CN1660064A - Nateglinide self-emulsifying drug delivery system - Google Patents

Abstract

A self-emulsifying medicine releasing system of Nagelienai features that the Nagelienain in molecular form exists in a self-emulsifying medicine releasing system for automatically emulsifying it in human body for easy absorption.

Description

Nateglinide self-emulsifying drug delivery system

[technical field]

The invention relates to the technical field of medicine, and relates to a new oral drug delivery system for nateglinide, that is, a self-emulsifying drug delivery system for nateglinide.

[Background technique]

Nateglinide is the second Meglitinide drug after repaglinide. It is a derivative of phenylalanine. The Chinese chemical name is N-(trans-4-isopropylcyclohexanecarbonyl)-D- Phenylalanine, the English name is Nateglinide, the molecular formula is C ₁₉ H ₂₇ NO ₃ , and the molecular weight is 317.43. According to literature reports, compared with repaglinide and traditional sulfonylurea drugs, nateglinide has the following advantages:

(1) The mechanism of action is novel

This product closes the ATP-dependent K+ channel on the pancreatic B cell membrane, causing Ca2+ influx, increasing the intracellular Ca2+ concentration, thereby stimulating insulin secretion.

(2) Fast onset and short duration of action

This product only stimulates the pancreas to secrete insulin quickly and briefly when eating, and has a quick onset and a short duration of action, while traditional oral antidiabetic drugs continue to stimulate insulin secretion, and the stimulation is excessive, especially between meals , often make patients feel hungry, and even encourage patients to take snacks between meals when using sulfonylurea drugs, so that excess insulin can be metabolized. This extra eating causes patients to gain weight and they are often obese to begin with.

(3) Definite curative effect

This product has completed clinical research in the United States and Japan successively. According to reports, 80 patients with type II diabetes mellitus were subjected to a randomized double-blind controlled clinical study. The results showed that the improvement rate of postprandial blood glucose level was 88.8%. Reduced to 48.5mg/dL, glycosylated hemoglobin value decreased to 0.69%: after 1 year of continuous treatment with this product, the blood sugar level was stable.

(4) Flexible administration

Take the medicine before meals each time, one less dose will be taken if one less meal is taken, and one more dose will be taken if one extra meal is added. You don't have to strictly abide by the meal time, which is very convenient. The follow-up survey of more than 2,500 patients abroad shows that the patients are very satisfied with the flexibility of the administration of this product. 77% of the patients feel that being able to postpone or skip a meal just reduces the burden, and more than 95% of the patients Choose to continue taking this product.

(5) Excellent pharmacokinetic properties

This product is rapidly absorbed and eliminated in the body, and there is no accumulation in the body. The peak blood concentration of this product is about 0.5 hours after oral administration of 60 mg, and the half-life is about 1 hour. About 95% is excreted through feces. Diabetics with insufficiency or kidney disease will be very beneficial.

(6) Known as "in vitro pancreas"

The effect of this product is mainly focused on reducing postprandial hyperglycemia. Blood sugar can promote nateglinide to stimulate insulin release. In the presence of glucose, nateglinide can promote insulin secretion by about 50% compared with that without glucose, so its effect is It's like an "external pancreas" that only provides insulin when needed.

(7) First-line therapeutic drugs for patients with early and mild diabetes

For mild patients whose blood sugar levels cannot be effectively controlled by diet or exercise alone, other anti-diabetic drugs are often used as an adjuvant, and once the drug is used, it is very easy to induce hypoglycemia. Because of the above characteristics, nateglinide is the first-line treatment drug. The best choice, it can be used as a regular hypoglycemic drug for such patients.

For patients who only rely on diet or exercise to control blood sugar levels, faced with all kinds of delicious temptations, they often dare not eat or go on excessive diets because of fear of blood sugar rise, which not only causes strong psychological pressure for these patients, but also easily causes Malnutrition will cause different degrees of harm to the body. For such patients, this product can be taken in time to avoid the occurrence of the above situation.

(8) Has a unique effect on glucagon secretion

In vitro studies have shown that the secretion of this product on glucagon is different from that of sulfonylureas. When nateglinide perfusion is over, the insulin level quickly returns to normal, and the glucagon level increases, which is no different from the physiological value. However, after glibenclamide stopped perfusion, the insulin level continued to increase, and the secretion of glucagon continued to decrease, which was significantly lower than the physiological value. The above results show that the effect of this product on stimulating the release of glucagon is rapid and short-lived, and quickly returns to normal. This effect makes the patient recover quickly even if hypoglycemia occurs after taking the drug.

(9) Good security

The comparative study between this product and sulfonylurea drugs shows that the incidence of hypoglycemia is about 50% lower than that of the latter, and the time of hypoglycemia is also different. The hypoglycemia of this product mainly occurs during the day, while gliben Urea usually occurs after midnight, and hypoglycemia at night is particularly dangerous, because patients cannot detect its occurrence in time. Long-term use of this product will not cause drug-induced hypoglycemia caused by drug accumulation.

Although nateglinide has the above advantages, its special physical and chemical properties greatly limit its efficacy. (1) The drug is almost insoluble in water, and its oral bioavailability is low. Food affects the absorption of this product, which can reduce the bioavailability of this product; (2) Up to now, nateglinide has been found to have B, H There are five crystal forms including , L, S and VH, and the clinically effective crystal form is only H. The existence of its polymorphic form is extremely harsh on the synthesis and preparation process of nateglinide. Moreover, the factors that affect the transformation of the crystal form include: the refining or recrystallization method of the drug; the pulverization and grinding process in the preparation process; the solvent in the wet granulation; the temperature and drying method; tablet pressure and many other factors will affect the crystal form. change. Even if the effective crystal form is selected when feeding, it is difficult to ensure the content of the effective crystal form in the preparation obtained after a series of preparation processes. These properties of nateglinide make it more complicated to prepare the H-type crystal that meets the requirements, and the production cost increases. In order to ensure that nateglinide does not undergo crystal transformation during the preparation process, wet If the dry granulation process is used, the nateglinide raw material has high static electricity, poor fluidity, and the material is difficult to mix, which brings a lot of inconvenience to the preparation production. Even if the dry granulation process is adopted, the nateglinide is crushed After processes such as , pressurization, etc., there is also the possibility of crystal transformation.

[Content of the invention]

In order to overcome the above-mentioned shortcomings of nateglinide, the present invention adopts a special preparation technology to prepare it into a new type of preparation—self-emulsifying drug delivery system. The nateglinide exists in the drug delivery system in a molecular state, and after taking the drug, it is spontaneously emulsified in the body to form an emulsion with a particle size below 100nm or 2-2000nm, thereby promoting the absorption of the drug. The drug delivery system can fundamentally solve the above-mentioned shortcomings of nateglinide. At the same time:

(1) Improve the bioavailability of nateglinide;

(2) Eliminate the influence of food on drug absorption;

(3) Solve many problems caused by the polymorphic form of nateglinide;

(4) Purposes such as reducing production costs.

Nateglinide self-emulsifying drug delivery system, including nateglinide and auxiliary materials, the auxiliary materials contain emulsifier, co-emulsifier, oil phase or two of them, and the weight ratio of each component is: nateglinide 1-50 %, 50-99% of auxiliary materials.

The possible weight ratios of the following substances as auxiliary materials in the drug delivery system are: emulsifier 0-95%, co-emulsifier 0-95%, oil phase 0-50%.

The nateglinide oral self-emulsifying drug delivery system is a uniform, transparent solution containing the drug formed by the oil phase, non-ionic surfactants and co-emulsifiers. In the presence of surfactants, spontaneous emulsification forms nanoemulsions with a particle size of 2-2000 nm or less than 100 nm, which is called self-emulsifying drug delivery systems (SMEDDS). In the self-emulsifying drug delivery system of the present invention, nateglinide is dissolved in the content of the drug delivery system in molecular form, so there is no influence of polymorphism on nateglinide. Therefore, no matter what crystal form of nateglinide is fed, as long as it is dissolved in an appropriate solvent, it can be made into an effective preparation. Therefore, the requirements for the production process and preparation process of nateglinide can be greatly reduced, and the production cost can be further reduced significantly.

It can be seen that the research and development of nateglinide self-emulsifying drug delivery system not only has strong social benefits, but also has strong economic benefits.

[Description of drawings]

Fig. 1 is the dissolution curve chart of different dosage forms of nateglinide in aqueous medium.

Fig. 2 is a graph showing the dissolution curves of different dosage forms of nateglinide in pH 1.0 buffer.

Fig. 3 is a graph showing the dissolution curves of different dosage forms of nateglinide in pH 3.0 buffer.

[Detailed ways]

1. Establishment of basic prescription

(1) Selection of oil phase

The mass fraction (w/w) of oil phase in the self-emulsifying drug delivery system involved in the present invention is generally 0～50%, in the present invention requires the medicine that can dissolve prescription quantity with less oil phase, and at low temperature There will be no drug precipitation under storage conditions, and it will be easily emulsified by the emulsifier in the prescription when it meets water. The oil phase used in the present invention has improved soybean oil, peanut oil, safflower oil, olive oil and other natural vegetable oils and fatty acid esters, especially medium chain length fatty acid glycerides ( medim-chain glyceride). In addition to the commonly used orally edible vegetable oils, the following oils can also be used in the present invention:

Arlacel 80(HLB＝4.3) Sorbitan Oleate

Arlacel 86 (HLB＝2.8) Glyceryl Oleate: Propylene Glycol (90:10)

Capmul MCM (HLB＝5.5～6.0) Coconut Oil C8/C10 Monoglyceride or Diglyceride

Captex 200(oil) Coconut Oil C8/C10 Propylene Glycol Diester

Captex 355(oil) Coconut Oil C8/C10 Triglycerides

Miglyol 812(oil) Coconut Oil C8/C10 Triglycerides

Myvacet(oil) Purified acetylated monoglycerides

Myverol 18-92 (HLB=3～7) Purified sunflower oil monoglyceride (containing 90% linoleic acid glyceride)

Soybean oil is mainly triglycerides containing oleic acid (25%) and linoleic acid (54%)

Peceol(HLB＝3) Glyceryl Oleate

Maisine (HLB＝3) Glyceryl Linoleate

Gelucire 44/14(HLB＝14) Macrogol Glyceryl Laurate

(2) Choice of emulsifier

High HLB nonionic emulsifiers are used in the present invention. The strong hydrophilicity of the emulsifier is necessary for the immediate formation of oil-in-water emulsion droplets and the diffusion of the self-emulsion in a water-soluble environment, which can make the self-emulsification process faster. Emulsifiers are amphiphilic, and they themselves can dissolve a relatively large amount of hydrophobic drugs, which can prevent drug deposition in the gastrointestinal tract and prolong the dissolved state of drug molecules, which is very important for effective absorption. What selected among the present invention is different kinds of emulsifiers such as liquid or solid ethoxylated polyoxyethylene glycerides, polyoxyethylene oleate, Tween80. Its dosage is 0-95%. In addition, the following emulsifiers are also applicable in the nateglinide self-emulsifying drug delivery system involved in the present invention:

Ophase 31(HLB＝4.0) Liquid Lecithin

Cremophor EL (HLB＝13.5) Polyoxyethylene castor oil

Labrafac CM10(HLB＝10) Coconut Oil C8/C10 Polyethylene Glycerides

Labrafil M 1944 CSD (HLB＝3～4) Mainly almond oleic acid macrogol glyceride

Labrafil M 2125 CS (HLB＝3～4) Mainly is macrogol glyceride of almond oleate

Tagat TO (HLB＝11.3) Polyoxyethylene (25) glycerol trioleate

Tween 80 (HLB＝11.0) Polyoxyethylene (20) Sorbitan Oleate

Labrasol (HLB＝14) Macrogol-8-Glyceryl Caprylate/Caprate

(3) Selection of co-emulsifier

The co-emulsifier applicable to the present invention is ethylene glycol monoethyl ether (transcutol), ethanol, propylene glycol, dry oil, polyethylene glycol (molecular weight is at 200-600), propylene carbonate (propylene carbonate), glycerol furfural, dimethyl Isosorbide or a mixture of the above substances in any proportion.

(4) Basic prescription of nateglinide self-emulsifying drug delivery system

Nateglinide 30

Oil phase 100

Emulsifier 150

Co-emulsifier 150  

A total of 1,000 softgels or capsules were made

Note: 1. The amount of nateglinide contained in each capsule in the prescription can be increased or decreased according to the actual situation, and the range is not limited.

2. The ratio of nateglinide raw material: oil phase: emulsifier: co-emulsifier in the prescription is any ratio within the range of 1:0-50:0-200:0.5-200.

3. The oil phase used in the prescription can be soybean oil, peanut oil, safflower oil, olive oil, medium-chain fatty acid glycerides with chain length between C8～C10, sorbitol oleate, glyceryl oleate/propylene glycol ( 90/10), coconut oil C8/C10 mono- or diglycerides, coconut oil C8/C10 propylene glycol diesters, coconut oil C8/C10 triglycerides, coconut oil C8/C10 triglycerides, purified acetylated monoglycerides Esters, Purified Sunflower Oil Monoglycerides (90% Glyceryl Linoleate), Triglycerides Containing Oleic (25%) and Linoleic (54%), Glyceryl Oleate, Glyceryl Linoleate, Poly Ethylene glycol laurate, etc., any one or a mixture of two or more in any proportion.

4. The emulsifier used in the prescription can be ethoxylated polyoxyethylene glyceride, polyoxyethylene oleate, Tween80, lecithin, polyoxyethylene castor oil, coconut oil C8/C10 polyethylene glycol glyceride, almond Macroglyceryl Oleate, Macroglycerol Almond Oleate, Polyoxyethylene(25) Trioleate, Polyoxyethylene(20) Sorbitan Oleate, Macrogol-8- Glyceryl caprylic acid/capric acid ester, etc., any one or a mixture of two or more in any ratio.

5. The co-emulsifier used in the prescription can be ethylene glycol monoethyl ether (transcutol), ethanol, propylene glycol, dry oil, polyethylene glycol (molecular weight 200-600), propylene carbonate (propylene carbonate), glycerin furfural , dimethyl isosorbide, etc., any one or a mixture of two or more in any proportion.

Embodiment one:

The composition of the prescription is as follows: (g)

Naglinide 30

Ethylene glycol monoethyl ether (Transcutol P) 180

Tween80 100

Ethyl oleate 20  

A total of 1000 soft capsules were made

Preparation process: Weigh the prescribed amount of nateglinide, add the prescribed amount of ethylene glycol monoethyl ether, Tween80, shake it in a constant temperature shaking bath at 40°C and 100 rpm for about 1 hour to dissolve it, and then add the prescribed amount Amount of ethyl oleate, stirred evenly, and compressed into capsules after the liquid medicine dropped to room temperature.

Take 2 drops of the content of nateglinide self-emulsifying soft capsule in 100ml distilled water, stir it clearly, and measure the particle size of the milk droplet with a laser particle size analyzer: the effective particle size is 54.7nm, and the polydispersity is 0.103.

Embodiment two:

The composition of the prescription is as follows: (g)

Naglinide 30

Laborosol 108

Ethylene glycol monoethyl ether (Transcutol P) 185

Maisine 35-1 27  

A total of 1000 soft capsules were made

Preparation process: Weigh the prescribed amount of nateglinide, add the prescribed amount of Laborosol and ethylene glycol monoethyl ether, shake it in a constant temperature shaking bath at 40°C and 100 rpm for about 1 hour to dissolve it, and then add the prescribed amount Amount of Maisine 35-1, stirred evenly, and pressed into capsules after the liquid drops to room temperature.

Take 2 drops of the content of nateglinide self-emulsifying soft capsule in 100ml distilled water, stir it clearly, and measure the particle size of the milk droplet with a laser particle size analyzer: the effective particle size is 62.8nm, and the polydispersity is 0.098.

Embodiment three:

The composition of the prescription is as follows: (g)

Naglinide 30

Laborosol 117

Ethylene glycol monoethyl ether (Transcutol P) 190

Ethyl oleate 43  

A total of 1000 soft capsules were made

Preparation process: Weigh the prescribed amount of nateglinide, add the prescribed amount of Laborosol, Tween80, shake it in a constant temperature shaking bath at 40°C and 100 rpm for about 1 hour to dissolve it, and then add the prescribed amount of ethyl oleate , stirred evenly, and pressed into capsules after the medicinal solution dropped to room temperature.

Embodiment four:

The composition of the prescription is as follows: (g)

Naglinide 30

Dimethylisosorbide 660

Tween80 135

Miglyol 812 45  

A total of 1000 soft capsules were made

Preparation process: Weigh the prescribed amount of nateglinide, add the prescribed amount of dimethyl isosorbide, Tween80, shake it in a constant temperature shaking bath at 40°C and 100 rpm for about 1 hour to dissolve it, and then add the prescribed amount Miglyol 812, stirred evenly, and compressed into capsules after the medicine solution dropped to room temperature.

Embodiment five:

The composition of the prescription is as follows: (g)

Naglinide 30

Ethylene glycol monoethyl ether (Transcutol P) 202

Tween 80 112

Labrasol 86

Maisine 35-1 40  

A total of 1000 soft capsules were made

Preparation process: Weigh the prescribed amount of nateglinide, add the prescribed amount of ethylene glycol monoethyl ether, Laborosol, Tween 80, shake it in a constant temperature shaking bath at 40°C and 100 rpm for about 1 hour to dissolve it, Then add the prescribed amount of Maisine 35-1, stir evenly, and compress it into capsules after the liquid drops to room temperature.

Embodiment six:

The composition of the prescription is as follows: (g)

Naglinide 3

LABRAFIL M 1944 CS 50

LABRASOL 47  

A total of 100 soft capsules were made

Preparation process: Weigh the prescribed amount of nateglinide, add the prescribed amount of LABRAFIL M1944 CS and Laborosol, shake in a constant temperature shaking bath at 40°C and 100 rpm for about 1 hour to dissolve, stir evenly, and wait for the liquid to drop Compressed into capsules after reaching room temperature.

Embodiment seven:

The composition of the prescription is as follows: (g)

Naglinide 3

Tween 80 90

Maisine 35-1 7 7

A total of 100 soft capsules were made

Preparation process: Weigh the prescribed amount of nateglinide, add the prescribed amount of Tween 80, shake Maisine35-1 in a constant temperature shaking bath at 40°C and 100 rpm for about 1 hour to dissolve, stir evenly, and wait for the liquid to drop Compressed into capsules after reaching room temperature.

Embodiment eight:

The composition of the prescription is as follows: (g)

Naglinide 30

Ethylene glycol monoethyl ether (Transcutol P) 100

Tween 80 100

A total of 100 soft capsules were made

Preparation process: Weigh the prescribed amount of nateglinide, add the prescribed amount of ethylene glycol monoethyl ether (Transcutol P), Tween 80, shake in a constant temperature shaking bath at 40°C and 100 rpm for about 1 hour to make it Dissolve, stir evenly, and compress into capsules after the liquid medicine drops to room temperature.

2. Dissolution study of nateglinide self-emulsifying drug delivery system

The prepared nateglinide self-emulsifying drug delivery system was compared with the nateglinide tablets and capsules for dissolution test.

Dissolution test method:

According to "Chinese Pharmacopoeia" 2000 edition two appendix XC method 2, respectively use water, pH1.0 and pH3.0 buffer solution as dissolution medium, rotating speed 50 rev/min, sample 2ml respectively at different time points, take the filtrate Carry out the measurement while replenishing an equal volume of isothermal medium.

test methods:

Adopt high performance liquid chromatography to measure sample, chromatographic condition is:

Chromatographic column: Octadecylsilane bonded silica gel column Inertsil ODS-3, 250×4.6mm, 5μm

Mobile phase: Phosphate buffer solution (dissolve 8.5g dipotassium hydrogen phosphate in 1000ml water, adjust acidity to 6.5 with phosphoric acid)-methanol (35:75)

Detection wavelength: 210nm

Column temperature: 40°C

Flow rate: 1.0ml/min

test results:

The cumulative dissolution percentage of nateglinide at each time point is plotted against time, and the dissolution curves of denateglinide self-emulsifying drug delivery system and comparative dosage forms in different media are shown in Figures 1-3.

It can be seen from Figures 1-3 that the dissolution rate and the dissolution degree at each time point of the nateglinide self-emulsifying drug delivery system of the present invention are much higher than other dosage forms. It can be concluded that the self-emulsifying drug delivery system of nateglinide involved in the present invention has obvious in vitro release advantages compared with the existing preparations, thus, the absorption rate and degree of absorption of nateglinide in the body will inevitably be improved. ; At the same time, nateglinide exists in the molecular state in the self-emulsifying drug delivery system, and there is no polymorph problem.

Claims (10)

1. Nateglinide self-emulsifying drug delivery system, including nateglinide and auxiliary materials. The auxiliary materials contain emulsifier, co-emulsifier, oil phase or two of them. The weight ratio of each component is: nateglinide 1 ～50%, auxiliary material 50～99%. 2. The nateglinide self-emulsifying drug delivery system according to claim 1, characterized in that the emulsifier is 0-95%, the co-emulsifier is 0-95%, and the oil phase is 0-50%. 3. The nateglinide self-emulsifying drug delivery system according to claim 1 or 2, characterized in that the emulsifier is a nonionic surfactant. 4. The nateglinide self-emulsifying drug delivery system according to claim 3 is characterized in that the emulsifier can use lecithin, polyoxyethylene (hydrogenated) castor oil, Labrafac CM 10, Labrafil M1944 CSD, Labrafil M 2125 CS , Tagat TO, Tween 80, Labrasol, or a mixture of two or more of these substances. 5. by claim 1 or 2 described nateglinide self-emulsifying drug release system, it is characterized in that co-emulsifier can use ethanol, propylene glycol, glycerol, polyethylene glycol (molecular weight is at 200-600), propylene carbonate Propylene carbonate, transcutol, glycerol furfural, dimethyl isosorbide, or a mixture of two or more of these substances. 6. The nateglinide self-emulsifying drug delivery system according to claim 1 or 2, characterized in that the oil phase is natural vegetable oil or vegetable oil or fatty acid ester after structural modification and hydrolysis. 7. The nateglinide self-emulsifying drug delivery system according to claim 6 is characterized in that the fatty acid ester is a medium chain fatty acid glyceride with a chain length between _C8 ～ _C10 , Arlacel 80, Arlacel86, Capmul MCM, Captex 200(oil), Captex 355(oil), Miglyol 812(oil), Myvacet(oil), Myverol 18-92, Glyceryl Oleate, Glyceryl Linoleate, Macrogol Laurate, Ethyl oleate, ethyl linoleate, etc. 8. The nateglinide self-emulsifying drug delivery system according to claim 1, characterized in that the content can be self-emulsified in an aqueous medium. 9. The nateglinide self-emulsifying drug delivery system according to claim 1, characterized in that it is a dosage form that can be administered orally, including capsules, soft capsules, solutions and other dosage forms. 10. The nateglinide self-emulsifying drug delivery system according to claim 1, characterized in that the nateglinide before preparation can be in any crystal form.

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