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CN-121971409-A - Controlled release preparation and application thereof in diabetic osteoporosis

CN121971409ACN 121971409 ACN121971409 ACN 121971409ACN-121971409-A

Abstract

The invention discloses a controlled release preparation and application thereof in preparing a medicament for treating diabetic osteoporosis, wherein the controlled release preparation comprises the following components of englitjing, alendronate sodium, a barrier coating material, an enteric controlled release coating material, a filler, a disintegrating agent and a lubricant; the enteric controlled release coating material comprises a pH sensitive modifier. The preparation process includes the steps of preparing enteric sodium alendronate pellet, mixing and forming. The preparation has reduced gastrointestinal reaction and improved stability.

Inventors

  • LIU MINGMING
  • XU HAIYAN

Assignees

  • 连云港市第二人民医院(连云港市临床肿瘤研究所)
  • 徐州医科大学

Dates

Publication Date
20260505
Application Date
20260205

Claims (10)

  1. 1. The controlled release preparation is characterized by comprising the following components of enggliflozin, alendronate sodium, a release coating material, an enteric controlled release coating material, a filler, a disintegrating agent and a lubricant, wherein the enteric controlled release coating material comprises a pH sensitive regulator.
  2. 2. The compound controlled release preparation according to claim 1, wherein, Engliflozin with release amount of more than or equal to 80% in 30min under the condition of pH1.2 dissolution medium; the alendronate sodium is an enteric pellet multiparticulate drug release system, the release amount of which is less than or equal to 10% in 120min under the dissolution medium with the pH of 1.2 and more than or equal to 80% in 30min under the dissolution medium with the pH of 4.5-5.5.
  3. 3. The controlled release formulation according to claim 1, wherein the dosage of the unit preparation of the active ingredient enggliflozin is 5-20mg and the dosage of the unit preparation of alendronate sodium is 10-30mg.
  4. 4. The controlled release formulation of claim 1, wherein the release coating material comprises a film forming material, a plasticizer and an anti-sticking agent, wherein the film forming material is hypromellose or hydroxypropyl cellulose, the plasticizer is polyethylene glycol 400, and the anti-sticking agent is talc.
  5. 5. The compound controlled release preparation according to claim 1, wherein the enteric controlled release coating material is a mixture of hypromellose phthalate, triethyl citrate and micro-powder silica gel, and the mixture comprises the following components in parts by weight: 80-95 parts of hydroxypropyl methylcellulose phthalate; 5-15 parts of triethyl citrate; 1-10 parts of micro silica gel; 0.5-3 parts of pH sensitive regulator.
  6. 6. The controlled release formulation of claim 1 or 5, wherein the pH sensitive modifier is at least one of succinic acid, fumaric acid, adipic acid.
  7. 7. The controlled release formulation of claim 1, wherein the filler is at least one of microcrystalline cellulose, lactose, mannitol, sorbitol, maltodextrin, isomalt, starch, pregelatinized starch, dibasic calcium phosphate, calcium sulfate, and calcium carbonate; At least one of the disintegrating agent cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, cross-linked povidone, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose; the lubricant is at least one of magnesium stearate, talcum powder and sodium stearyl fumarate.
  8. 8. A method of preparing a controlled release formulation according to claim 1, comprising the steps of: The first step is that alendronate sodium enteric-coated pellets are prepared S1, preparing a soft material: Dry mixing alendronate sodium, filler and disintegrating agent in high-efficiency wet granulator until uniformity, and adding purified water to wet mix to obtain soft material; s2, preparing the pill-containing medicine by using an extrusion spheronizer and a fluidized bed: the sieve opening of the extruder is 1.0mm, the extrusion speed is 30rpm, the rotating speed of a turntable of the rounding machine is 500-1000rpm, the rounding time is 2-5min, the air inlet temperature of the fluidized bed is 40-70 ℃ and the air inlet quantity is 5-20HZ for drying; s3, coating a release coating: Dissolving a release coating material in purified water to obtain release coating solution with the solid content of 10-20%, and performing bottom spray coating by using a fluidized bed, wherein the weight of the release coating is increased by 3-10% of the weight of the pill-containing core; The air inlet temperature of the fluidized bed is 40-70 ℃, the air inlet quantity is 5-15m 3 /h, the inner diameter of the nozzle is 0.5-1.0mm, the liquid spraying speed is 3-8mL/min, and the atomization pressure is 0.2-0.5MPa; S4, enteric coating: dissolving enteric controlled release coating material in ethanol water solution to obtain enteric coating solution with solid content of 5-10%, and performing bottom spray coating with fluidized bed to obtain enteric coating with weight gain of 10-30% of the weight of isolated pill core; The air inlet temperature of the fluidized bed is 40-70 ℃, the air inlet quantity is 5-15m 3 /h, the inner diameter of the nozzle is 0.5-1.0mm, the liquid spraying speed is 3-8mL/min, and the atomization pressure is 0.2-0.5MPa; Second step, total mixing Uniformly mixing alendronate sodium enteric-coated pellets, englitazone, a filler, a disintegrating agent and a lubricant to obtain a total mixed intermediate; third step, forming And (3) performing formulation process molding on the total mixed intermediate in the second step to obtain the controlled release preparation of the englitazone alendronate sodium.
  9. 9. The method of controlled release formulation according to claim 8, wherein the shaped dosage form is one of a tablet, a capsule, and a granule.
  10. 10. Use of a controlled release formulation according to claim 1 for the manufacture of a medicament for the prevention or treatment of Diabetic Osteoporosis (DOP).

Description

Controlled release preparation and application thereof in diabetic osteoporosis Technical Field The invention belongs to the field of pharmaceutical preparations, and in particular relates to a controlled release preparation of Enagliflozin alendronate sodium and application thereof in preparation of a medicament for treating diabetic osteoporosis. Background Diabetic osteoporosis (diabetic osteoporosis, DOP) is a systemic, metabolic bone disease that is susceptible to fracture such as reduction of bone mass per unit volume, change of microstructure of bone tissue, reduction of bone strength, increase of bone fragility, etc. which are complicated with diabetes, and is one of important complications of diabetes in skeletal system. Severely affects the quality of life of the patient and places a severe economic burden on society. The cause of osteoporosis due to diabetes is mainly twofold: 1. Increased excretion and bone loss Typical symptoms of diabetes are polydipsia, diuresis, and in this physical change, a large amount of calcium and phosphate substances are discharged from the body along with urine. If the necessary calcium supplement is lacking at this time, the negative balance of the calcium of the patient is caused, a series of hormone level changes are then initiated, the osteolytic effect is enhanced, and finally the bone decalcification and the osteoporosis are caused. 2. Insufficient calcium absorption and reduced bone synthesis Active vitamin D can increase the absorption of calcium in vivo, and the level of active vitamin D in the diabetic patients is often lower, which affects the absorption of minerals such as calcium, phosphorus and the like in intestinal tracts. The decrease in insulin sensitivity typical of type 2 diabetes is more damaging to bone than snowy frosting, which affects the normal metabolism of protein and reduces bone matrix synthesis. All these factors are combined together, which ultimately results in reduced bone matrix, trabecular destruction, and reduced bone density in diabetics, becoming a high risk group for the onset of osteoporosis. Alendronate sodium has been clinically popularized and applied as a bone metabolism regulator. The amino bisphosphonate has strong affinity with the intra-osseous hydroxyapatite, can enter into bone matrix hydroxyapatite crystals, can inhibit the activity of the osteoclast when the osteoclast is dissolved into the crystals, can indirectly inhibit the bone resorption through the osteoblast, has obvious curative effect on treating DOP patients by using the alendronate sodium, can effectively improve the bone metabolism of the DOP patients and promote the increase of bone density level. However, alendronate sodium has a special chemical structure, contains two phosphate groups (-PO 3H 2), is converted into a free acid form at low pH, and can easily adhere to the inner walls of esophagus and stomach after swelling in water, and released free acid can stimulate mucous membrane cells. Therefore, the clinical application of the alendronate sodium at present has a plurality of limitations, for example, the dosage of the current specifications of the commercial alendronate sodium tablet products clearly requires at least 30 minutes before breakfast of patients to empty stomach and take the alendronate sodium with a large amount of warm boiled water, and the patients need to stand and lie in bed immediately after taking the alendronate sodium, which possibly causes esophageal irritation or ulcerative esophagitis. In order to solve the problems and facilitate clinical patients to take the medicine, the alendronate sodium is developed and designed to be 70mg in one day and taken once a week from 10mg in one day. Although the design reduces the difficulty of frequent drug administration, the risk of impact effect of single high dose is not neglected, short blood concentration peak value can be caused, the risk of acute phase reaction is increased, and local gastrointestinal irritation is more concentrated. For example, patent CN1582949A, CN101756932A, CN101756931A, CN104840444A, CN101632680A, CN101601662A, CN101623292 discloses a technical scheme for preparing alendronate sodium or enteric-coated preparations containing alendronate sodium, the conventional enteric-coated preparations are generally positioned at the duodenal horizontal part (pH about 6.5) or jejunum (pH 6.5-7.5) at the release position, and have delayed onset of action and large fluctuation of bioavailability. In view of the foregoing, there is a great clinical need for alendronate sodium that has high patient compliance and that can rapidly release the drug at a specific duodenal onset (pH of about 4.5-6) to increase or provide stable bioavailability, while reducing gastrointestinal irritation. Disclosure of Invention The inventor researches find that the pH sensitive regulator is added into the enteric coating material, so that the rapid and accurate release of alendronate sodium in