LU101026B1

LU101026B1 - Metformin hydrochloride/berbamine hydrochloride compound sustained-release suspension formulation and preparation method thereof.

Info

Publication number: LU101026B1
Application number: LU101026A
Authority: LU
Inventors: Yang Yu; Yan He; Hongfei Liu; Xiaochi Ma; Jun Chen
Original assignee: Jiangsu Sunan Pharmaceutical Ind Co Ltd
Priority date: 2017-05-26
Filing date: 2017-10-31
Publication date: 2019-04-09
Also published as: LU101026A1; CN107174580A; WO2018214402A1

Description

DESCRIPTION

METFORMIN HYDROCHLORIDE/BERBAMINE HYDROCHLORIDE COMPOUND SUSTAINED-RELEASE SUSPENSION FORMULATION AND PREPARATION METHOD THEREOF

TECHNICAL FIELD

The present invention discloses a metformin hydrochloride/berbamine hydrochloride compound sustained-release suspension formulation and a preparation method thereof, and belongs to the field of pharmaceutic preparation technologies.

BACKGROUND

Epidemiological survey shows that, with the increase of age, the incidence of diabetes is getting higher and higher, and has become one of the world's three major diseases; 1 8.3% of the patients are over 60 years old, and the elderly are difficult to swallow tablets. The berbamine hydrochloride has multiple pharmacologic actions, and has obtained better effects while being clinically used for treating type II DM in recent years. Hypoglycemic effect ca be achieved by promoting the repairing of pancreatic ß cell, increasing the hepatic glucose consumption, improving insulin resistance, correcting lipid disorders, inhibiting the activity of disaccharides such as sucrase and maltase.

The metformin is widely applied in type II diabetes due to minor adverse reactions, and its status has been increasingly concerned. However, since the metformin is a highly water-soluble drug, its low bioavailability, short half-life and large fluctuations in clinical use of common tablets require large doses of repeated administration to maintain effective plasma concentration patients with poor compliance, the main side effects after taking is gastrointestinal reaction, and the lactic acidosisis caused after overdose. However, since the metformin hydrochloride has extremely good water solubility, the simple keleton-type materials are usually insufficient to hold back the release of the metformin hydrochloride, and a coating is usually needed to further sustain the release of the drug, thus bringing about the potential danger of burst release of the drug when the coating is broken; moreover, due to the larger dose of the metformin hydrochloride itself, and the sustained-release materials, the tablet weight will be close to lg, which leads to inconvenience to take. In this way, it is more important to prepare the sustained-release formulation of particulate dispersing-type metformin hydrochloride.

As the quarternary ammonium salt of berberine, the berbamine hydrochloride (Berbamine hydrochloride, BH) is slightly soluble in water or ethyl alcohol, is very slightly soluble in trichloromethane, and is insoluble in diethyl ether. The berbamine hydrochloride has an inhibiting effect on both gram-positive and gram-negative bacteria, and can be also used for treating multiple non-infective diseases, such as treating arrhythmia, hypertension, hyperlipidaemia, type-ll diabetes, etc. The berbamine hydrochloride is extremely bitter, the traditional berbamine hydrochloride tablets or capsules after oral administration, are disintegrated in stomach, and the majority of drug components are degraded by gastric acid, while ordinary enteric-coated formulation drugs are mainly released in small intestine, most of the drugs are absorbed into the bloodstream through the small intestine, and the drug metabolism is inactivated due to the first pass effect. SUMMARY

Object of the invention: in view of the technical problems above, the present invention provides a metformin hydrochloride/berbamine hydrochloride compound sustained-release suspension formulation and a preparation method thereof.

Technical solution: in order to reach the object above, the present invention provides a metformin hydrochloride/berbamine hydrochloride compound sustained-release suspension formulation, which is mainly made of cation exchange resin, metformin hydrochloride, berbamine hydrochloride, imprégnant, plasticiser, suspending agent and other auxiliary materials.

The cation exchange resin is Amberlite* IRP69, Amberlite* IRP670, Amberlite* IRP88 or Amberlite* IRP64.

The imprégnant is selected from one or more of methylcellulose, glycerol, and PEG6000; the plasticizer is selected from one or more of diethyl phthalate, dibutyl sebacate, and PEG400; and the suspending agent is selected from one or more of PVP, HPMC, tragacanthin, Carbopol, and Avicel RC591.

The other auxiliary materials are corrigent, antioxidant or/and antiseptic.

The corrigent can be selected from mannitol, xylitol, stevioside, lactose, fructose, cane sugar, proteoglycan, maltitol, glycyrrhizin, sodium cyclamate, gelatin, aspartame, banana essence, pineapple essence, vanillin, orange essence, flavoring orange essence, mint essence, ginseng essence, strawberry essence, citrate, and citric acid; and in order to guarantee the stability of the main drug, a proper amount of antioxidant and antiseptic can also be added.

In the compound sustained-release suspension formulation, the contents of the metformin hydrochloride and the berbamine hydrochloride are respectively 0.4-0.6g/5ml and 0.2-0.4g/5ml. A preparation method of the metformin hydrochloride/berbamine hydrochloride compound sustained-release suspension formulation comprises the following steps of: respectively mixing metformin hydrochloride and berbamine hydrochloride with cation exchange resin at first to prepare two drug-carrying resins, then respectively dipping the two drug-carrying resins into imprégnant, drying the two drug-carrying resins after finishing dipping, respectively using a sustained-release material and plasticizer to prepare drug-carrying resin microcapsules, and finally adding a suspending agent and other auxiliary materials, thus obtaining the compound sustained-release suspension formulation. A preparation method of the drug-carrying resin is as follows: adding cation exchange resin into a metformin hydrochloride solution or berbamine hydrochloride solution with a concentration of 1.0-2.0mg/ml, magnetically stirring the mixture under room temperature for 2-6h, washing away the uncombined drugs on the surface of the resin by double distilled water, and then drying, thus obtaining the drug-carrying resin.

The dipping time is 0.5-1 h. A preparation method of the drug-carrying resin microcapsule is as follows: dissolving acrylic resin (sustained-release material) into acetone, then adding the dipped drug-carrying resin and plasticizer, magnetically stirring the drug-carrying resin and the plasticizer to make the two be evenly dispersed to form a suspension, then adding the suspension into mixed liquor of liquid paraffin and span 80 that are evenly mixed under a stirring condition under the stirring condition, then stirring the mixture for 3-5h in 30°C water bath, filtering and washing the mixture by petroleum ether, and then drying the mixture, thus obtaining the drug-carrying resin microcapsule

The technical solution adopted by the present invention to solve the problem of difficulty in swallowing and bad taste of the drug is as follows: the international advanced ion exchange technology and sustained-release particle coating technology are used to develop a new-generation sustained-release formulation—ion exchange resin suspension; based on the principle of ion exchange, the drug and the ion exchange resin are combined to form a drug resin compound, so as to control the constant-speed release of the drug without being affected by pH value, enzymatic activity and the volume of gastrointestinal fluid; the special dipping treatment to the drug resin compound increases the plasticity of the drug resin, avoids the expansion of the resin in the gastrointestinal tract to result in the breaking of a controlled release membrane; and the drug resin drug-carrying technology is used to greatly increase the stability of the metformin hydrochloride and the berbamine hydrochloride in the suspension, so as to reach the needs on the clinic application.

Although, the drug combination of the metformin hydrochloride and the berbamine hydrochloride is currently available, there has not been any compound drug resin sustained-release suspension, indicating that the sustained-release suspension formulation is very difficult for those skilled in the art on technology. Aiming at the problems of low drug loading and easy swelling during the storage of the suspension to cause the breaking of the coating membrane, the present invention adopts an optimized drug loading process and impregnation means to creatively prepare the metformin hydrochloride/berbamine hydrochloride compound sustained-release suspension formulation. Its advantage lies in that different sustained-release materials and doses can be used for coating the two, and even different coating processes can be used, so that the two can realize synergetic drug release, which increases the treatment effect and shortens the disease process. Meanwhile, the compound liquid sustained-release formulations in paediatrics are also enriched.

Due to the reversibility of ion exchange, after being orally taken into the gastrointestinal tract, the drug resin has reverse ion exchange reaction with the physiologic ions in the gastrointestinal tract to sustainably release the drug, and play the curative effect. The ion exchange resin generally contains a perssad that can be ionized and activated, and can be mutually adsorbed with ionizing drugs via electrostatic interaction. After the drug enters the interior of the resin, the bad odor can be greatly reduced; moreover, the amount of saliva excreted by the oral cavity is relatively less, the ion concentration is very low, the staying time of the resin particles in the oral cavity during oral medication is very short, and the drug has entered the stomach before desorption.

Meanwhile, as the sustained-release system of oral drug resin, its advantage further lies in that the drug release rate of the drug is not affected by pH value, enzyme, temperature and other physical factors of the gastrointestinal tract, and the drug release rate is prolonged to 8-12h through the coating; and the drug resin compound or microencapsulation drug resin prepared into the suspension is particularly suitable for those patients with difficulty in swallowing to take.

Technical effect: compared with the prior art, the metformin hydrochloride/berbamine hydrochloride compound sustained-release suspension formulation obtained according to the present invention is convenient to take, can be taken by dose, and can solve the problem that the oral solid sustained-release formulation made of large dose drugs is difficult to swallow. The present invention adopts a multi-unit drug-release system, and a drug-release behavior is the total of all particle drug-release behaviors with better reproducibility and consistency; and meanwhile, the case of excessively high local concentration easily caused by the fragmentation of the oral solid sustained-release formulation can be avoided.

BRIEF DESCRIPTION OF DRAWINGS

Fig. 1 is a curve chart of in vitro release of a metformin hydrochloride/berbamine hydrochloride sustained-release dry suspension formulation prepared according to an embodiment 1 ; and

Fig. 2 is a curve chart of in vitro release of a metformin hydrochloride sustained-release tablet sold in market.

DETAILED DESCRIPTION

The technical solution of the invention is further described in details through specific embodiments, but it is necessary to point out that the following embodiments are only used for describing the contents of the invention, and do not limit the protection scope of the invention. A preferred preparation technology is as follows: 1. Preparation of drug resin

Cation exchange resin is added into a drug solution to magnetically stir under room temperature. Regular sampling is conducted to test the concentration of the drug in the solution. Balance is reached when the concentration of the drug no longer changes with the time, then the uncombined drugs on the surface of the resin are washed away by double distilled water and then the remaining is dried under 40°C-60°C, thus obtaining the drug-carrying resin. 2. Dipping of drug resin A proper amount of drug-carrying resin is taken and 20% PEC6000 solution is added, then the mixture is stir for 0.5h, and the sieved and dipped drug resin is dried. 3. Preparation of drug resin microcapsule

Acrylic resin is dissolved in acetone, and then the dipped drug-carrying resin and PEG400 are added, and managerially stirred for a certain time to make the latter two be evenly dispersed to form a suspension. The suspension is added into a mixed liquor of liquid paraffin and span 80 which are evenly mixed under the stirring condition, then the mixture is stirred for 4h in 30°C water bath, the obtained microcapsule is filtered and washed by petroleum ether, and dried under 40°C, thus obtaining the drug resin microcapsule. 4. Preparation of drug resin microcapsule suspension A certain amount of the drug-resin microcapsule and a proper amount of suspending agent (one or more of PVP, HPMC, tragacanth, Carbopol, and Avicel RC591) are taken and evenly mixed to obtain the drug-resin sustained-release dry suspension. In addition, in order to improve the taste of the dry suspension, a proper amount of corrigent can also be added, such as mannitol, xylitol, stevioside, lactose, fructose, cane sugar, proteoglycan, maltitol, glycyrrhizin, sodium cyclamate, gelatin, aspartame, banana essence, pineapple essence, vanillin, orange essence, flavoring orange essence, mint essence, ginseng essence, strawberry essence, citrate, citric acid, and so on; and in order to guarantee the stability of main drug, appropriate antioxidant, antiseptic, etc. In order to guarantee the stability of the main drug, a proper amount of antioxidant and antiseptic can further be added.

The embodiments above are intended to further illustrate the present invention, rather than limiting the scope thereof.

Detailed embodiments

The metformin hydrochloride/berbamine hydrochloride compound sustained-release suspension according to the present invention is prepared according to the preparation technology above.

Embodiment 1 : 1. Preparation of drug resin 200mg ion exchange resin (Amberlite* IRP69) was taken and 200ml metformin hydrochloride solution with a concentration of 2.0mg/ml was added, then the mixture was magnetically stirred for 2h under room temperature. The uncombined drugs on the surface of the resin were washed away by double distilled water, and then the resin was dried under 60°C, thus obtaining drug-carrying resin. 200mg ion exchange resin (Amberlite* IR.P88) was taken and 200ml berbamine hydrochloride solution with a concentration of 2.0mg/ml was added, then the mixture was magnetically stirred for 6h under room temperature. The uncombined drugs on the surface of the resin were washed away by double distilled water, and then the resin was dried under 60°C, thus obtaining drug-carrying resin. 2. Dipping of drug resin 100mg drug-carrying resin was taken respectively and 20% PEG6000 solution with proper amount was added, then the mixture was stirred for 0.5h, and the dipped drug resin was dried and sieved. 3. Preparation of drug resin microcapsule 40mg acrylic resin was dissolved in 8ml acetone, then 200mg dipped drug-carrying resin and 1ml PEG400 were added, then the mixture was stirred for a certain time till the latter two were evenly dispersed to form a suspension. The suspension was added into a mixed liquor of 24ml liquid paraffin and 1ml span 80 that were evenly mixed under a stirring condition, then the mixture was stirred for 5h in 30°C water bath, the obtained microcapsule was filtered and washed by petroleum ether, and dried under 40°C, thus obtaining the drug resin microcapsule.

Preparation of drug resin microcapsule suspension 250mg CMC-Na was dissolved in a certain amount of water, and cooled to the room temperature after complete dissolution, 200mg polysorbate 80 was added to bath in ice for 0.5h, and 1 50mg drug resin microcapsule (100mg metformin hydrochloride drug-carrying resin microcapsule and 50mg berbamine hydrochloride drug-carrying resin microcapsule) was added to bath in ice for a certain time, and then the mixture was evenly stirred.

Embodiment 2: 1. Preparation of drug resin 200mg ion exchange resin (amberlite irp69) was taken and 200ml metformin hydrochloride solution with a concentration of 1.0mg/ml was added, then the mixture was magnetically stirred for 2h under room temperature. The uncombined drugs on the surface of the resin were washed away by double distilled water, and then the resin was dried under 60°C, thus obtaining drug-carrying resin. 200mg ion exchange resin (amberlite irp88) was taken and 200ml berbamine hydrochloride solution with a concentration of 1.0mg/ml was added, then the mixture was magnetically stirred for 3h under room temperature. The uncombined drugs on the surface of the resin were washed away by double distilled water, and then the resin was dried under 60°C, thus obtaining drug-carrying resin. 2. Dipping of drug resin 100mg drug-carrying resin was taken respectively and 20% PEG6000 solution with proper amount was added, then the mixture was stirred for 0.5h and 0.8h, and the dipped drug resin was dried and sieved. 3. Preparation of drug resin microcapsule 60mg acrylic resin was dissolved in 8ml acetone, then 200mg dipped drug-carrying resin and 1ml PEG400 were added, then the mixture was stirred for a certain time till the latter two were evenly dispersed to form a suspension. The suspension was added into a mixed liquor of 24ml liquid paraffin and 1ml span 80 that were evenly mixed under a stirring condition, then the mixture was stirred for 4h in 30°C water bath, the obtained microcapsule was filtered and washed by petroleum ether, and dried under 40°C, thus obtaining the drug resin microcapsule. 4. Preparation of drug resin microcapsule suspension 250mg CMC-Na was dissolved a certain amount of water, and cooled to the room temperature after complete dissolution, 200mg polysorbate 80 was added to bath in ice for 0.5h, and 1 50mg drug resin microcapsule (90m gmetformin hydrochloride drug-carrying resin microcapsule and 60mg berbamine hydrochloride drug-carrying resin microcapsule) was added to bath in ice for a certain time, and then the mixture was evenly stirred.

Test example 1 In vitro release degree test of metformin hydrochloride/berbamine hydrochloride compound sustained-release suspension formulation

The in vitro test is an important means for selecting prescription and determining technology, and plays an important role on controlling the quality of the formulation, which mainly inspects the quantity through a dissolution rate. 900ml HCI solution with a concentration of 0.1mol/L subjected to deaeration was used as a release medium in the present invention, wherein the rotating speed was 50r/min and the temperature was 37°C. According to the oar method operation in Appendix XC of Chinese Pharmacopoeia 2000 Edition, 5ml was respectively sampled at 2, 4, 6, 8, 10 and 1 2h and filtered through a 0.45pm microfiltration membrane, then the primarily filtered liquid was discarded, and the subsequently filtered liquid was taken for standby application, then a corresponding medium of the same temperature and same volume was supplemented in time, and the absorbancy of the subsequently filtered liquid was tested.

The test result was shown in Fig. 1. The result showed that the in vitro releasing degree of the metformin hydrochloride/berbamine hydrochloride compound sustained-release suspension formulation prepared in the embodiment 1 was 75%-85% at 10h. Therefore, the drug could be slowly released in vivo.

Although the invention has been described according to the specific embodiments above, it shall be admitted that those skilled in the art can make various modifications and conversions to the invention, and these modifications and conversions shall also belong to the scope of the invention defined by the appended claims.