A sustained-release preparation of glucose and a method for preparing the same

Abstract

The present application provides a glucose sustained-release preparation. By using a special core prescription, the surface of the core is smooth and neat, and the roundness is good, and good sustained-release effect can be achieved after the sustained-release layer is packaged.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, and provides a glucose sustained-release preparation and its preparation method. Background Technology

[0002] Glycogen storage disease (GSD) is a group of disorders caused by congenital enzyme deficiencies that impair glycogen metabolism. Most cases are autosomal recessive, and the incidence varies by ethnicity. Glycogen storage disease is classified as a rare disease, with complex subtypes resulting from differences in the specific enzymes deficient. Accurate national statistics on its incidence are lacking; however, according to European data, the incidence rate in Europe is approximately 1 in 20,000 to 1 in 25,000.

[0003] This is a hereditary disease, with symptoms appearing at birth. As children grow older, they develop significant symptoms of hypoglycemia, such as weakness, sweating, vomiting, seizures, and coma, and may develop ketoacidosis. Due to the gradual accumulation of glycogen, the liver and spleen become enlarged. Affected children experience growth retardation, have no intellectual disability, are short in stature, obese, have pale yellow skin, a distended abdomen, a significantly enlarged and hard liver, poor muscle development, and weakness, especially in the lower limbs. Most children with this condition do not survive to adulthood, often dying from acidosis-induced coma. Mild cases may improve in adulthood.

[0004] Clinically, this disease is mainly treated with dietary guidance and raw cornstarch therapy. The basic principles are to maintain blood glucose at a relatively stable normal level, avoid transient hyperglycemia after meals which would increase glycogen accumulation, and avoid symptoms such as fasting hypoglycemia caused by the patient's inability to mobilize glycogen, so that the child can achieve normal growth and development, and avoid a series of complications caused by blood glucose fluctuations (which can be life-threatening in severe cases). Dietary guidance generally involves feeding small amounts frequently with a high-protein, low-fat, and low-sugar diet to maintain normal blood glucose levels, especially a midnight snack to avoid hypoglycemia the following morning. Other treatments include infection prevention and correction of acidosis. Currently, raw cornstarch therapy is the most common treatment for glycogen storage disease, especially suitable for infants and children. It is estimated that 20,000-50,000 patients in Asia have received this treatment, and approximately 10,000-30,000 in China. The therapeutic principle of raw cornstarch is that it releases glucose slowly and continuously through human digestion, thereby maintaining the patient's blood glucose level.

[0005] However, while raw cornstarch treatment is inexpensive, its administration has several drawbacks: 1) It requires frequent administration, at least four times a day, usually between meals, especially around 3 AM; 2) It has strict requirements, necessitating the use of "raw" cornstarch—cooked starch or cornmeal porridge is unsuitable—and must be taken with cold water, even in winter, which many patients find difficult to accept; 3) The dosage is large, as raw cornstarch expands in volume after being dissolved in cold water, making it difficult for children to consume a therapeutic dose at once; 4) It has poor tolerance, as young children's digestive systems often cannot tolerate it, easily leading to diarrhea; 5) It has poor compliance, requiring long-term medication, but the complex administration method causes inconvenience in daily life; 6) Commercially available raw cornstarch varies greatly in quality, resulting in significant differences in treatment efficacy; 7) Raw cornstarch contains fewer sustained-release active ingredients, thus increasing the dosage for children.

[0006] To address this issue, CN2015110005824 discloses a glucose sustained-release formulation with good sustained-release properties, capable of gradually and slowly releasing glucose over 6 hours with a release rate of 40-70%, thus making it a potential substitute for raw corn starch in the treatment of glycogen storage disease. However, it suffers from problems such as uneven core surface and poor roundness. Summary of the Invention

[0007] To address this problem, the present invention provides a glucose sustained-release formulation. By using a special core formulation, it solves the problems of uneven core surface and poor roundness. After encapsulation with the sustained-release layer, a good sustained-release effect can be achieved.

[0008] In one embodiment of the present invention, the glucose sustained-release formulation comprises a pellet core and a sustained-release layer, wherein the pellet core comprises glucose, a diluent, and a binder.

[0009] In one embodiment of the present invention, the diluent is selected from one or more of microcrystalline cellulose, starch, pregelatinized starch, lactose, mannitol, and dextrin; the binder is selected from one or more of polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, starch paste, dextrin, gum arabic, ethyl cellulose, and konjac flour.

[0010] In one embodiment of the present invention, the glucose is glucose monohydrate, anhydrous glucose, or a mixture of the two.

[0011] In one embodiment of the present invention, the glucose content in the pellet core is 55%-90% by mass, preferably 65%-85%; the total diluent content is 10%-35% by mass, preferably 15%-25%; and the total binder content is 0.5%-8% by mass, preferably 0.5%-5%, more preferably 1%-3%.

[0012] In one embodiment of the present invention, the pellet core includes a core component and a centrifugation packaging component. The first portion of glucose, diluent, and binder used in preparing the core is referred to as the core component, and the second portion of glucose, diluent, and binder used in centrifugation packaging is referred to as the centrifugation packaging component. The glucose, diluent, and binder used in the core component and the centrifugation packaging component may be the same or different.

[0013] In one embodiment of the present invention, the proportions of the core components are as follows: First part: glucose 55%-80%, preferably 60%-70%, more preferably 60%-65%; First part: diluent 15%-40%, preferably 20%-40%, more preferably 30%-40%; First part: binder 0.5%-10%, preferably 1%-5%, more preferably 1%-3%; The proportions of the centrifuged packaging components are as follows: Second part: glucose 70%-95%, preferably 75%-90%, more preferably 80%-85%; Second part: diluent 10%-30%, preferably 10%-25%, more preferably 10%-20%; Second part: binder 0.5%-7%, preferably 1%-5%, more preferably 1%-3%.

[0014] In one embodiment of the present invention, the ratio of the mother nucleus component to the centrifuged package fraction is 1:5-15, preferably 1:10.

[0015] In one embodiment of the present invention, the sustained-release layer has a weight gain of 15%-25% relative to the pellet core, preferably 19-20%.

[0016] In one embodiment of the present invention, the sustained-release layer comprises a sustained-release material, a pore-forming agent, and a plasticizer. The sustained-release material accounts for 70%-80% of the weight of the sustained-release layer, preferably 75%-80%; the pore-forming agent accounts for 12%-18% of the weight of the sustained-release layer, preferably 13%-16%; and the plasticizer accounts for 7%-8% of the weight of the sustained-release layer, preferably 7.5%-8%.

[0017] In one embodiment of the present invention, the sustained-release material is ethyl cellulose, the pore-forming agent is hydroxypropyl cellulose, and the plasticizer is triethyl citrate.

[0018] In one embodiment of the present invention, the raw and excipient composition of the glucose sustained-release formulation is as follows (parts by weight):

[0019]

[0020] In one embodiment of the present invention, the method for preparing the glucose sustained-release formulation is as follows:

[0021] (1) Preparation of the parent nucleus: Glucose was pulverized and sieved, and the undersize portion was kept for later use. A povidone aqueous solution was prepared. Microcrystalline cellulose and glucose were added sequentially to a wet granulator for mixing. The povidone aqueous solution was added, and granulation was performed. After granulation, the wet parent nucleus was sieved, and the undersize portion was collected.

[0022] (2) Preparation of pellet core: Prepare a povidone aqueous solution, weigh corn starch, microcrystalline cellulose and glucose according to the prescription dosage, put them into a wet mixing granulator to mix, and then put them into a centrifuge along with the mother core to make pellet cores. After polishing, dry and sieve for later use.

[0023] (3) Sustained-release coating: Prepare an ethanol solution. Under stirring, add the prescribed amounts of hydroxypropyl cellulose and ethyl cellulose, and continue stirring until the solution becomes clear and transparent. Then add the prescribed amount of triethyl citrate and continue stirring to dissolve; use a fluidized bed to coat the pellet core with a sustained-release film, and dry after coating.

[0024] In one embodiment of the present invention, the glucose sustained-release formulation is used to treat glycogen storage disease. Detailed Implementation

[0025] Example 1

[0026] A glucose pellet core, the raw and auxiliary materials of which are composed of the following by weight:

[0027]

[0028] Its preparation method is as follows:

[0029] (1) Preparation of the parent nucleus: Glucose was pulverized and sieved, and the undersize portion was kept for later use. A povidone aqueous solution was prepared. Microcrystalline cellulose and glucose were added sequentially to a wet granulator for mixing. The povidone aqueous solution was added, and granulation was performed. After granulation, the wet parent nucleus was sieved, and the undersize portion was collected.

[0030] (2) Preparation of pellet core: Prepare a povidone aqueous solution, weigh corn starch, microcrystalline cellulose and glucose according to the prescription dosage, put them into a wet mixing granulator to mix, and then put them into a centrifuge along with the mother core to make pellet cores. After polishing, dry and sieve for later use.

[0031] Determining the roundness and flatness of the pellet core: By observing the surface condition of the pellet core under a high-powered microscope, it can be observed that the pellet core is round and the surface of the pellet core is smooth and flat.

[0032] Example 2

[0033] A glucose sustained-release formulation, the raw and excipient composition of which is as follows (parts by weight):

[0034]

[0035] Its preparation method is as follows:

[0036] (1) Preparation of the parent nucleus: Glucose was pulverized and sieved, and the undersize portion was kept for later use. A povidone aqueous solution was prepared. Microcrystalline cellulose and glucose were added sequentially to a wet granulator for mixing. The povidone aqueous solution was added, and granulation was performed. After granulation, the wet parent nucleus was sieved, and the undersize portion was collected.

[0037] (2) Preparation of pellet core: Prepare a povidone aqueous solution, weigh corn starch, microcrystalline cellulose and glucose according to the prescription dosage, put them into a wet mixing granulator to mix, and then put them into a centrifuge along with the mother core to make pellet cores. After polishing, dry and sieve for later use.

[0038] (3) Sustained-release coating: Prepare an ethanol solution. Under stirring, add the prescribed amounts of hydroxypropyl cellulose and ethyl cellulose, and continue stirring until the solution becomes clear and transparent. Then add the prescribed amount of triethyl citrate and continue stirring to dissolve; use a fluidized bed to coat the pellet core with a sustained-release film, and dry after coating.

[0039] Dissolution test

[0040] Measurement method:

[0041] Dissolution was determined using the paddle method (Chinese Pharmacopoeia 2015 Edition, Part IV, General Chapter 0931, Method II). For the reference stock solution: Accurately weigh 0.273 g of anhydrous glucose reference standard (approximately equivalent to 0.3 g of glucose), place it in a 50 ml volumetric flask, add an appropriate amount of solvent, sonicate to dissolve, and dilute to the mark. Shake well to obtain the reference stock solution. (Glucose 6 mg / ml)

[0042] Reference standard series solutions: Accurately measure 1 ml, 3 ml, 4 ml, 5 ml, and 6 ml of the reference standard stock solution and place them into 100 ml, 50 ml, 50 ml, 50 ml, and 50 ml volumetric flasks, respectively. Dilute to the mark with solvent and shake well to obtain the dissolution reference standard series solutions (0.06 mg / ml, 0.36 mg / ml, 0.48 mg / ml, 0.6 mg / ml, and 0.72 mg / ml).

[0043] Test solution: Sampling points are 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, 12h, and 16h. After sampling, filter the solution, take 3ml of the filtrate, place it in a 10ml volumetric flask, dilute to the mark with acetonitrile, and shake well. Determine the dissolution rate.

[0044] Measurement results:

[0045] Sampling time point (h) 0 0.5 1 2 4 6 8 10 12 16 Dissolution rate (%) 0 0 1 9 52 69 77 81 85 88

Claims

1. A glucose sustained-release formulation, characterized in that, The glucose sustained-release formulation comprises a pellet core and a sustained-release layer, wherein the pellet core comprises glucose, a diluent, and a binder.

2. The glucose sustained-release formulation according to claim 1, characterized in that, The glucose is selected from anhydrous glucose, glucose monohydrate, or a mixture of the two; the diluent is selected from one or more of microcrystalline cellulose, starch, pregelatinized starch, lactose, mannitol, and dextrin; the binder is selected from one or more of polyvinylpyrrolidone, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, starch paste, dextrin, gum arabic, ethyl cellulose, and konjac flour.

3. The glucose sustained-release formulation according to any one of claims 1-2, characterized in that, The mass percentage of glucose in the pellet core is 55%-90%, preferably 65%-85%; the mass percentage of diluent is 10%-35%, preferably 15%-25%; and the mass percentage of binder is 0.5%-8%, preferably 0.5%-5%, more preferably 1%-3%.

4. The glucose sustained-release formulation according to any one of claims 1-3, characterized in that, The micro-pellet core includes a core and a centrifugal packaging component. The core includes a first part of main material, diluent, and binder. The centrifugal packaging component includes a second part of main material, diluent, and binder. The main material, diluent, and binder used in the core and the centrifugal packaging component may be the same or different.

5. The glucose sustained-release formulation according to any one of claims 1-4, wherein the ratio of the core component to the centrifuged packaged component is 1:5-15, preferably 1:

10.

6. The glucose sustained-release formulation according to any one of claims 1-5, characterized in that, The sustained-release layer has a weight gain of 15%-25% relative to the pellet core, preferably 19-20%.

7. The glucose sustained-release formulation according to any one of claims 1-6, characterized in that, The sustained-release layer comprises a sustained-release material, a pore-forming agent, and a plasticizer, wherein the sustained-release material accounts for 70%-80% of the weight of the sustained-release layer, preferably 75%-80%; the pore-forming agent accounts for 12%-18% of the weight of the sustained-release layer, preferably 13%-16%; and the plasticizer accounts for 7%-8% of the weight of the sustained-release layer, preferably 7.5%-8%.

8. The glucose sustained-release formulation according to any one of claims 1-7, characterized in that, The sustained-release material is ethyl cellulose, the pore-forming agent is hydroxypropyl cellulose, and the plasticizer is triethyl citrate.

9. The glucose sustained-release formulation according to any one of claims 1-8, characterized in that, The raw and excipient composition of the glucose sustained-release formulation is as follows (parts by weight):

10. The glucose sustained-release formulation according to any one of claims 1-9, characterized in that, The preparation method of the glucose sustained-release formulation is as follows: (1) Preparation of the mother core: Glucose is crushed and sieved, and the sieve part is taken for later use. Povidone aqueous solution is prepared. Microcrystalline cellulose and glucose are added to a wet granulator in sequence for mixing. Povidone aqueous solution is added and then granulation is performed. After granulation, the wet mother core is sieved and the sieve part is taken. (2) Preparation of pellet core: Prepare a povidone aqueous solution, weigh corn starch, microcrystalline cellulose and glucose according to the prescription dosage, put them into a wet mixing granulator to mix, and then put them into a centrifuge along with the mother core to make pellet cores. After polishing, dry and sieve for later use. (3) Sustained-release coating: Prepare an ethanol solution, add the prescribed amount of hydroxypropyl cellulose and ethyl cellulose while stirring, and continue stirring until the solution is clear and transparent. Then add the prescribed amount of triethyl citrate and continue stirring to dissolve. Use a fluidized bed to coat the pellet core with a sustained-release coating, and dry after coating.

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