130-180N. 1000 pieces were prepared.

6. Wrapping and isolating layer

400ml of purified water is taken and heated to 50 ℃, 30g of Kollicoat Protect, 20g of talcum powder and 10g of silicon dioxide are sequentially added and mixed uniformly to form coating liquid. And (3) placing 1000 pieces of the sustained-release tablet core of the traumatic injury bone-growing tablet prepared in the step (5) in a coating machine (BGB-6A type, pharmaceutical equipment factories of Changzhou city), controlling the air inlet temperature to be 70-75 ℃, controlling the air inlet pressure to be 0.35Mpa, controlling the temperature of the tablet to be 36-40 ℃, controlling the rotating speed of the coating machine to be 6-9 rpm, and using up the coating liquid to ensure that the isolation layer is completely coated with the tablet core.

7. Coated quick-release gastric soluble layer

Taking 800ml of 30% ethanol solution, sequentially adding 60g of Kollicoat IR, 3g of sodium carbonate and 80g of traumatic injury extract, and stirring uniformly to obtain the coating liquid of the stomach quick-release layer.

And (3) placing the sustained-release tablet cores (1000 tablets) coated with the isolation layers prepared in the step (6) into a coating pan, controlling the temperature of an air inlet to be 55-70 ℃, controlling the pressure of air inlet to be 0.3Kp, controlling the temperature of the tablets to be 30-35 ℃, and controlling the rotating speed of a coating machine to be 6-12 rpm until the coating liquid is used up.

8. Coating a gastric soluble film coat:

and (3) taking 100ml of purified water, sequentially adding 20g of Kollicoat Protect, 10g of talcum powder and 4g of silicon dioxide, uniformly mixing to obtain a gastric-soluble film coating solution, placing the sustained-release tablet core (1000 tablets) coated with the quick-release layer prepared in the step (7) in a high-efficiency coating machine, controlling the air inlet temperature to be 65-80 ℃, controlling the air inlet pressure to be 0.25MPa, controlling the tablet temperature to be 30-35 ℃, controlling the rotating speed of the coating machine to be 7-10 rpm, and obtaining the gastric-soluble film coating solution until the coating solution with the amount of the prescription is used up.

Example 2

(1) Release rate measurement of sustained-release tablet core

① Experimental instrument

ZRS-8 model intelligent medicine dissolving instrument, UV-260 ultraviolet spectrophotometer.

① Release conditions

Solvent: 1000ml of phosphate buffer solution with pH6.8 is used as release medium

Temperature: 37 +/-0.5 DEG C

The method comprises the following steps: the rotation basket method (first XC method, an appendix of the second part of the Chinese pharmacopoeia 2010 edition) has a rotation speed of 100 revolutions per minute.

③ Degrees of Release determination

a selection of measurement wavelengths

A proper amount of the sustained-release tablet core is precisely weighed to prepare a solution containing 50mg and a blank auxiliary material solution with a corresponding concentration per ml, and the solution is scanned by UV-260 at 200 nm-400 nm, the result shows that the maximum absorption of the sustained-release tablet core of the traumatic injury osteogenesis tablet is at 346nm, and the blank auxiliary material is not absorbed at the position, so 333nm is determined as the release degree measuring wavelength of the product, and the mixed solution of rutin 50ug and salvianolic acid B10ug has a larger absorption peak at 346nm and is in a linear relation with the concentration of the mixture, so the mixed solution can be used as a reference solution for measuring the release degree, and the release degrees of the salvia miltiorrhiza, the warbone and the glabrous sarcandra herb are indirectly measured by taking.

b selection of the Release Medium

According to the requirement of supplementary declaration data notice of the drug evaluation center of the State drug administration, phosphate buffer solution with pH of 6.8 is used as a release medium of the product.

c method and selection of rotational speed

According to the requirement of supplementary declaration data notification of the drug evaluation center of the State drug administration, a basket rotating method (XC first method which is an appendix of the second part of the 2010 edition of Chinese pharmacopoeia) is adopted, and the rotating speed is 100 revolutions per minute.

determination of d sampling time points

According to the requirements of supplementary declaration data notice of the drug evaluation center of the State drug administration, the sampling points are determined to be 1 hour, 3 hours and 10 hours.

Method for measuring e-release

Taking the product, according to a device for a release degree determination method (XC first method which is an appendix of the second part of the 2010 edition of Chinese pharmacopoeia), taking 1000ml of phosphate buffer solution with pH6.8 as a release medium, rotating at 100 revolutions per minute, operating according to the method, respectively taking 5ml of the solution after 1, 3 and 10 hours, filtering, and timely supplementing the same amount of blank medium into an operation container; taking 1ml of the subsequent filtrate, placing the subsequent filtrate in a 50ml measuring flask, adding phosphate buffer solution with pH6.8 to dilute to scale, and shaking up to be used as test solution; an appropriate amount of reference substance is precisely weighed, and phosphate buffer solution with pH6.8 is used for preparing reference substance mixed solution containing rutin 50ug and salvianolic acid B10ug per 1 ml. The two solutions were taken, and absorbance was measured at a wavelength of 333nm by spectrophotometry (appendix IV A of the second part of the 2010 edition of the Chinese pharmacopoeia), and the degree of release (referred to as cumulative release) of each tablet was calculated.

④ test production sample Release test

The release amount of the test production sample and the reference preparation (prepared in laboratory) at 1, 3 and 10 hours was measured according to the release amount measuring method, and the measurement results are shown in Table 1.

TABLE 1 measurement of Release Rate (% Release amount in the indicated amount)

The release degrees of the three batches of trial-manufactured samples all meet the regulations.

⑤ measurement of Release degree of three batches of samples produced in batches

The release of the mass-produced samples (50 ten thousand tablets per batch) was measured at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24 hour points from the reference preparation (prepared in the laboratory) and the results are shown in Table 2.

TABLE 2 measurement of the release of the product and the control

The results of the sample release rate measurement of batch production in three batches of workshops show that the release rate reaches over 95 percent within 24 hours, and the test result is not different from a reference preparation prepared in a laboratory, so that the aim of slowly and stably releasing the active pharmaceutical ingredients of the medicament within 24 hours is fulfilled. 20140604 sample drug release curves are shown in figure 1.

(2) Disintegration time limit of quick release layer

Preparing artificial gastric juice: the method is carried out according to the item of the appendix XV of the second part of the 2010 edition of the Chinese pharmacopoeia.

Taking 6 test samples, respectively placing the test samples in glass tubes of hanging baskets, adding baffles, placing 700ml of artificial gastric juice with the temperature of 37 +/-1 ℃ in a beaker, and starting a disintegration tester for checking. The results of the examination are shown in Table 3.

TABLE 3 measurement results of disintegration time of immediate release layer in artificial gastric juice

As can be seen from Table 3, the extracts of eucommia bark, achyranthes and native copper can be released within 10 minutes in the artificial gastric juice, and the design purpose that the active components of the native copper, such as metal ions of copper, iron and the like are absorbed at the duodenum part is realized.

Claims (1)

1. A preparation method of a quick-release-slow-release traumatic injury bone-growing tablet comprises the steps of preparing a slow-release tablet core according to the prescription amount, and sequentially coating an isolation layer, a stomach quick-release layer and a common film coat, and is characterized in that: the method comprises the following process steps:

(1) preparing extracts of Saviae Miltiorrhizae radix, rhizoma corydalis, ZUOGU and herba Pileae Scriptae;

pulverizing 1200g of salvia miltiorrhiza, 1200g of rhizoma corydalis, 1600g of glabrous sarcandra herb and 1600g of shigu into coarse powder, sequentially performing ultrasonic extraction with 90%, 70% and 40% ethanol at 50 ℃ for 1.0 hour each time, combining liquid medicines, recovering ethanol under reduced pressure, concentrating to obtain an extract with a relative density of 1.10 at 60 ℃, uniformly dispersing by using a colloid mill for high-speed emulsion, and performing spray drying to obtain 300-320 g of traumatic injury extract A for later use;

(2) preparation of extracts of eucommia and achyranthes bidentata:

taking 400g of eucommia bark and 400g of achyranthes bidentata, crushing into coarse powder, adding 60% and 30% ethanol, performing ultrasonic extraction at 50 ℃ for 1.0 hour respectively, combining extracting solutions, recovering under reduced pressure, performing centrifugal treatment at low temperature of 0 ℃, wherein the revolution of a centrifugal machine is 8000r/min, adding a centrifugate to a treated AB-8 macroporous resin column, eluting with water, 30% ethanol and 60% ethanol in sequence, recovering an ethanol solution under reduced pressure, concentrating to an extract with the relative density of 1.10 measured at the temperature of 60 ℃, and performing spray drying to obtain fine powder;

(3) decocting 300g of Pyritum in water, concentrating, drying, and pulverizing;

(4) uniformly mixing the eucommia ulmoides and achyranthes bidentata extracts prepared in the step (2) with the native copper extract prepared in the step (3) to obtain traumatic injury extracts B80-90 g;

(5) preparing a sustained-release tablet core:

putting 300g g of traumatic injury extract A prepared in the step (1), 10g of hydroxypropyl methylcellulose SHK10M 20g and 200g of fumaric acid into a one-step granulator, uniformly mixing, preheating to 50 ℃, adding 90g of 30% isopropanol as an adhesive, wherein the steam pressure is 0.4-0.6 MPa, the compressed air is 0.6MPa, the temperature of the material is ensured to be 55 +/-5 ℃, finally the moisture of the material is less than 2.5% (wt), granulating, adding 100g of magnesium stearate, uniformly mixing, putting the mixture on a tablet press, adopting phi 14 x 8mm oval punching tablets, and controlling the hardness of the tablets to be 130-180N;

(6) coating an isolation layer:

taking 400ml of purified water, heating to 50 ℃, sequentially adding 30g of Kollicoat Protect, 20g of talcum powder and 10g of silicon dioxide, and uniformly mixing to obtain a coating solution; putting 1000 sustained-release tablet cores of the traumatic injury bone-growing tablets prepared in the step (5) into a coating machine, controlling the air inlet temperature to be 70-75 ℃, controlling the air inlet pressure to be 0.35Mpa, controlling the tablet temperature to be 36-40 ℃, controlling the rotating speed of the coating machine to be 6-9 rpm, and using up the coating liquid to ensure that the tablet cores of the isolating layer are completely coated;

(7) coating a quick-release gastric soluble layer:

taking 800ml of 30% ethanol solution, sequentially adding Kollicoat IR 60g, sodium carbonate 3g and traumatic injury extract B80g, and stirring to obtain coating solution for stomach quick-release layer;

(8) coating a gastric soluble film coat:

and (3) taking 100ml of purified water, sequentially adding 20g of Kollicoat Protect, 10g of talcum powder and 4g of silicon dioxide, uniformly mixing to obtain the gastric-soluble film coating liquid, placing 1000 sustained-release tablet cores coated with the quick-release layer prepared in the step (7) into a high-efficiency coating machine, controlling the air inlet temperature to be 65-80 ℃, controlling the air inlet pressure to be 0.25MPa, controlling the tablet temperature to be 30-35 ℃, and controlling the rotating speed of the coating machine to be 7-10 rpm until the coating liquid with the amount according to the prescription is used up, thus obtaining the gastric-soluble film coating liquid.

Images