阅读说明：本技术 一种藏红花组合物及其制备方法 (Saffron composition and preparation method thereof ) 是由 张勇 张轶 郑顺利 于 2020-06-01 设计创作，主要内容包括：本发明提供一种藏红花的组合物及其制备方法,含有藏红花、骨架剂、粘结剂、冻干保护剂和崩解剂、或甜味剂。特征在于所述组合物中,骨架剂的重量百分比为5％～20％,粘结剂的重量百分比为0.2％～1.0％,冻干保护剂的重量百分比为1％～10％,崩解剂的重量百分比为4％～20％,或甜味剂的重量百分比为0.2％～0.5％,所述崩解剂选自HP-β-CD,藏红花为微粉化处理的粒径D90≤50μm。本发明为口腔速溶片,成型性好,表面光洁,易于脱模,不易破碎,崩解迅速。(The invention provides a saffron composition and a preparation method thereof, and the saffron composition contains saffron, a skeleton agent, a binder, a freeze-drying protective agent, a disintegrating agent or a sweetening agent. Characterized in that in the composition, the weight percentage of the skeleton agent is 5-20%, the weight percentage of the binder is 0.2-1.0%, the weight percentage of the freeze-drying protective agent is 1-10%, the weight percentage of the disintegrant is 4-20%, or the weight percentage of the sweetener is 0.2-0.5%, the disintegrant is selected from HP-beta-CD, and the particle size D90 of the saffron subjected to micronization treatment is not more than 50 μm. The oral instant tablet has the advantages of good formability, smooth surface, easy demoulding, difficult crushing and rapid disintegration.)

1. A composition comprising saffron, a matrix agent, a binder, a lyoprotectant, and a disintegrant, or comprising a sweetener.

2. Composition according to claim 1, characterized in that said saffron is a micronized saffron having a particle size D90 ≤ 50 μm, preferably D90 ≤ 15 μm.

3. The composition according to claim 1, characterized in that saffron content per formulation unit is 1-200 mg, preferably 1-80 mg.

4. The composition of claim 1, wherein the matrix agent is selected from mannitol, the binder is selected from pullulan, the lyoprotectant is selected from dextran-70, the disintegrant is selected from HP- β -CD, or the sweetener is selected from sucralose.

5. The composition of claim 1, wherein the composition comprises 5-20% by weight of the matrix agent, 0.2-1.0% by weight of the binder, 1-10% by weight of the lyoprotectant, 4-20% by weight of the disintegrant, or 0.2-0.5% by weight of the sweetener.

6. A method of preparing the composition of claim 1, comprising the steps of:

1) weighing disintegrating agent and purified water, placing in a beaker, preparing into solution, adding stigma croci Sativi, and stirring;

2) adding the skeleton agent, the binder, the freeze-drying protective agent and the sweetening agent into the solution, and continuously stirring;

3) shearing, stirring and degassing until no obvious bubbles exist;

4) stirring continuously by a stirrer, transferring a specified volume into a bubble cap, and freezing and forming;

5) freeze-drying;

6) and (6) packaging.

7. A composition, comprising the following components: 73.17 wt% saffron, 9.15 wt% mannitol, 0.37 wt% pullulan, 3.66 wt% dextran-70, 0.37 wt% sucralose and 13.29 wt% HP-beta-CD;

preferably, the composition comprises per unit formulation: 80.00m of saffron, 10.00mg of mannitol, 0.40mg of pullulan, 0.40mg of dextran-704.00 mg, 0.40mg of sucralose and 14.53mg of HP-beta-CD.

8. A method of preparing the composition of claim 7, comprising the steps of:

1) weighing HP-beta-CD and purified water with the formula amount or the same proportion expanded, placing the HP-beta-CD and the purified water into a beaker to prepare a solution, adding saffron with the formula amount, placing the solution on a magnetic stirrer, and stirring the solution for 1 hour at the rotating speed of 600r/min for later use;

2) adding mannitol, pullulan, dextran-70 and sucralose into the solution, and continuously stirring for 30 min;

3) then shearing, stirring for 10min at the rotating speed of 1500r/min, and degassing until no obvious bubbles exist;

4) stirring continuously at the rotating speed of 600r/min by using a stirrer, and transferring a specified volume into a bubble cap to be frozen and formed by a low-temperature refrigerator at the temperature of-40 ℃;

5) freeze-drying;

6) and (6) packaging.

9. The method of claim 8, wherein the curve parameters used in the lyophilization process of step 5) are as follows:

loading at-30 deg.C;

freezing at-30 deg.C for 0:30 hr;

evacuating to a vacuum degree of 200 μ bar;

drying at-30 deg.C under vacuum degree of 200 μ bar for 0:50 hr;

drying at-25 deg.C under vacuum degree of 200 μ bar for 0:05 hr;

drying at-25 deg.C under vacuum degree of 200 μ bar for 1:00 hr;

drying at-20 deg.C under vacuum degree of 200 μ bar for 0:05 hr;

drying at-20 deg.C under vacuum degree of 200 μ bar for 1:00 hr;

drying at-15 deg.C under vacuum degree of 200 μ bar for 0:05 hr;

drying at-15 deg.C under vacuum degree of 200 μ bar for 2:00 hr;

drying at-10 deg.C under vacuum degree of 200 μ bar for 0:05 hr;

drying at-10 deg.C under vacuum degree of 200 μ bar for 1:00 hr;

drying at 0 deg.C under vacuum degree of 200 μ bar for 0:10 hr;

drying at 0 deg.C under vacuum degree of 200 μ bar for 0:30 hr;

drying at 10 deg.C under vacuum degree of 200 μ bar for 0:10 hr;

drying at 10 deg.C under vacuum degree of 200 μ bar for 2:00 hr.

Technical Field

The invention relates to the field of medicinal preparations, in particular to a saffron composition and a preparation method thereof.

Background

Saffron is the dry stigma of Crocus sativus (Crocus sativus L.) of perennial herb of Iridaceae, also known as saffron and Crocus sativus, and is originally produced in Europe and Central Asia. Saffron crocus is imported from India and Iran through Tibet, and now, the artificial planting of saffron crocus in Tibet, Zhejiang, Shanghai and other places in China is realized; it is one of the most expensive spices in the world, and is mainly used as a medicine in China except for being used as a spice, a dye and a food additive. India and iran are the major origins of saffron, and massohards of iran and silinaga of india are the largest saffron producing areas in the world today. Stigma croci has effects of promoting blood circulation, dredging channels, nourishing blood, removing blood stasis, relieving swelling and pain, resolving stagnation, and resolving hard mass, and can be used for treating symptoms such as melancholy, chest distress, hematemesis, typhoid attack, absentmindedness, amenorrhea, puerperal blood stasis, abdominal pain, and traumatic injury. The Chinese pharmacopoeia (Japanese pharmacopoeia (England pharmacopoeia) (European pharmacopoeia)) has been recorded.

The fact that saffron is loaded in 'hui medical literature' in the dynasty of Ganchang hui in the Western Tang province indicates that the research on saffron by Chinese medicine has been long, the recommended dosage in 'Chinese pharmacopoeia' in 2015 is 1-3 g, the saffron is taken by decoction or soaking in boiling water, and the 11-month national health Commission and the State market regulatory Bureau in 2019 formally list the saffron in the homology of medicine and food, means that people hope to eat a product containing the saffron in a fast and convenient mode, and undoubtedly put forward higher requirements for producers.

Regarding the preparation products of saffron, chinese patent 201710933738.7, name: a lyophilized powder product of stigma croci Sativi is prepared by lyophilizing fresh medicinal materials to obtain granule, and taking with water. Chinese patent 201511022775.X, name: a solid beverage containing stigma croci Sativi, and its preparation method and application are prepared by extracting stigma croci Sativi, and administering with water. Chinese patent CN106418092A, name: a stigma croci Sativi solid beverage is prepared by mixing stigma croci Sativi, fructus Siraitiae Grosvenorii, Ginseng radix, semen Armeniacae amarum and flos Lonicerae, pulverizing, and making into oral liquid.

Chinese patent 201910536985.2 discloses a freeze-dried orally disintegrating preparation, which comprises volatile components 4-20 parts, hydroxypropyl beta-cyclodextrin 8-100 parts, adhesive 4-20 parts, skeleton agent 4-20 parts, and suspending agent 0.1-0.6 part by weight. The active ingredient in this patent is a volatile ingredient selected from volatile oils of natural plants such as pinene, camphor, menthol, isoborneol, cinnamaldehyde, paeonol, borneol, menthone, etc., which are completely different from the physicochemical properties of saffron of the present invention.

Chinese patent 200410038822.5 discloses an oral instant preparation containing pullulan in auxiliary materials and a production method thereof. The oral instant preparation comprises a matrix and an effective dose of main drugs, wherein the matrix mainly comprises the following raw materials in parts by weight: 1-10 parts of a skeleton supporting agent and 1-10 parts of pullulan, wherein the main drug can be water-soluble or water-insoluble drug, and when the main drug is water-insoluble or main solvent, a thickening suspending agent can be added into the matrix; the preparation method of the oral instant preparation comprises the steps of dissolving, degassing, injection molding, quick freezing, freeze drying and the like, wherein an ice crystal incubation step can be added after the quick freezing in the method. The oral instant preparation has better formability, smoother surface, easy demoulding and difficult breakage; the range and proportion relation of the framework forming agent are more widely required.

In conclusion, the prior art has not reported a saffron crocus oral immediate-release preparation.

At present, when the freeze-drying method is adopted for preparing the tablets, the liquid is generally filled in the tablets by about 0.4ml to 0.5ml, so that the content of each main component is limited. If the main component exceeds a certain range, there occurs a problem that a satisfactory liquid which can be dispensed cannot be prepared, or even if it can be lyophilized into a tablet, rapid disintegration of the tablet cannot be achieved.

Disclosure of Invention

The invention aims to prepare a saffron quick-release tablet, and saffron can reach higher content (the recommended dosage of Chinese pharmacopoeia is 1-3 g), so that the saffron quick-release tablet can be quickly disintegrated in the middle. A large number of experiments lead the inventor to unexpectedly find that the two difficulties can be solved very well by adopting hydroxypropyl-beta-cyclodextrin (HP-beta-CD), and the addition of the hydroxypropyl-beta-cyclodextrin (HP-beta-CD) can increase the dissolution of the main component during the early liquid preparation and also can be helpful for continuing the disintegration after freeze-drying. And the disintegration performance of other common disintegrants is greatly reduced after the disintegrants are dissolved in water and dried. The experiment shows that the HP-beta-CD is dissolved in water and then freeze-dried, has obvious disintegration performance and is very suitable for the preparation process of the product. The process is characterized in that a solution is required to be formed first to be prepared by freeze drying, and the solution state is indispensable.

HP-beta-CD is a hydrophilic derivative formed by condensing beta-CD and 1, 2 epoxypropane. The compound is used in medicine, food and environmental protection, particularly as a medicine auxiliary material, and has the main functions of: 1 increasing the solubility of the drug; 2, the stability of the medicine is improved; 3, improving the bioavailability of the medicine; 4, the toxic and side effects of the medicine are reduced; 5 masking the bitter taste of the Chinese medicine. Its use as a disintegrant has not been clearly reported.

The effect of HP-beta-CD in the product is summarized as follows: (1) when the liquid is prepared, a certain dissolution assisting effect is achieved, so that more main components are dispersed into the liquid; (2) after freeze-drying, the regular pore channel structure of the freeze-dried tablet skeleton is more regular, and when meeting water, the freeze-dried tablet is highly water-soluble, so that the freeze-dried tablet is disintegrated more rapidly.

The product is a tablet, which can be obtained in a variety of ways. However, the product is a freeze-dried tablet, and therefore, the product must be prepared into a liquid state at first to complete the sub-packaging. If the prepared liquid is not good in property and can not be subpackaged, the subsequent process can not be finished.

Freeze-drying tablets, key several procedures: the preparation method comprises the steps of liquid preparation, split charging, freeze-drying and packaging, wherein the liquid preparation is very important, and if the liquid is not well prepared, split charging cannot be carried out, the split charging dosage is not accurate, freeze-drying cannot be carried out to form tablets, or the hardness of the freeze-dried tablets is not enough, so that packaging cannot be finished. Whether the tablet is qualified or not and whether the tablet can be released or not after being prepared into the tablet is basically determined by a key process of solution preparation.

The invention solves the problem that the drug-loading rate of the main component is increased, namely the total volume of the tablet is not changed, but the rapid disintegration can be realized under the condition of large dose of the main component, and the rapid disintegration after the saffron crocus traditional Chinese medicine is pulverized into powder is solved.

Specifically, the invention provides the following technical scheme:

a composition comprising saffron, a matrix agent, a binder, a lyoprotectant, and a disintegrant, or comprising a sweetener.

Preferably, for said composition, wherein said saffron is micronized saffron having a particle size of D90 ≤ 50 μm, preferably D90 ≤ 15 μm.

Preferably, the content of saffron in each preparation unit is 1-200 mg, preferably 1-80 mg.

Preferably, for the composition, the matrix agent is selected from mannitol, the binder is selected from pullulan, the lyoprotectant is selected from dextran-70, the disintegrant is selected from HP-beta-CD, or the sweetener is selected from sucralose.

Preferably, in the composition, the weight percentage of the skeleton agent is 5-20%, the weight percentage of the binder is 0.2-1.0%, the weight percentage of the freeze-drying protective agent is 1-10%, the weight percentage of the disintegrating agent is 4-20%, or the weight percentage of the sweetening agent is 0.2-0.5%.

A method of making a composition as described in any of the preceding paragraphs, comprising the steps of:

1) weighing disintegrating agent and purified water, placing in a beaker, preparing into solution, adding stigma croci Sativi, and stirring;

2) adding the skeleton agent, the binder, the freeze-drying protective agent and the sweetening agent into the solution, and continuously stirring;

3) shearing, stirring and degassing until no obvious bubbles exist;

4) stirring continuously by a stirrer, transferring a specified volume into a bubble cap, and freezing and forming;

5) freeze-drying;

6) and (6) packaging.

A composition, wherein the composition comprises the following components: 73.17 wt% saffron, 9.15 wt% mannitol, 0.37 wt% pullulan, 3.66 wt% dextran-70, 0.37 wt% sucralose and 13.29 wt% HP-beta-CD;

preferably, the composition comprises per unit formulation: 80.00m saffron, 10.00mg mannitol, 0.40mg pullulan, 0.40mg dextran-704.00 mg sucralose and 14.53mg HP-beta-CD14.

A process for the preparation of the above-described composition comprising the steps of:

1) weighing HP-beta-CD and purified water with the formula amount or the same proportion expanded, placing the HP-beta-CD and the purified water into a beaker to prepare a solution, adding saffron with the formula amount, placing the solution on a magnetic stirrer, and stirring the solution for 1 hour at the rotating speed of 600r/min for later use;

2) adding mannitol, pullulan, dextran-70 and sucralose into the solution, and continuously stirring for 30 min;

3) then shearing, stirring for 10min at the rotating speed of 1500r/min, and degassing until no obvious bubbles exist;

4) stirring continuously at the rotating speed of 600r/min by using a stirrer, and transferring a specified volume into a bubble cap to be frozen and formed by a low-temperature refrigerator at the temperature of-40 ℃;

5) freeze-drying;

6) and (6) packaging.

Preferably, for the preparation method, the curve parameters used in the lyophilization process of the step 5) are as follows:

loading at-30 deg.C;

freezing at-30 deg.C for 0:30 hr;

evacuating to a vacuum degree of 200 μ bar;

drying at-30 deg.C under vacuum degree of 200 μ bar for 0:50 hr;

drying at-25 deg.C under vacuum degree of 200 μ bar for 0:05 hr;

drying at-25 deg.C under vacuum degree of 200 μ bar for 1:00 hr;

drying at-20 deg.C under vacuum degree of 200 μ bar for 0:05 hr;

drying at-20 deg.C under vacuum degree of 200 μ bar for 1:00 hr;

drying at-15 deg.C under vacuum degree of 200 μ bar for 0:05 hr;

drying at-15 deg.C under vacuum degree of 200 μ bar for 2:00 hr;

drying at-10 deg.C under vacuum degree of 200 μ bar for 0:05 hr;

drying at-10 deg.C under vacuum degree of 200 μ bar for 1:00 hr;

drying at 0 deg.C under vacuum degree of 200 μ bar for 0:10 hr;

drying at 0 deg.C under vacuum degree of 200 μ bar for 0:30 hr;

drying at 10 deg.C under vacuum degree of 200 μ bar for 0:10 hr;

drying at 10 deg.C under vacuum degree of 200 μ bar for 2:00 hr.

Detailed Description

The following examples are intended to illustrate the invention and should not be construed as limiting the scope of the invention to the preparation of the saffron composition of 11000 unit formulations of the examples

The prescription for each unit formulation is shown in the following table:

TABLE 1 prescription for each unit preparation

The preparation process of the composition comprises the following steps:

the "prescribed amount" described below refers to 1000 times the "content per unit formulation" listed in the above table.

1) Weighing HP-beta-CD and purified water according to the prescription amount, and placing the HP-beta-CD and the purified water into a beaker to prepare a solution. Adding formula amount of stigma croci Sativi (micropowder treatment, particle diameter D90 is less than or equal to 50 μm) on a magnetic stirrer, stirring at 600r/min for 1 hr;

2) adding mannitol, pullulan, dextran-70 and sucralose into the solution, and continuously stirring for 30 min;

3) then shearing, stirring for 10min at the rotating speed of 1500r/min, and degassing until no obvious bubbles exist;

4) stirring continuously at the rotating speed of 600r/min by using a stirrer, and transferring a specified volume into a bubble cap to be frozen and formed by a low-temperature refrigerator at the temperature of-40 ℃;

5) freeze-drying;

wherein the curve parameters of the freeze-drying process are shown in the following table:

TABLE 2 Curve parameters of the lyophilization Process

6) And (5) packaging to obtain the product.

Example 2 Effect test/screening test

The judgment standards of each index of the composition are as follows:

1. standard of disintegration:

one tablet was taken and put into 50ml of water at 37 c, and the disintegration of the tablet in water was observed and recorded. The beaker was gently shaken, and disintegration was observed and recorded, if necessary. The observations are shown in the following table:

table 3 observation of disintegration of tablets in water

2. Tablet texture

Observing whether the sheet shape is full and is crown-shaped, and covering the bottom layer of the aluminum nest. If the section is complete and powder falls off, the touch piece is touched by fingers to describe the feeling. The results are shown in the following table:

table 4 tablet texture observations

3. Taste of the product

The tablets were removed and placed on the tongue without chewing and without water until the tablets completely disintegrated and all suspended matter in the mouth was spitted out, rinsed and the feeling and taste of the tablets in the mouth was recorded.

In order to verify the performance of the saffron compositions of different formulations provided by the present invention, after tablets were prepared according to the preparation method provided in the above example 1, the following formulations 1 to 30 were screened according to the criteria (disintegration criteria, tablet texture criteria, mouth feel criteria) provided in the above example 2. The specific process comprises the following steps:

1. prescription screening process

1.1 selection of adjuvants

TABLE 5 screening of recipes 1-3

The above table illustrates: on the basis of adopting mannitol, pullulan and xanthan gum as auxiliary materials, polysorbate 80 and PVP-K30 are screened as disintegrating agents, so that a solution meeting the production requirement cannot be prepared, the next procedure cannot be carried out, and the prescription is abandoned.

TABLE 6 screening of recipes 4-5

The above table illustrates: the influence of sodium alginate on the prescription is considered, and the test result shows that the solution state is viscous, and even though the solution can be subpackaged, the disintegration after freeze-drying is not required.

TABLE 7 screening of recipes 6-7

The above table illustrates: and (3) investigating the influence of respectively adding the pullulan, the polysorbate 80, the xanthan gum, the sodium carboxymethyl starch, the dextran-70 and the like on the tablets. The results show that the addition of these adjuvants has not solved the preparation of tablets and other new adjuvants need to be selected.

1.2 examination of solubilization and disintegration effects of hydroxypropyl-. beta. -cyclodextrin (HP-. beta. -CD) formulations 8-10 of Table 8

The above table illustrates: the effect can be obviously improved and further optimized by adding hydroxypropyl-beta-cyclodextrin (HP-beta-CD). Formula 1-10 saffron is not micronized.

1.3 investigating the effect of saffron micronization on lyophilized tablets

The saffron in the following prescription 11-15 is micronized, and the particle size is D90 ≤ 50 μm.

TABLE 9 screening of recipes 11-15

The above table illustrates: optimizing the prescription, including the saffron particle size D90 not more than 50 μm, and the dosage of each auxiliary material, finally determining the better.

1.4 investigation of the Effect of HP-beta-CD content on Freeze-dried tablets

TABLE 10 screening of recipes 15-19

The prescription is optimized, the obtained tablets are tested, and the prescriptions 15-17 with the weight percentage of HP-beta-CD in the range of 4-20 percent meet the requirements on the texture and disintegration of the tablets. Tablets of formula 18 having a weight percent of HP-beta-CD of less than 4% disintegrate poorly, and tablets of formula 19 having a weight percent of HP-beta-CD of greater than 20% have insufficient hardness to meet the requirements.

1.5 investigation of the Effect of Freeze-drying protective agent dextran-70 on Freeze-dried tablets

TABLE 11 screening of prescriptions 15 and prescriptions 20-23

The formula is optimized, the obtained tablets are tested, and the best tablets are obtained when the dextran-70 shown in the formula 15 is used as the freeze-drying protective agent. Trehalose, glucose, lactose or albumin are selected as the freeze-drying protective agent for the formulas 20-23, wherein the tablets of the formulas 20 and 22 are too slow to disintegrate, and the liquid medicine used in the preparation stages of the tablets of the formulas 21 and 23 is layered and has insufficient hardness, so that the tablets do not meet the requirements.

1.6 investigation of the Effect of Xanthan Gum on Freeze-dried tablets

TABLE 12 screening of prescriptions 15 and prescriptions 24-27

The formula is optimized, the obtained tablets are tested, when the xanthan gum is not used in the composition (formula 15), the obtained tablets are best and meet the requirements on disintegration and the like, and the formula with the xanthan gum is 24-27, the obtained tablets have overlarge hardness and slow disintegration and do not meet the requirements of orally disintegrating tablets.

1.7 investigating the effect of saffron particle size D90 > 50 μm on freeze-dried tablets

TABLE 13 screening of prescriptions 15 and prescriptions 28-30

Optimizing the prescription, detecting the obtained tablet, when the particle diameter D90 of saffron is less than or equal to 50 μm, especially less than or equal to 15 μm (prescriptions 15 and 28), the obtained tablet meets the requirements on disintegration, tablet hardness and the like, while prescriptions 29 and 30 with the particle diameter D90 of more than 50 μm have poor liquid medicine state in the preparation stage, have layering phenomenon, and the obtained tablet disintegrates gradually and does not meet the requirements of orally disintegrating tablets.

It will be understood by those skilled in the art that the foregoing is only exemplary of the present invention, and is not intended to limit the invention, which is intended to cover any variations, equivalents, or improvements therein, which fall within the spirit and scope of the invention.