CN104825389B - A kind of Berberine hydrochloride self-micro emulsion formulation and preparation method thereof - Google Patents

Abstract

The invention discloses a berberine hydrochloride self-microemulsion preparation with good oral bioavailability and a preparation method thereof. The berberine hydrochloride self-microemulsion preparation is composed of the following components in mass ratio: 3-5% berberine hydrochloride, 3-5% penetration enhancer, 40-50% oil phase, 30-40% emulsifier and 10-20% co-emulsifier; wherein, the penetration enhancer is sodium caprate or sodium oleate; the oil phase is isopropyl myristate, isopropyl palmitate, peppermint oil, rose oil or lemon oil . The invention wraps BBR in the oil nucleus by adopting innovative microemulsion, avoids intestinal metabolism, improves its biofilm permeability, improves its bioavailability, reduces dosage, and avoids constipation; and the production process is simple, the solid preparation is stable, The invention is convenient to transport, carry and take, can avoid bitter taste, has good acceptability, and has good prospects for popularization and application.

Description

A kind of berberine hydrochloride self-microemulsion preparation and preparation method thereof

technical field

The invention belongs to the technical field of pharmaceutical preparations. More specifically, it relates to a berberine hydrochloride self-microemulsion preparation with good oral bioavailability and a preparation method thereof.

Background technique

Berberine (BBR) is the main active ingredient of Chinese medicine Coptis chinensis, and it has been clinically used for many years in the treatment of intestinal infection and bacillary dysentery. A large number of recent experiments and clinical studies have shown that BBR can also effectively reduce blood sugar and blood lipids, and has a wide range of pharmacological effects. However, due to poor biofilm permeability of BBR (accounting for 56% of the administered dose) and significant intestinal first-pass elimination (accounting for 43.5% of the administered dose), its absolute bioavailability is extremely low (0.52%), and large doses ( 0.9-1.5 g/day) long-term use can cause problems such as constipation, which greatly limits its clinical application.

In order to improve the oral bioavailability of berberine hydrochloride, a self-microemulsion delivery system of berberine hydrochloride was studied. Self-microemulsifying drug delivery system (SMEDDS) is a mixed system composed of drug oil phase, emulsifier and co-emulsifier. The main feature of this drug delivery system is that it encounters body fluids and O/W microemulsions of 10nm~200nm are spontaneously formed under the peristalsis of the gastrointestinal tract. It can improve drug dissolution and self-emulsify to form fine emulsion droplets when the system is in contact with gastrointestinal fluid, thus having a large interface area and low Surface tension increases drug biomembrane permeability, thereby improving bioavailability. For example, Long Xiaoying et al. (2012), Song Yu et al. (2014), Gui Shuangying et al. (2009), Lu Xiuling (2012) etc. conducted relevant research on the berberine microemulsion system. However, due to the different microemulsion formulations, the self-microemulsion preparations have significantly different improvement effects on the oral bioavailability of berberine hydrochloride.

In order to better improve the oral bioavailability of berberine hydrochloride, ensure the safety and effectiveness of the drug, and provide a theoretical basis for its better application, we still need our unremitting research and exploration.

Contents of the invention

The technical problem to be solved by the present invention is to overcome the defects and deficiencies of the existing berberine hydrochloride self-microemulsion drug delivery system, that is, it cannot guarantee that berberine hydrochloride will not be metabolized in the intestinal tract. The invention provides a new berberine hydrochloride self-microemulsion preparation. By adopting innovative microemulsions to wrap BBR in the oil core, avoiding intestinal metabolism and improving its biofilm permeability, it is expected to reduce dosage (avoid constipation) and improve its bioavailability; the product form is self-microemulsion (self- microemulsions, SME) capsules (SMEC).

The object of the present invention is to provide a berberine hydrochloride self-microemulsion preparation with good oral bioavailability.

Another object of the present invention is to provide a preparation method of the berberine hydrochloride self-microemulsion preparation.

The above object of the present invention is achieved through the following technical solutions:

A berberine hydrochloride self-microemulsion preparation with good oral bioavailability is characterized in that it consists of the following components by mass ratio: 3-5% berberine hydrochloride, 3-5% penetration enhancer, 40-50 % oil phase, 30-40% emulsifier and 10-20% co-emulsifier; wherein, the penetration enhancer is sodium caprate or sodium oleate; the oil phase is isopropyl myristate (IPM), Isopropyl palmitate (IPP), peppermint, rose, or lemon oil.

Wherein, the emulsifier is polyoxyethylene ether-40 hydrogenated castor oil (Cremophor RH40), polyoxyethylene 10 oleyl ether (Brij97) or poloxamer; the co-emulsifier is ethanol or glycerin.

Preferably, the poloxamer is poloxamer PF127 or poloxamer PF68.

Preferably, the penetration enhancer is sodium caprate.

Preferably, the oily phase is isopropyl myristate or peppermint oil.

More preferably, the oily phase is peppermint oil.

The preparation method of above-mentioned berberine hydrochloride self-microemulsion preparation comprises the steps:

S1. according to the formula described in claim 1, berberine hydrochloride, oil phase, emulsifier and co-emulsifier are mixed, heated and stirred to obtain clear solution, i.e. pre-microemulsion;

S2. Add the pre-microemulsion obtained in S1 to distilled water at 37°C and stir slightly to form a self-microemulsion; or use the pre-microemulsion obtained in S1 as a preparation product, and form a self-microemulsion under the peristalsis of the stomach after oral administration.

In addition, the application of the above-mentioned berberine hydrochloride self-microemulsion preparation should also be within the protection scope of the present invention, and the application includes the application in the preparation of berberine pharmaceutical preparations.

The reason for the poor absorption of melonine is mainly due to the metabolism in the small intestine and the poor permeability of the intestinal biofilm. Therefore, the starting point of our design is to use sodium caprate as the biofilm penetration enhancer, and use microemulsion to wrap melonine in the oil of microemulsion. core, and ensure that the prepared oil core will not be degraded in the intestinal tract. Therefore, we first screened the oil phase in the formula. After a lot of research and exploration, we finally came to the use of isopropyl myristate, palm Isopropyl myristate, peppermint oil, rose oil, or lemon oil work well, especially isopropyl myristate or peppermint oil.

At the same time, the emulsifiers of microemulsions were also studied and screened. The results showed that polyoxyethylene ether-40 hydrogenated castor oil (Cremophor RH40), polyoxyethylene 10 oleyl ether (Brij97) or poloxamer were selected as emulsifiers. , which can be perfectly coordinated with the overall formula of berberine hydrochloride self-microemulsion preparation, so as to achieve the purpose of improving the bioavailability of berberine hydrochloride.

In addition, it is well known to those skilled in the art that the formulation selection of pharmaceutical preparations is a complicated process, which cannot be completed through simple combination and patchwork. For a successful drug formula, each component must achieve the optimal ratio to ensure the efficacy or even improve the efficacy of the drug. At the same time, the selected excipients must be safe and orally acceptable. The present invention has obtained the above-mentioned berberine hydrochloride self-microemulsion formulation through a large number of experimental studies, which can effectively improve the oral bioavailability of berberine by increasing the membrane permeability of intestinal growth and avoiding metabolism; and the dose reduction It can effectively avoid constipation; the capsule can also avoid bitter taste, which lays the foundation for the development of new berberine drugs with new indications.

The present invention has the following beneficial effects:

The present invention wraps berberine (BBR) in the oil nucleus by adopting innovative microemulsion, which can not only avoid intestinal metabolism, but also improve the permeability of its biofilm, and can significantly improve the oral bioavailability of berberine. Reduced dosage can avoid problems such as constipation.

The product obtained in the present invention is in the form of self-microemulsions (self-microemulsions, SME) capsules (SMEC), the production process is simple, the solid preparation is stable, convenient to transport, carry and take, and can also avoid bitterness; further according to the requirements of new drug declaration, complete The preclinical pharmaceutical work has laid the foundation for the development of new berberine drugs with new indications.

Description of drawings

Fig. 1 is the bioavailability of different fenugreek preparation systems.

Detailed ways

The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments, but the embodiments do not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the technical field.

Unless otherwise specified, the reagents and materials used in the present invention are commercially available.

Embodiment 1 berberine hydrochloride self-microemulsion preparation

1. Prepare the following components in mass ratio: 3-5% berberine hydrochloride, 3-5% penetration enhancer, 40-50% oil phase, 30-40% emulsifier and 10-20% co-emulsifier.

Wherein, the penetration enhancer is sodium caprate or sodium oleate; the oil phase is isopropyl myristate, isopropyl palmitate, peppermint oil, rose oil or lemon oil. The emulsifier is polyoxyethylene ether-40 hydrogenated castor oil, polyoxyethylene 10 oleyl ether, poloxamer PF127 or poloxamer PF68; the co-emulsifier is ethanol or glycerol.

2. Preparation:

S1. according to the formula described in claim 1, berberine hydrochloride, oil phase, emulsifier and co-emulsifier are mixed, heated and stirred to obtain clear solution, i.e. pre-microemulsion;

S2. Add the pre-microemulsion obtained in S1 into distilled water at 37° C. and stir slightly to form a self-microemulsion.

Example 2 SD rat bioavailability experiment

1. Dosing regimen

Healthy SD rats (200 ± 20 g) were given different cinnamon preparations (100 mg/kg), and intravenous (intravenous, iv) injection (6 mg/kg) was used as the control preparation, before and after administration, respectively At 0.167 h, 0.5 h, 1.0 h, 1.5 h, 2.0 h, 4.0 h, 6.0 h, 8.0 h, 10 h, and 12 h, 0.40 mL of blood was taken from the orbital vein, and the blood samples were processed according to the assay method, and the blood drug concentration was determined by HPLC .

2. Blood sample processing

Take 0.45 mL of blood from SD rats and put it in a centrifuge tube treated with sodium heparin, centrifuge at 3500 rpm for 15 min, take 0.15 mL of supernatant plasma, add 0.30 mL of acetonitrile to precipitate protein, vortex for 3 min, then centrifuge at 10000 rpm for 10 min, take The supernatant was passed through a 0.22 µm filter membrane, and the BBR content was determined by HPLC.

3. Determination of the content of benignine

Chromatographic conditions: Sunfire C18 column (250 mm×4.6 mm, 5 µm); detection wavelength: 262 nm; column temperature: 30°C; injection volume: 20 µL; elution mobile phase: acetonitrile: 0.2 % phosphoric acid aqueous solution (0.27:0.73).

Drawing of the standard curve: Take 120 μL of blank plasma and add 7 parts in total, add 30 μL of the working solution of baconium reference substance to make the concentration respectively 0.05, 0.10, 0.20, 0.50, 1.00, 2.00, 5.00 μg·mL ^-1 , according to the plasma Sample processing operation, weighted linear regression calculation of blood drug concentration C by peak area.

4. Data processing

The measured Cm, Tm, and trapezoidal method were used to calculate AUC, and Fa was calculated according to the formula (AUC oral/D oral)/(AUC iv/D iv)×100%.

5. The results are shown in Figure 1 and Table 1.

Table 1 Pharmacokinetic parameters of SD rats orally administered orally with the self-microemulsion and intravenously with the solution

Compared with the Xiaomao base suspension group: a: P<0.05 , b: P<0.01 . Compared with soybean oil group: c: P<0.05 , d: P< 0.01 .

Soybean oil-containing self-microemulsion (BBR-ETR-SNEDDS) has a 12-fold increase in the absorption of fenneline suspension. However, the self-microemulsion containing isopropyl myristate and peppermint oil (BBR-AETR-SNEDDS) increased the absorption of anodine by 25 and 32 times, because isopropyl myristate and peppermint oil are in the gastrointestinal tract. There is no lipolysis or less lipolysis in the road, so that the small alkaloids are not caused by intestinal metabolism.

Claims (3)

1. a berberine hydrochloride self-microemulsion preparation, is characterized in that, is made of the component of following mass ratio: 3～5% berberine hydrochloride, 3～5% penetration enhancer, 40～50% oil phase, 30-40% emulsifier and 10-20% co-emulsifier; wherein, the penetration enhancer is sodium caprate or sodium oleate; the oil phase is peppermint oil; the emulsifier is polyoxyethylene ether-40 hydrogenated castor oil, polyoxyethylene 10 oleyl ether or poloxamer; the co-emulsifier is ethanol or glycerol. 2. according to the described berberine hydrochloride self-microemulsion preparation of claim 1, it is characterized in that, described poloxamer is poloxamer PF127 or poloxamer PF68. 3. berberine hydrochloride self-microemulsion preparation according to claim 1, is characterized in that, described penetration enhancer is sodium caprate.