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

Abstract

The present application provides a glucose sustained-release suspension which improves the oral sensation and increases the compliance of patients, especially children, by using a special prescription of smooth excipients.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, and provides a glucose sustained-release suspension 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 inherited in an autosomal recessive manner, and the incidence varies by ethnicity. Currently, GSD remains a rare disease. Due to the complex subtypes resulting from differences in the specific enzymes deficient, there are no accurate statistics on its incidence in different countries. According to European data, the incidence rate in Europe is approximately 1 / 20,000 to 1 / 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 serving as a substitute for raw corn starch in the treatment of glycogen storage disease. However, it still suffers from problems such as a heavy granular texture, poor taste, and difficulty in maintaining a stable suspension. Summary of the Invention

[0007] To further improve the taste of this formulation, the present invention provides a glucose sustained-release suspension that improves the taste and ease of administration by using specially formulated smooth excipients, thereby increasing patient compliance, especially in children.

[0008] In one embodiment of the present invention, the glucose sustained-release suspension comprises glucose sustained-release microspheres and a smoothing excipient, wherein the smoothing excipient is colloidal microcrystalline cellulose.

[0009] In one embodiment of the present invention, the ratio of glucose sustained-release microspheres to smoothing excipients is 10:1-50:1, preferably 15:1-30:1, and most preferably 16:1-25:1.

[0010] In one embodiment of the present invention, the smoothing excipient can be packaged together with the sustained-release microspheres or packaged separately.

[0011] In one embodiment of the present invention, the glucose sustained-release microspheres sequentially comprise a core and a sustained-release layer.

[0012] In one embodiment of the present invention, the pellet core comprises glucose, a diluent, and a binder. 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.

[0013] In one embodiment of the present invention, the glucose is glucose monohydrate, anhydrous glucose, or a mixture of the two.

[0014] 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%.

[0015] 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.

[0016] 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%.

[0017] 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%.

[0018] 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%.

[0019] 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.

[0020] In one embodiment of the present invention, the glucose sustained-release suspension formulation comprises the following:

[0021]

[0022]

[0023] or

[0024]

[0025] In one embodiment of the present invention, the method for preparing the glucose sustained-release suspension is as follows:

[0026] (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.

[0027] (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.

[0028] (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.

[0029] (4) Smoothing excipients: Mix the sustained-release microspheres with smoothing excipients or package them separately to obtain the finished product.

[0030] In one embodiment of the present invention, the glucose sustained-release suspension is used to treat glycogen storage disease. Detailed Implementation

[0031] Example 1

[0032] The formulation of glucose sustained-release microcapsules is as follows:

[0033]

[0034] Its preparation method is as follows:

[0035] (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.

[0036] (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.

[0037] (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.

[0038] Example 2

[0039] The formulation uses different smoothing excipients and its composition is as follows:

[0040]

[0041] Add the above-mentioned smoothing excipients to a beaker, add 60ml of warm water to dissolve, then add 30g of the sustained-release microspheres from Example 1, stir to suspend, and obtain the finished product.

[0042] Smoothing effect evaluation

[0043] (1) Pour the finished product out of the beaker and observe the amount of finished product pellets remaining at the bottom of the beaker.

[0044] (2) Three volunteers tasted the finished product.

[0045]

[0046]

Claims

1. A glucose sustained-release suspension, characterized in that, The glucose sustained-release suspension comprises glucose sustained-release microspheres and a smoothing excipient, wherein the smoothing excipient is colloidal microcrystalline cellulose.

2. The glucose sustained-release suspension as described in claim 1, characterized in that, The ratio of glucose sustained-release microspheres to smoothing excipients is 10:1-50:1, preferably 15:1-30:1, and most preferably 16:1-25:

1.

3. The glucose sustained-release suspension according to any one of claims 1-2, characterized in that, The glucose sustained-release microspheres sequentially comprise a core and a sustained-release layer.

4. The glucose sustained-release suspension according to any one of claims 1-3, characterized in that, The pellet core comprises glucose, a diluent, and a binder, wherein the glucose is selected from anhydrous glucose, glucose monohydrate, or a mixture thereof; the diluent is selected from one or more of microcrystalline cellulose, starch, pregelatinized starch, lactose, mannitol, and dextrin; and 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.

5. The glucose sustained-release suspension according to any one of claims 1-4, 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%.

6. The glucose sustained-release suspension 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 suspension 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. 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 suspension 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 suspension according to any one of claims 1-8, characterized in that, The raw and auxiliary materials composition of the glucose sustained-release suspension, by weight, is as follows: or 10. The glucose sustained-release suspension according to any one of claims 1-9, characterized in that, The glucose sustained-release suspension is prepared 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. (4) Smoothing excipients: Mix the sustained-release microspheres with smoothing excipients or package them separately to obtain the finished product.

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