Granules of composition containing rhizoma polygonati as well as preparation method and application of granules

Abstract

The invention discloses granules of a composition containing rhizoma polygonati. The granules comprise the following components in percentage by weight: 30%-50% of composition dry paste powder, 38%-58% of a filling agent, 0.1%-20% of an adhesive and 0.1%-2% of a flow aid, the composition comprises rhizoma polygonati, fructus lycii, flos chrysanthemi and radix glehniae. Wherein the filling agent is dextrin; wherein the adhesive is maltodextrin or povidone; wherein the flow aid is colloidal silicon dioxide. According to the composition disclosed by the invention, proper auxiliary materials and an adding mode thereof are selected, so that the inherent properties of the original extract are improved, the extract is not easy to soften, the caking tendency caused by moisture absorption or heat absorption among particles is avoided, and the caking probability is reduced.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine, in particular to a granule of a composition containing Rhizoma Polygonati, and a preparation method and application thereof. BACKGROUND

[0002] Traditional Chinese medicine ingredients are complex, and there are more hydrophilic components such as polysaccharides, tannins and proteins. The granules are extremely easy to absorb moisture, and are extremely easy to become soft, the appearance color becomes dark, and caking occurs under the condition of temperature rise, which not only brings difficulties to the preparation production and storage, but also affects the quality and efficacy of the preparation. The granules prepared by simply using dextrin as an excipient appear softening and caking during long-term storage, resulting in quality problems of the granules. The test results show that the softening and caking of the granules gradually become more serious with the increase of temperature.

[0003] There is no related report on the granule of the composition containing Rhizoma Polygonati and the preparation method and application thereof as claimed in the present application in the prior art. SUMMARY

[0004] Therefore, the present application provides a granule of a composition containing Rhizoma Polygonati, which comprises: 30-50% of composition dry paste powder by weight, 38-58% of filler by weight, 0.1-20% of binder by weight, and 0.1-2% of glidant by weight.

[0005] The composition comprises Rhizoma Polygonati, Fructus Lycii, Chrysanthemum and North Adenophora.

[0006] The filler is dextrin.

[0007] The binder is malt dextrin or povidone.

[0008] The glidant is colloidal silicon dioxide.

[0009] Further, the composition dry paste powder is 35-46% by weight.

[0010] Further, the filler is 38-54% by weight.

[0011] Further, the binder is 5-15% by weight.

[0012] Further, the glidant is 0.5-1.5% by weight.

[0013] Further, the composition dry paste powder is 36-45% by weight.

[0014] Further, the filler is 43-53% by weight.

[0015] Furthermore, the adhesive comprises approximately 10% by weight.

[0016] Furthermore, the gliding agent comprises approximately 1% by weight.

[0017] Furthermore, the mass ratio of the filler, the adhesive, and the flow aid is (50-150):(10-60):(0.5-10).

[0018] Furthermore, the mass ratio of the filler, the adhesive, and the flow aid is (80-100):(20-40):(1-4).

[0019] Furthermore, the filler is not selected from one or more of the following: lactose, mannitol, β-cyclodextrin, and soluble starch.

[0020] Furthermore, the gliding agent is not calcium sulfate or calcium hydrogen phosphate.

[0021] Furthermore, the weight of the dry extract powder of the composition = weight of the clear extract sample after constant weight / weight of the clear extract sample before drying × weight of the clear extract.

[0022] According to another aspect of the present invention, a method for preparing the above-mentioned granules is provided, the method comprising the following steps:

[0023] (1) Prepare the clear paste and an appropriate amount of binder, mix them evenly, spray them into an appropriate amount of filler, granulate, and obtain the first granule.

[0024] (2) Weigh an appropriate amount of filler, add water to obtain a filler solution, add a flow aid to the filler solution, mix well, and then spray it into the first granule to granulate, thereby obtaining a second granule; and

[0025] (3) The second granule is dried and sieved to obtain the granule.

[0026] Furthermore, the granulation method is a one-step granulation method.

[0027] Furthermore, the mass ratio of the adhesive to the water is 0.1 to 0.5, for example, about 0.3.

[0028] Furthermore, the endpoint of this drying process is a moisture content of ≤6%.

[0029] Furthermore, the granules in this granule are those that can all pass through a 10-mesh sieve but cannot pass through an 80-mesh sieve.

[0030] Furthermore, the preparation method further includes the step of mixing the sieved particles and then filling the particles.

[0031] Furthermore, the mass ratio between the filler in step (1) and the filler in step (2) is 2 to 5, for example, 3 to 4.

[0032] Furthermore, the preparation method of this ointment includes the following steps:

[0033] (1) Weigh an appropriate amount of the composition, add water and decoct to obtain a decoction or combine the decoctions and filter to obtain a filtrate;

[0034] (2) Concentrate the filtrate, allow it to stand, and centrifuge to obtain the centrifuged liquid; and

[0035] (3) Concentrate the centrifuged liquid to obtain a clear extract.

[0036] Furthermore, the composition includes Polygonatum sibiricum, Lycium barbarum, Chrysanthemum morifolium, and Adenophora stricta.

[0037] Furthermore, this Polygonatum is processed Polygonatum.

[0038] Furthermore, the mass ratio of the prepared Polygonatum, the wolfberry, the chrysanthemum and the North American ginseng is (2-4):(1-3):(1-3):(1-3).

[0039] Furthermore, the mass ratio of the prepared Polygonatum sibiricum, the wolfberry, the chrysanthemum, and the North American ginseng is (2.4–3.6):(1.6–2.4):(1.6–2.4):(1.6–2.4).

[0040] Furthermore, the mass ratio of the prepared Polygonatum, the wolfberry, the chrysanthemum, and the North American ginseng is approximately 3:2:2:2.

[0041] Furthermore, the mass ratio of the water to the composition is 6 to 20.

[0042] Furthermore, the mass ratio of the water to the composition is 8 to 12, for example, about 10.

[0043] Furthermore, the decoction is prepared 1 to 4 times, for example, 2 times.

[0044] Furthermore, the simmering time is 10 to 60 minutes per batch, for example, about 30 minutes per batch.

[0045] Furthermore, the settling time is 8 to 24 hours, for example, about 12 hours.

[0046] Furthermore, the endpoint of the filtrate concentration is that the relative density of the filtrate is 1.05 to 1.10 at a certain temperature.

[0047] Furthermore, the endpoint of the centrifugal liquid concentration is that the relative density of the centrifugal liquid at a certain temperature is 1.15 to 1.20.

[0048] Furthermore, this temperature is 45–60°C, for example, about 50°C.

[0049] According to another aspect of the invention, the use of the above-described granules in the preparation of a medicament for the prevention and / or treatment of dry eye syndrome is provided.

[0050] Furthermore, the composition further includes other pharmaceutically acceptable excipients.

[0051] Furthermore, the other pharmaceutically acceptable excipient is selected from one or more of the following: diluents, wetting agents, disintegrants, inclusion agents, flavoring agents, sustained-release agents, lubricants, dispersants, plasticizers, light-blocking agents, and antioxidants.

[0052] Furthermore, this dry eye syndrome is caused by environmental factors, age, diabetes, video terminals, and / or other eye diseases.

[0053] Furthermore, the composition further comprises one or more drugs and / or extracts for treating dry eye syndrome.

[0054] Furthermore, the drug is selected from one or more of the following: artificial tears, autologous serum, drugs that promote tear secretion, drugs that reduce ocular surface inflammation, and drugs that treat blepharitis.

[0055] Furthermore, the drug that promotes tear secretion is selected from one or more of the following: bromoxynil, pilocarpine, and neostigmine.

[0056] Furthermore, the drug that reduces inflammation on the ocular surface is cyclosporine A.

[0057] The beneficial effects of this invention are:

[0058] The composition of the present invention improves the inherent properties of the original extract by selecting appropriate excipients and their addition methods, making it less prone to softening, avoiding the tendency of particles to clump due to moisture or heat absorption, and reducing the probability of clumping. Detailed Implementation

[0059] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0060] Unless otherwise stated, all technical and scientific terms and abbreviations used herein have the meanings commonly understood by one of ordinary skill in the field of this invention or the field of application of such terms. While any methods, conditions, substances, or materials similar to or equivalent to those disclosed herein may be used in the practice of this invention, preferred methods, conditions, substances, or materials are described herein.

[0061] This invention is intended to cover all options, variations, and equivalents that may be included in the field of prior art as defined in the claims. Those skilled in the art will recognize many similar or equivalent methods and substances described herein that can be applied in the practice of this invention. This invention is by no means limited to the description of methods and substances.

[0062] The singular forms “a,” “an,” and “the” used in the specification and appended claims include plural indicators unless the context clearly specifies otherwise.

[0063] In this invention, the term "comprising" and "including" are synonymous. The terms "comprising," "including," "having," "containing," or any other variations thereof as used herein are intended to cover a non-exclusive inclusion. For example, a composition, step, method, article, or apparatus that includes the listed elements is not necessarily limited to those elements, but may include other elements not expressly listed or elements inherent to such a composition, step, method, article, or apparatus.

[0064] As described in the background section, existing traditional Chinese medicine composition granules suffer from softening and clumping during storage. To address this issue, the present invention provides a granule containing a composition of Polygonatum sibiricum, wherein the granule comprises: 30%–50% by weight of a dry extract powder of the composition, 38%–58% by weight of a filler, 0.1%–20% by weight of a binder, and 0.1%–2% by weight of a flow aid;

[0065] The composition contains Polygonatum sibiricum, Lycium barbarum, Chrysanthemum morifolium, and Adenophora stricta.

[0066] The filler is dextrin.

[0067] The adhesive is either maltodextrin or polyvinylpyrrolidone.

[0068] The flow aid is colloidal silica.

[0069] In this invention, when weight percentage, time, temperature, ratio, or other values ​​or parameters are expressed as ranges, preferred ranges, or a series of upper and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pairing of any upper or preferred value with any lower or preferred value, regardless of whether the range is disclosed individually. For example, when the range “30–50” is disclosed, the described range should be interpreted as including ranges “30–50”, “30–45”, “30–40”, “30–35”, “35–50”, “35–45”, “35–40”, “40–50”, “40–45”, “45–50”, etc. When numerical ranges are described herein, unless otherwise stated, the range is intended to include its endpoints and all integers and fractions within that range.

[0070] In a preferred embodiment, the dry powder of the composition is 35% to 46% by weight.

[0071] In a preferred embodiment, the filler has a weight percentage of 38% to 54%.

[0072] In a preferred embodiment, the adhesive has a weight percentage of 5% to 15%.

[0073] In a preferred embodiment, the gliding agent comprises 0.5% to 1.5% by weight.

[0074] In a preferred embodiment, the dry powder of the composition is 36% to 45% by weight.

[0075] In a preferred embodiment, the filler has a weight percentage of 43% to 53%.

[0076] In a preferred embodiment, the adhesive accounts for approximately 10% by weight.

[0077] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 10%" includes 10% ± 5%, or from 9.5% to 10.5%.

[0078] In a preferred embodiment, the glidin is present at approximately 1% by weight.

[0079] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 1%" includes 1% ± 5%, or from 0.95% to 1.05%.

[0080] In a preferred embodiment, the mass ratio of the filler, the adhesive, and the flow aid is (50-150):(10-60):(0.5-10).

[0081] In a preferred embodiment, the mass ratio of the filler, the adhesive and the flow aid is (80-100):(20-40):(1-4).

[0082] In a preferred embodiment, the filler is not selected from one or more of the following: lactose, mannitol, β-cyclodextrin, and soluble starch.

[0083] In a preferred embodiment, the flow aid is not calcium sulfate or calcium hydrogen phosphate.

[0084] In a preferred embodiment, the weight of the dry extract powder of the composition = the weight of the extract sample after constant weight / the weight of the extract sample before drying × the weight of the extract.

[0085] According to another aspect of the present invention, a method for preparing the above-mentioned granules is provided, the method comprising the following steps:

[0086] (1) Prepare the clear paste and an appropriate amount of binder, mix them evenly, spray them into an appropriate amount of filler, granulate, and obtain the first granule.

[0087] (2) Weigh an appropriate amount of filler, add water to obtain a filler solution, add a flow aid to the filler solution, mix well, and then spray it into the first granule to granulate, thereby obtaining a second granule; and

[0088] (3) The second granule is dried and sieved to obtain the granule.

[0089] In a preferred embodiment, the granulation method is a one-step granulation method.

[0090] In a preferred embodiment, the mass ratio of the adhesive to the water is 0.1 to 0.5, for example, about 0.3.

[0091] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 0.3" includes ±5% of 0.3, or from 0.285 to 0.315.

[0092] In a preferred embodiment, the drying endpoint is a moisture content of ≤6%.

[0093] In a preferred embodiment, the granules are those that can pass through a 10-mesh sieve but not an 80-mesh sieve.

[0094] In a preferred embodiment, the preparation method further includes the step of mixing the sieved particles and then filling the particles.

[0095] In a preferred embodiment, the mass ratio between the filler in step (1) and the filler in step (2) is 2 to 5, for example, 3 to 4.

[0096] In a preferred embodiment, the preparation method of the ointment includes the following steps:

[0097] (1) Weigh an appropriate amount of the composition, add water and decoct to obtain a decoction or combine the decoctions and filter to obtain a filtrate;

[0098] (2) Concentrate the filtrate, allow it to stand, and centrifuge to obtain the centrifuged liquid; and

[0099] (3) Concentrate the centrifuged liquid to obtain a clear extract.

[0100] In a preferred embodiment, the composition includes Polygonatum sibiricum, Lycium barbarum, Chrysanthemum morifolium, and Adenophora stricta.

[0101] In a preferred embodiment, the Polygonatum is processed Polygonatum.

[0102] In a preferred embodiment, the mass ratio of the prepared Polygonatum sibiricum, the wolfberry, the chrysanthemum and the North American ginseng is (2-4):(1-3):(1-3):(1-3).

[0103] In a preferred embodiment, the mass ratio of the prepared Polygonatum sibiricum, the Lycium barbarum, the Chrysanthemum morifolium, and the Adenophora stricta is (2.4–3.6):(1.6–2.4):(1.6–2.4):(1.6–2.4).

[0104] In a preferred embodiment, the mass ratio of the prepared Polygonatum sibiricum, the wolfberry, the chrysanthemum, and the North American ginseng is about 3: about 2: about 2: about 2.

[0105] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 3" includes 3 ± 5%, or from 2.85 to 3.15.

[0106] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 2" includes 2 ± 5%, or from 1.9 to 2.1.

[0107] In a preferred embodiment, the mass ratio of the water to the composition is 6 to 20.

[0108] In a preferred embodiment, the mass ratio of the water to the composition is 8 to 12, for example, about 10.

[0109] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 10" includes ±5% of 10, or from 9.5 to 10.5.

[0110] In a preferred embodiment, the decoction is performed 1 to 4 times, for example, 2 times.

[0111] In a preferred embodiment, the simmering time is 10 to 60 minutes per cycle, for example, about 30 minutes per cycle.

[0112] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 30" includes 30 ±5%, or from 28.5 to 31.5.

[0113] In a preferred embodiment, the settling time is 8 to 24 hours, for example, about 12 hours.

[0114] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 12" includes ±5% of 12, or from 11.4 to 12.6.

[0115] In a preferred embodiment, the endpoint of the filtrate concentration is when the relative density of the filtrate is 1.05 to 1.10 at a certain temperature.

[0116] In a preferred embodiment, the endpoint of the centrifugal fluid concentration is that the relative density of the centrifugal fluid at a certain temperature is 1.15 to 1.20.

[0117] In a preferred embodiment, the temperature is 45–60°C, for example, about 50°C.

[0118] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 50" includes 50 ± 5%, or from 47.5 to 52.5.

[0119] According to another aspect of the invention, the use of the above-described granules in the preparation of a medicament for the prevention and / or treatment of dry eye syndrome is provided.

[0120] In this invention, the term "treatment" also includes "prevention," unless specifically stated otherwise. The terms "therapeutic" and "therapeutically" should be understood accordingly.

[0121] In this invention, the term "treatment" includes alleviating, suppressing, or improving symptoms or conditions of a disease; suppressing the development of complications; improving or preventing underlying metabolic syndromes; suppressing the development of a disease or symptom, such as controlling the progression of a disease or condition; reducing a disease or symptom; alleviating a disease or symptom; reducing complications arising from a disease or symptom; or preventing or treating signs arising from a disease or symptom. As used herein, a pharmaceutical composition or pharmaceutical preparation, upon administration, may improve a disease, symptom, or condition, particularly by improving its severity, delaying onset, slowing disease progression, or reducing the duration of the condition. Whether the administration is fixed or intermittent, continuous or intermittent, it may be attributable to or related to the administration.

[0122] According to another aspect of the invention, the above-described granules are provided for the prevention and / or treatment of dry eye syndrome.

[0123] According to another aspect of the invention, a method for preventing and / or treating dry eye syndrome is provided by administering a therapeutically effective amount of the aforementioned granules.

[0124] In a preferred embodiment, the composition further comprises other pharmaceutically acceptable excipients.

[0125] In this invention, the term "pharmaceutically acceptable" means a substance, such as a carrier or diluent, that does not destroy the biological activity or properties of a compound and is relatively non-toxic, such that, when administered to an individual, it will not cause unwanted biological effects or interact with any of its constituent components in a harmful manner.

[0126] In this invention, the term "pharmaceuticalally acceptable excipient" refers to a carrier and / or excipient that is pharmacologically and / or physiologically compatible with the subject and the active ingredient (i.e., capable of eliciting the desired therapeutic effect without causing any undesirable local or systemic effects), which is well known in the art (see, for example, Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995).

[0127] In a preferred embodiment, the other pharmaceutically acceptable excipient is selected from one or more of the following: diluents, wetting agents, disintegrants, inclusion agents, flavoring agents, sustained-release agents, lubricants, dispersants, plasticizers, light-blocking agents, and antioxidants.

[0128] In a preferred embodiment, the dry eye syndrome is caused by environmental factors, age, diabetes, video terminals, and / or other eye diseases.

[0129] In a preferred embodiment, the composition further comprises one or more drugs and / or extracts for treating dry eye syndrome.

[0130] In a preferred embodiment, the drug is selected from one or more of the following: artificial tears, autologous serum, drugs that promote tear secretion, drugs that reduce ocular surface inflammation, and drugs that treat blepharitis.

[0131] In a preferred embodiment, the tear-promoting drug is selected from one or more of the following: bromoxynil, pilocarpine, and neostigmine.

[0132] In a preferred embodiment, the drug for reducing ocular surface inflammation is cyclosporine A.

[0133] The high-temperature and accelerated tests of this invention are stability tests conducted under conditions higher than those for long-term storage, which can reflect the stability of the drug during long-term storage to a certain extent in a shorter time. Therefore, the appearance of the granules is observed under high-temperature conditions (50℃±2℃, RH60%±5%) and accelerated conditions (40℃±2℃, RH75%±5%) to evaluate the granule quality.

[0134] In addition, to assess the overall quality of the particles, their moisture content, solubility, and angle of repose parameters were also tested.

[0135] The technical problem solved by this invention is achieved by the following technical solution:

[0136] The proportions of each component in the granule composition containing Polygonatum provided by this invention are as follows:

[0137]

[0138]

[0139] The preferred embodiment of the present invention is as follows:

[0140] Composition dry paste powder 35％-46％ Filler 38％-54％ Binder 5-15％ Glidant 0.5％-1.5％

[0141] The optimal solution of this invention is:

[0142] Composition dry paste powder 36％-45％ Filler 43％-53％ Binder 10％ Glidant 1％

[0143] The composition of the dry extract powder has the following active pharmaceutical ingredient composition (based on 1000g of finished product):

[0144] Preparation of polygonatum 240-360g Medlar fruit 160-240g Chrysanthemum 160-240g North adenosma 160-240g

[0145] The preferred composition of the active pharmaceutical ingredient (based on the production of 1000g of finished product) is as follows.

[0146] Preparation of polygonatum 300g Medlar fruit 200g Chrysanthemum 200g North adenosma 200g

[0147] The preparation method of the ointment is as follows: weigh the above four raw materials, add 6-20 times the amount of water, preferably 8-12 times; decoct 1-4 times, preferably 2-3 times; each time for 0.5-4 hours, preferably 0.5-2 hours, combine the decoctions, filter, concentrate the filtrate to a suitable density, let stand overnight, centrifuge, and concentrate the centrifuged liquid into a thick ointment.

[0148] The preferred method for preparing the ointment is to weigh the above four raw materials, add 10 times the amount of water and decoct twice, each time for 0.5 hours, combine the decoctions, filter, concentrate the filtrate to a density of 1.05-0.10 (50℃), let stand overnight, centrifuge, and concentrate the centrifuged liquid to a density of 1.15-1.20 (50℃) to form a thick ointment.

[0149] The filler is selected from dextrin; the binder is selected from maltodextrin or povidone; and the flow aid is selected from colloidal silica.

[0150] The preparation process of the granule formulation of the composition containing Polygonatum of the present invention is as follows:

[0151] (1) The clear paste is used as the binder and the filler is used as the base material. The granulation is carried out by one-step granulation method.

[0152] (2) Dissolve the binder in an appropriate amount of water at a mass ratio of 30:100. Add a flow aid to the solution and mix well. Use this solution as the binder and the granules from step (1) as the base material. Continue granulation until the end.

[0153] (3) Dry the material until the moisture content is ≤6%;

[0154] (4) After drying, the material is sieved to retain particles between 80-10 mesh.

[0155] (5) Particle filling after total mixing.

[0156] This invention is suitable for large-scale production and effectively solves the problem of softening and clumping of the composition containing Polygonatum during storage.

[0157] The evaluation method used in this invention is as follows:

[0158] (1) The granules of the composition containing Polygonatum were placed in a stability sample box and the storage conditions were set as follows: temperature 50℃±2℃ and relative humidity 60%±5%. The appearance of the granules was tested at 0 days, 5 days, 10 days and 30 days and compared with that at 0 days to evaluate the quality change.

[0159] (2) The granules of the composition containing Polygonatum were placed in a stability sample retention box and the storage conditions were set as follows: temperature 40℃±2℃ and relative humidity 75%±5%. The appearance of the granules was tested in 0 months, 1 month, 2 months, 3 months and 6 months and compared with that in 0 months to evaluate the quality change.

[0160] (3) Moisture content: Rapid moisture analyzer (105℃, infrared heating).

[0161] (4) Solubility: Take 10g of sample (one bag for single-dose packaging), add 200ml of hot water, stir for 5 minutes, and observe immediately. It should be completely melted or slightly turbid.

[0162] (5) Angle of repose: Intelligent powder property tester.

[0163] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or conditions recommended by the manufacturer.

[0164] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0165] The features mentioned above in this invention, or the features mentioned in the embodiments, can be combined arbitrarily. All features disclosed in this patent specification can be used in any compositional form, and each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the disclosed features are merely general examples of equivalent or similar features.

[0166] Example

[0167] Example 1

[0168] Preparation of the extract: 300g of Polygonatum sibiricum, 200g of Lycium barbarum, 200g of Chrysanthemum morifolium, and 200g of Adenophora stricta. Add 10 times the amount of water to the above four ingredients and decoct twice, 0.5 hours each time. Combine the decoctions, filter, and concentrate the filtrate to a density of 1.05-0.10 (50℃). Let stand overnight, centrifuge, and concentrate the centrifuged liquid to a density of 1.15-1.20 (50℃) to obtain a thick extract.

[0169] Method for determining the weight of dry extract powder in the ointment: Accurately measure a certain volume of the ointment sample into a suitable glass weighing bottle that has been dried to constant weight, and place it in a drying oven at 105℃ until constant weight. Calculate using the following formula:

[0170] G = W1 / W2 × W

[0171] In the formula, G represents the weight of the dry ointment powder contained in the ointment.

[0172] W1 is the weight of the test sample after constant weight.

[0173] W2 represents the weight of the extract sample before drying.

[0174] W represents the weight of the ointment.

[0175] In all subsequent embodiments, the calculation method for dry powder is the same as the above formula.

[0176] Example 2

[0177] The extract was prepared according to the method described in Example 1, and the formulation process was studied. 100g of maltodextrin was added to the extract and mixed thoroughly. 400g of dextrin was used as a base material for one-step granulation until the extract was completely sprayed. 100g of dextrin was dissolved in water, and 10g of colloidal silica was added and mixed thoroughly. This mixture was then sprayed into the granules until granulation was complete. The granules were dried at 60℃ until the moisture content was ≤6%, sieved, and particles between 80-10 mesh were retained. The granules were then filled into containers. The moisture content was measured at 2.5%, the solubility was satisfactory, and the angle of repose was 38.95°.

[0178] Example 3

[0179] The extract was prepared according to the method described in Example 1, and the formulation process was studied. 150g of maltodextrin was added to the extract and mixed thoroughly. 350g of dextrin was used as a base material for one-step granulation until the extract was completely sprayed. 100g of dextrin was dissolved in water, and 10g of colloidal silica was added and mixed thoroughly. This mixture was then sprayed into the granules until granulation was complete. The granules were dried at 60℃ until the moisture content was ≤6%, sieved, and particles between 80-10 mesh were retained. The granules were then filled into containers. The moisture content was measured at 2.87%, the solubility was satisfactory, and the angle of repose was 39.32°.

[0180] Example 4

[0181] The extract was prepared according to the method described in Example 1, and the formulation process was studied. 200g of maltodextrin was added to the extract and mixed thoroughly. 300g of dextrin was used as a base material for one-step granulation until the extract was completely sprayed. 100g of dextrin was dissolved in water, and 10g of colloidal silica was added and mixed thoroughly. This mixture was then sprayed into the granules until granulation was complete. The granules were dried at 60℃ until the moisture content was ≤6%, sieved, and particles between 80-10 mesh were retained. The granules were then filled into containers. The moisture content was measured at 2.97%, the solubility was satisfactory, and the angle of repose was 40.21°.

[0182] Example 5

[0183] The extract was prepared according to the method described in Example 1, and the formulation process was studied. 200g of maltodextrin was added to the extract and mixed thoroughly. 320g of dextrin was used as a base material for one-step granulation until the extract was completely sprayed. 80g of dextrin was dissolved in water, and 10g of colloidal silica was added and mixed thoroughly. This mixture was then sprayed into the granules until granulation was complete. The granules were dried at 60℃ until the moisture content was ≤6%, sieved, and particles between 80-10 mesh were retained. The granules were then filled into containers. The moisture content was measured at 2.74%, the solubility was satisfactory, and the angle of repose was 41.33°.

[0184] Example 6

[0185] The extract was prepared according to the method described in Example 1, and the formulation process was studied. 200g of maltodextrin was added to the extract and mixed thoroughly. 320g of dextrin was used as a base material for one-step granulation until the extract was completely sprayed. 80g of dextrin was dissolved in water, and 20g of colloidal silica was added and mixed thoroughly. This mixture was then sprayed into the granules until granulation was complete. The granules were dried at 60℃ until the moisture content was ≤6%, sieved, and particles between 80-10 mesh were retained. The granules were then filled into containers. The moisture content was measured at 2.68%, the solubility was satisfactory, and the angle of repose was 39.84°.

[0186] Example 7

[0187] The extract was prepared according to the method described in Example 1, and the formulation process was studied. 100g of povidone was added to the extract and mixed thoroughly. 400g of dextrin was used as a base material for one-step granulation until the extract was completely sprayed. 100g of dextrin was dissolved in water, and 10g of colloidal silica was added and mixed thoroughly. This mixture was then sprayed into the granules until granulation was complete. The granules were dried at 60℃ until the moisture content was ≤6%. The granules were sieved, retaining particles between 80-10 mesh, and then filled into containers. The moisture content was measured at 2.93%, the solubility was satisfactory, and the angle of repose was 38.62°.

[0188] Example 8

[0189] The extract was prepared according to the method described in Example 1, and the formulation process was studied. 200g of maltodextrin was added to the extract and mixed thoroughly. 320g of dextrin was used as a base material for one-step granulation until the extract was completely sprayed. 100g of dextrin was dissolved in water, and 5g of colloidal silica was added and mixed thoroughly. This mixture was then sprayed into the granules until granulation was complete. The granules were dried at 60℃ until the moisture content was ≤6%, sieved, and particles between 80-10 mesh were retained. The granules were then filled into containers. The moisture content was measured at 2.66%, the solubility was satisfactory, and the angle of repose was 40.36°.

[0190] Example 9

[0191] The process will be scaled up 100 times and repeated using commercial production equipment. Prescription medicinal materials will be fed into a 3-ton extraction tank. The extract will be concentrated using a double-effect concentrator to a density of 1.05-0.10 (50℃), allowed to stand overnight, centrifuged, and the centrifuged liquid concentrated to a density of 1.15-1.20 (50℃) to form a thick paste. Maltodextrin will be added to the clear paste and mixed thoroughly. A portion of the dextrin will be used as a base material for one-step granulation until the clear paste is completely sprayed. The remaining dextrin will be fully dissolved in water, and colloidal silica will be added and mixed thoroughly. This mixture will continue to be sprayed into the granules until granulation is complete. The granules will be dried at 60℃ until the moisture content is ≤6%, sieved, and particles between 80-10 mesh will be retained. The final mixture will be used for later use. Granulation will be carried out using a granulation filling machine, 12.5g / bag, with a filling weight variation within ±5%. The moisture content will be 2.81%, solubility will be acceptable, and the angle of repose will be 39.12°.

[0192] Comparative Example 1

[0193] The extract was prepared according to the method described in Example 1, and the formulation process was studied. 100g of maltodextrin was added to the extract and mixed thoroughly. 400g of lactose was used as a base material for one-step granulation until the extract was completely sprayed. 100g of lactose was dissolved in water, and 10g of colloidal silica was added and mixed thoroughly. This mixture was then sprayed into the granules until granulation was complete. The granules were dried at 60℃ until the moisture content was ≤6%, sieved, and particles between 80-10 mesh were retained. The granules were then filled into containers. The moisture content was measured to be 3.21%, the solubility was satisfactory, and the angle of repose was 39.54°.

[0194] Comparative Example 2

[0195] The extract was prepared according to the method described in Example 1, and the formulation process was studied. 100g of maltodextrin was added to the extract and mixed thoroughly. 400g of mannitol was used as a base for one-step granulation until the extract was completely sprayed. 100g of mannitol was dissolved in water, and 10g of colloidal silica was added and mixed thoroughly. This mixture was then sprayed into the granules until granulation was complete. The granules were dried at 60℃ until the moisture content was ≤6%, sieved, and particles between 80-10 mesh were retained. The granules were then filled into containers. The moisture content was measured to be 3.05%, the solubility was satisfactory, and the angle of repose was 40.29°.

[0196] Comparative Example 3

[0197] The extract was prepared according to the method described in Example 1, and the formulation process was studied. 100g of maltodextrin was added to the extract and mixed thoroughly. 400g of β-cyclodextrin was used as a base material for one-step granulation until the extract was completely sprayed. 100g of β-cyclodextrin was dissolved in water, and 10g of colloidal silica was added and mixed thoroughly. This mixture was then sprayed into the granules until granulation was complete. The granules were dried at 60℃ until the moisture content was ≤6%, sieved, and particles between 80-10 mesh were retained. The granules were then filled into containers. The moisture content was measured to be 3.52%, the solubility was satisfactory, and the angle of repose was 43.59°.

[0198] Comparative Example 4

[0199] The extract was prepared according to the method described in Example 1, and the formulation process was studied. 100g of maltodextrin was added to the extract and mixed thoroughly. 400g of soluble starch was used as a base material for one-step granulation until the extract was completely sprayed. 100g of soluble starch was dissolved in water, and 10g of colloidal silica was added and mixed thoroughly. This mixture was then sprayed into the granules until granulation was complete. The granules were dried at 60℃ until the moisture content was ≤6%, sieved, and granules between 80-10 mesh were retained. The granules were then filled into containers. The moisture content was measured to be 3.18%, the solubility was satisfactory, and the angle of repose was 40.15°.

[0200] Comparative Example 5

[0201] The extract was prepared according to the method described in Example 1, and the formulation process was studied. 100g of maltodextrin was added to the extract and mixed thoroughly. 400g of dextrin was used as a base material for one-step granulation until the extract was completely sprayed. 100g of dextrin was dissolved in water, and 10g of calcium sulfate was added and mixed thoroughly. This mixture was then sprayed into the granules until granulation was complete. The granules were dried at 60℃ until the moisture content was ≤6%. The granules were sieved, retaining particles between 80-10 mesh, and then filled into containers. The moisture content was measured at 2.91%, solubility was unqualified, and the angle of repose was 41.25°.

[0202] Comparative Example 6

[0203] The extract was prepared according to the method described in Example 1, and the formulation process was studied. 100g of maltodextrin was added to the extract and mixed thoroughly. 400g of dextrin was used as a base material for one-step granulation until the extract was completely sprayed. 100g of dextrin was dissolved in water, and 10g of dicalcium phosphate was added and mixed thoroughly. This mixture was then sprayed into the granules until granulation was complete. The granules were dried at 60℃ until the moisture content was ≤6%. The granules were sieved, retaining particles between 80-10 mesh, and then filled into containers. The moisture content was measured at 2.92%, solubility was unacceptable, and the angle of repose was 41.66°.

[0204] Comparative Example 7

[0205] The extract was prepared according to the method described in Example 1, and the formulation process was studied. 100g of maltodextrin was added to the extract and mixed thoroughly. 500g of dextrin was used as a base material for one-step granulation. The granules were dried at 60℃ until the moisture content was ≤6%. 10g of colloidal silica was added and mixed thoroughly. The mixture was sieved, retaining particles between 80-10 mesh, and then filled into containers. The moisture content was measured at 2.77%, solubility was acceptable, and the angle of repose was 39.22°. Because colloidal silica is lightweight and has small particle size, it easily generates static electricity and agglomerates, causing significant difficulties in the mixing process and making it unsuitable for large-scale production.

[0206] Example 10

[0207] The particle samples obtained in Examples 2-9 and Comparative Examples 1-7 were subjected to high-temperature tests and accelerated tests at 40°C under the same conditions. The high-temperature tests were conducted under the following storage conditions: temperature 50°C ± 2°C and relative humidity 60% ± 5%. Samples were taken at 0, 5, 10, and 30 days to test the appearance of the particles, and the results were compared with those taken at 0 days to assess quality changes. The accelerated tests were conducted under the following storage conditions: temperature 40°C ± 2°C and relative humidity 75% ± 5%. Samples were taken at 0, 1, 2, 3, and 6 months to test the appearance of the particles, and the results were compared with those taken at 0 months to assess quality changes. The results are shown in Tables 1 and 2.

[0208] Table 1. Appearance characteristics of particles sampled at 0 days, 5 days, 10 days, and 30 days.

[0209]

[0210] Table 2. Appearance characteristics of particles sampled in October, January, February, March, and June.

[0211]

[0212]

[0213] As can be seen from the above embodiments and test results, the method of the present invention is simple, easy to operate, and suitable for large-scale production. It can effectively solve the problem of softening and clumping of the granules due to temperature rise during storage, and ensure the quality stability of the granule samples during long-term storage.

[0214] The embodiments of the present invention have been described in detail above. Specific examples have been used to illustrate the principles and implementation methods of the present invention. The descriptions of the embodiments above are only for the purpose of helping to understand the method and core ideas of the present invention. Furthermore, any changes or modifications made by those skilled in the art based on the ideas of the present invention, its specific implementation methods, and its application scope, are all within the scope of protection of the present invention. Therefore, the content of this specification should not be construed as a limitation of the present invention.

Claims

1. A granule formulation comprising a composition of Polygonatum sibiricum, characterized in that, The granules are composed of: 30% to 50% by weight of a dry powder composition, 38% to 58% by weight of a filler, 0.1% to 20% by weight of a binder, and 0.1% to 2% by weight of a flow aid. The composition comprises Polygonatum sibiricum, Lycium barbarum, Chrysanthemum morifolium, and Adenophora stricta. The filler is dextrin; The adhesive is maltodextrin or polyvinylpyrrolidone. The flow aid is colloidal silica.

2. The granules according to claim 1, characterized in that, The dry powder of the composition has a weight percentage of 35% to 46%; Preferably, the filler comprises 38% to 54% by weight; Preferably, the adhesive comprises 5% to 15% by weight; Preferably, the gliding agent has a weight percentage of 0.5% to 1.5%.

3. The granule according to claim 2, characterized in that, The dry powder of the composition has a weight percentage of 36% to 45%; Preferably, the filler comprises 43% to 53% by weight; Preferably, the adhesive comprises about 10% by weight; Preferably, the gliding agent comprises about 1% by weight.

4. The granules according to any one of claims 1 to 3, characterized in that, The mass ratio of the filler, the adhesive, and the flow aid is (50–150):(10–60):(0.5–10); Preferably, the mass ratio of the filler, the adhesive, and the flow aid is (80-100):(20-40):(1-4); Preferably, the filler is not selected from one or more of the following: lactose, mannitol, β-cyclodextrin and soluble starch; Preferably, the gliding agent is not calcium sulfate or calcium hydrogen phosphate; Preferably, the weight of the dry extract powder of the composition = the weight of the clear extract sample after constant weight / the weight of the clear extract sample before drying × the weight of the clear extract.

5. A method for preparing granules according to any one of claims 1 to 4, characterized in that, The preparation method includes the following steps: (1) Prepare the clear paste and an appropriate amount of binder, mix them evenly, spray them into an appropriate amount of filler, granulate, and obtain the first granule. (2) Weigh an appropriate amount of filler, add water to obtain a filler solution, add a flow aid to the filler solution, mix well, and then spray it into the first granule to granulate, thereby obtaining a second granule; and (3) The second granule is dried and sieved to obtain the granule.

6. The preparation method according to claim 5, characterized in that, The granulation method is a one-step granulation method; Preferably, the mass ratio of the adhesive to the water is 0.1 to 0.5, for example, about 0.3; Preferably, the drying endpoint is a moisture content of ≤6%; Preferably, the granules are those that can all pass through a 10-mesh sieve but cannot pass through an 80-mesh sieve; Preferably, the preparation method further includes the step of mixing the sieved particles and then filling them into containers; Preferably, the mass ratio between the filler in step (1) and the filler in step (2) is 2 to 5, for example, 3 to 4.

7. The preparation method according to claim 5, characterized in that, The preparation method of the ointment includes the following steps: (1) Weigh an appropriate amount of the composition, add water and decoct to obtain a decoction or combine the decoctions and filter to obtain a filtrate; (2) Concentrate the filtrate, allow it to stand, and centrifuge to obtain a centrifuged liquid; and (3) Concentrate the centrifuged liquid to obtain a clear extract; Preferably, the composition comprises Polygonatum sibiricum, Lycium barbarum, Chrysanthemum morifolium, and Adenophora stricta; Preferably, the Polygonatum is processed Polygonatum; More preferably, the mass ratio of the prepared Polygonatum sibiricum, the wolfberry, the chrysanthemum and the North American ginseng is (2-4):(1-3):(1-3):(1-3); More preferably, the mass ratio of the prepared Polygonatum sibiricum, the Lycium barbarum, the Chrysanthemum morifolium, and the Adenophora stricta is (2.4–3.6):(1.6–2.4):(1.6–2.4):(1.6–2.4). Preferably, the mass ratio of the prepared Polygonatum sibiricum, the wolfberry, the chrysanthemum, and the North American ginseng is approximately 3: approximately 2: approximately 2: approximately 2; Preferably, the mass ratio of the water to the composition is 6 to 20; More preferably, the mass ratio of the water to the composition is 8 to 12, for example, about 10; More preferably, the decoction is performed 1 to 4 times, for example, 2 times; More preferably, the decocting time is 10 to 60 minutes per cycle, for example, about 30 minutes per cycle; More preferably, the settling time is 8 to 24 hours, for example, about 12 hours; More preferably, the endpoint of the filtrate concentration is when the relative density of the filtrate at a certain temperature is 1.05 to 1.10; More preferably, the endpoint of the centrifugal liquid concentration is that the relative density of the centrifugal liquid at a certain temperature is 1.15 to 1.20; Particularly preferred is the temperature, which is 45–60°C, for example, about 50°C.

8. Use of the granules according to any one of claims 1 to 3 in the preparation of a medicament for the prevention and / or treatment of dry eye syndrome.

9. The use according to claim 8, characterized in that, The composition further includes other pharmaceutically acceptable excipients; Preferably, the other pharmaceutically acceptable excipients are selected from one or more of the following: diluents, wetting agents, disintegrants, inclusion agents, flavoring agents, sustained-release agents, lubricants, dispersants, plasticizers, light-blocking agents, and antioxidants.

10. The use according to claims 8 to 9, characterized in that, The dry eye syndrome mentioned refers to dry eye syndrome caused by environment, age, diabetes, video terminals and / or other eye diseases; Preferably, the composition further comprises one or more drugs and / or extracts for treating dry eye syndrome; Preferably, the drug is selected from one or more of the following: artificial tears, autologous serum, drugs that promote tear secretion, drugs that reduce ocular surface inflammation, and drugs that treat blepharitis; Preferably, the drug that promotes tear secretion is selected from one or more of the following: bromoxynil, pilocarpine, and neostigmine; Preferably, the drug for reducing ocular surface inflammation is cyclosporine A.

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