CN1698604A - β-cyclodextrin/amoxicillin inclusion compound and its composition with potassium clavulanate and preparation method - Google Patents

Abstract

The invention provides a beta-cyclodextrin / amoxicillin inclusion compound medicinal composition which comprises amoxicillin and beta cyclodextrin by the weight ratio of 1:2.5-1:5. In a preferred embodiment, the composition also comprises clavulanate potassium, wherein the mass ratio of amoxicillin and clavulanate potassium is 14:1-2:1, the supplementary materials are selected from crystalline cellulose, maize starch, citric acid, talcum powder, sodium carboxymethylstarch, stearic acid, calcium stearate, magnesium stearate, amylopectin, lactose, mannitol, crosslinked povidone, talcum powder, polyethylene glycol 4000, and low substituted methylcellulose propylene glycol ether. The invention also discloses the preparing process.

Description

β-cyclodextrin/amoxicillin inclusion compound and its composition with potassium clavulanate and preparation method

technical field

The invention relates to a pharmaceutical composition containing amoxicillin contained in β-cyclodextrin, a pharmaceutical composition composed of the pharmaceutical composition compounded with potassium clavulanate, and a preparation method of the two pharmaceutical compositions.

Background technique

The β-lactam antibiotic amoxicillin/clavulanate potassium compound preparation was originally researched and developed by the world-renowned GlaxoSmithKline pharmaceutical company, and was approved by the FDA on August 6, 1984. So far, this product has maintained its status as the world's best-selling drug for 13 consecutive years, ranking first in the world's anti-infective drugs. This product has been recorded in Chinese Pharmacopoeia.

Amoxicillin combined with clavulanic acid can inhibit staphylococcus, Haemophilus influenzae, catarrhalis, Escherichia coli, Klebsiella, Proteus mirabilis, Proteus vulgaris, Neisseria gonorrhoeae, Legionella, Bacteroides fragilis, etc. The β-lactamase produced by microorganisms destroys amoxicillin, so it is effective against enzyme-producing or non-enzyme-producing strains of the above-mentioned pathogenic bacteria. This product also has antibacterial effect on Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans, Clostridium, Peptococcus, Peptostreptococcus, etc. that do not produce β-lactamase. It can be used for lower respiratory tract, middle ear, sinus, skin tissue, urinary tract and other infections caused by the above-mentioned sensitive bacteria. It is also effective against Enterobacter urinary tract infection.

At present, the compound preparations of amoxicillin/clavulanate potassium on the domestic market include: tablets, capsules, chewable tablets, granules, syrups, powder injections, suspensions and other dosage forms, and the ratio of amoxicillin/clavulanate potassium is as follows: : 2:1, 4:1, 5:1, 7:1, 10:1 and 14:1 products. Amoxicillin/clavulanate potassium compound has obvious advantages over amoxicillin alone, but in our country, amoxicillin alone is much higher than its compound preparation. The reason for this contrast is mainly that the dissolution rate of the preparation is slow, the content of potassium clavulanate is unstable and the quality of the products needs to be improved. Amoxicillin is a semi-synthetic β-lactam antibiotic containing three moles of crystal water, a molecular weight of 419, and a water content of 12.0% to 15.0%. The unstable lactam ring of amoxicillin molecules is easily attacked by nucleophiles and electrophiles, and is prone to degradation. Due to poor water solubility, the dissolution performance of its oral preparations is not good. Potassium clavulanate has good water solubility, but is easily oxidized and has poor stability. The preparation is prone to discoloration and content declines rapidly during the shelf life. At present, preparation products mainly adopt methods such as adding antioxidants, compactly compressing tablets, coating treatment and air-sealed packaging to solve stability problems.

A large number of research results have shown that the supramolecular preparation technology of many pharmaceutical products using β-cyclodextrin (β-CD) for molecular inclusion can significantly improve the quality of pharmaceutical preparations, reduce the toxic and side effects of the original drug, improve the curative effect, and facilitate the use of patients. At present, 15 pharmaceutical preparations using β-CD and β-CDD as auxiliary materials have been marketed abroad. The application of supramolecular drug delivery preparation technology is mainly in the following aspects: improving the stability of pharmaceutical preparations; increasing the solubility of drugs; promoting Drug absorption, improve the bioavailability of drugs; reduce the stimulation of drugs to the body, reduce adverse drug reactions; mask the bad smell of drugs, which is convenient for patients to take; as a carrier for sustained release and targeted preparations; powdering of oily drugs is convenient for preparation preparation. Currently, amoxicillin and its compound preparation with clavulanate potassium have not yet been reported using β-cyclodextrin for molecular inclusion supramolecular technology preparations.

β-cyclodextrin can form supramolecular bodies (inclusion complexes) with organic molecules such as drugs in aqueous solution. When clathrates are formed, the hydrophobic cavity of β-CD with higher electron cloud density will generate electron cloud close to the drug guest molecule, which will shift or enhance the peak of the ultraviolet absorption spectrum of the guest. The relative change of UV absorption reflects the inclusion of drug guest and β-CD.

Contents of the invention

The object of the present invention is: adopting β-cyclodextrin and amoxicillin to make a solid powder clathrate, so that the stability, mechanical processing performance and dissolution characteristics of amoxicillin are significantly enhanced. The further object of the invention is to combine the inclusion compound of β-cyclodextrin/amoxicillin with potassium clavulanate to prepare a new type of preparation with high pressure strength, enhance the stability of potassium clavulanate, improve the pharmaceutical properties of the compound preparation, and improve the compound preparation. Preparation product quality. The present application will also provide preparation methods of the clathrates and compositions of the two drugs respectively.

It should be noted that after adding potassium clavulanate to the β-cyclodextrin/amoxicillin inclusion compound, it can be described as another pharmaceutical composition; For the description of the optimization scheme, the scope of the technical scheme of the two description methods is the same. The latter method is used to describe the application when requesting protection.

Use mixed phosphate buffer (pH=6.86) to prepare an amoxicillin solution with a concentration of about 2.3ug/ml. In order to keep the concentration of amoxicillin constant, use this solution to prepare a concentrated solution of β-CD, and gradually increase the concentration of β-CD. The results of ultraviolet scanning showed that the ultraviolet absorption of amoxicillin increased rapidly and regularly with the increase of β-CD concentration, indicating that amoxicillin and β-CD had a good inclusion effect. With accompanying drawing 1, the quantitative relationship (Hildebrand-Benesi formula) of β-CD concentration to ultraviolet absorption is measured the formation constant (inclusion constant Ka) that amoxicillin/β-cyclodextrin forms supramolecular body to be 357M-1 ( Y=-0.0028X+0.141; R2=0.986).

The phase solubility test showed that when the concentration of β-CD was 0, the intrinsic solubility of amoxicillin was equal to 4.58×10-6mol/L. With the increase of β-CD concentration, the solubility of amoxicillin increased obviously, and 0.7% β-CD increased the solubility of amoxicillin by 3.89 times. The solubility change of the system has the characteristics of an AL-type curve, indicating that a 1:1 clathrate is formed, and the solubility curve equation is Y=0.0022x+5×10-6 (R2=0.9928). The inclusion constant Ka obtained from the curve equation is 441M-1.

The supramolecular structure of organic molecules such as drugs and β-cyclodextrin is directly related to the molecular structure of drugs. Smaller drug molecules generally form 1:1 inclusion complexes, and larger molecules can form 1:1 or 1:1 inclusion complexes. 2 and a higher proportion of inclusion compounds, the determination of the inclusion ratio is of great value in determining the prescription of pharmaceutical preparations. The inclusion ratio of amoxicillin/β-cyclodextrin was determined by the continuous gradient experiment method, and a series of solutions with the same total molar concentration of amoxicillin and β-CD and a molar ratio of 1:3 to 3:1 were prepared to buffer Solution is the blank 228nm, measure the absorbance Acd of the system and the absorbance value A0 of the corresponding concentration of amoxicillin, calculate the ratio DA (DA=Acd/A0) of the absorbance value, and the molar ratio corresponding to the DA maximum is the inclusion ratio, which can be obtained as follows table results,

Amoxicillin xicillin: β-CD ΔA(10-2)

1:3 1.7

1:2 0.7

2:3 1.9

1:1 8.6

3:2 1.2

2:1 0.1

3:1 1.3

Among them, the absorbance value of the system mixed at a molar ratio of 1:1 has the largest difference, so amoxicillin and β-CD are clathrated at a ratio of 1:1, and the result is consistent with the phase solubility test.

Amoxicillin/β-CD inclusion complex (molar ratio 1:1) was prepared by grinding method, β-CD was added 1 to 5 times of water and amoxicillin at room temperature, ground for 5 hours, cooled, filtered, washed with water The solid was then vacuum-dried for 12 hours and passed through a 100-mesh sieve to obtain a white powder.

Four samples of amoxicillin, β-CD, clathrate, and physical mixture were taken for differential scanning calorimetry analysis: with Al2O3 as a reference, 5.0 mg of sample was accurately weighed, the measuring range was ±25μV, and the temperature rise range was 40℃～ 400°C, the heating rate is 10°C/min, and the DTA spectrum is made, see Figure 2.

It can be seen from the figure that amoxicillin has a decrystallization water peak at 103.8°C, there are two endothermic peaks of crystal transformation around 155°C~200°C, and a decomposition exothermic peak around 280°C; At 210°C are the endothermic peaks of β-CD deinclusion water and crystal transformation, respectively, and at 310.6°C are the melting-decomposition peaks. The mixture maintains the endothermic peaks of β-CD and amoxicillin, which is basically the superposition of the spectrum of each compound, indicating that there is no obvious intermolecular interaction in the mixture. However, the position and shape of each peak on the spectrum of the clathrate have changed, and the characteristic peak of amoxicillin crystal form conversion in the range of 110°C to 230°C after decrystallization water and clathrate water (155°C to 200°C) The specific heat disappears and becomes a stable state with constant specific heat, while the crystal form conversion peak of the system appears at 230°C, and the characteristic peak of amoxicillin's exothermic decomposition near 280°C disappears. However, the characteristic peaks of amoxicillin and β-CD changed, which indicated that the new system was an inclusion compound rather than a mechanical mixture.

Determine the content of amoxicillin in the inclusion compound, explore the stability of the preparation process, fix the feeding ratio of amoxicillin and β-CD, change the amount of water added, change the grinding time and adjust the temperature appropriately, and prepare three batches of drug content determination of the inclusion compound see table below clathrate Theoretical content Actual content X±RSD 14.29 14.15±0.42 Batch1 14.21 Batch2 14.29 14.09 Batch3 14.29 14.14

The results show that the preparation process of the clathrate has good reproducibility (RSD=0.42%), and the process method is stable and reliable.

Influence test of inclusion on the dissolution rate of amoxicillin: respectively take amoxicillin and the inclusion compound containing the same dose of amoxicillin to measure the dissolution rate. The determination method refers to the second part of the Chinese Pharmacopoeia 2000 edition, the mixed phosphate buffer solution pH=6.86 is the dissolution medium, the temperature is 37°C, and the rotation speed of the basket is 100r/min; 8ml samples are taken at 5, 10, 15, 20, 25, 30 and 40min , filter, and immediately add an equal amount of isothermal dissolution medium, measure the absorbance at 228nm of the sample solution, substitute it into the standard curve to calculate the concentration, and measure the dissolution rate of amoxicillin. The results are shown in Figure 3, and the experimental results show that the inclusion compound can significantly improve the dissolution rate of amoxicillin. The dissolution of the clathrate reaches 73% within 15 minutes, which is much higher than that of the bulk drug (8.9%). The dissolution rate of the crude drug was only 33.6% in 40 minutes, while the clathrate was more than 95.0%. Experiments have proved that cyclodextrin supramolecular technology can be used to improve the dosage form of amoxicillin, and it is a key technology to improve the dissolution rate of amoxicillin preparations.

Further adding the designed amount of potassium clavulanate and 10% to 30% of the total mass of commonly used pharmaceutical excipients (disintegrants, binders, fillers and lubricants, etc.) into the clathrate, and prepared various The existing oral dosage form of amoxicillin/potassium clavulanate ratio at present carries out the stability test of potassium clavulanate with the two methods of Pharmacopoeia 2000 edition, and the measurement result shows that clavulanic acid in clavulanate preparation (tablet) The stability of potassium content is significantly better than that of ordinary tablet products, and the appearance and mechanical properties of the preparation are obviously improved. The comparison test of amoxicillin dissolution between the new preparation and the inclusion compound is shown in Figure 4. The results show that the new preparation prepared by high pressure intensity basically maintains the high dissolution characteristics of the inclusion compound, can quickly disintegrate and dissolve, and the drug can be dissolved within 15 minutes. The dissolution rate is better than that of clathrate; however, due to the influence of other auxiliary materials and additives, its dissolution rate after 40 minutes is slightly lower than that of clathrate, and the dissolution rate of the formulation can reach 91.7% at 45 minutes. Experiments have proved that the inclusion compound of amoxicillin/β-cyclodextrin has the characteristics of rapid dissolution, good compatibility with other excipients and potassium clavulanate, and excellent mechanical processing performance. The inclusion technology has become an improved amoxicillin An important technical basis for the compound preparation of cillin-potassium clavulanate.

The scheme of completing the foregoing invention task of the application is:

The β-cyclodextrin/amoxicillin clathrate comprises: amoxicillin and β-cyclodextrin, and the mass ratio of the two is 1:2.5-1:5.

A further scheme: compound the above clathrate and potassium clavulanate to make amoxicillin-potassium clavulanate preparation, the mass ratio of amoxicillin/potassium clavulanate is 2:1～14: 1. Other excipients that need to be added can be selected: microcrystalline cellulose, corn starch, citric acid, talcum powder, sodium starch glycolate, stearic acid, calcium stearate, magnesium stearate, pregelatinized starch, lactose, Mannitol, crospovidone, talc, PEG4000 (polyethylene glycol 4000), low-substituted hydroxypropyl cellulose, micronized silica gel, sodium starch glycolate, PEG6000 (polyethylene glycol 6000).

Specifically, the solid preparation can be prepared according to one of the schemes in the following attached table:

plan: Components and proportions (mg) 1 2 3 4 5 6 Amoxicillin 100 100 100 100 100 100 Potassium clavulanate 7.14 10 14.28 20 25 50 β-cyclodextrin 500 400 400 300 250 250 Other accessories 70 100 100 180 150 170

The preparation method of β-cyclodextrin/amoxicillin clathrate comprises the following steps:

Mix β-cyclodextrin with 1 to 5 times the mass of water, and make a suspension at room temperature;

Add amoxicillin in a mass ratio of 1/5 to 2/5 (the best ratio is 1/3), mix evenly, and grind thoroughly;

Cool, filter, take the solid to dry, and crush through a 100-mesh sieve to obtain a solid powder clathrate.

More specifically, the specific conditions of the steps included in the preparation method are:

Mix β-cyclodextrin with 1 to 5 times the mass ratio of pure water (optimal ratio 2) at a temperature of 20 to 25°C to form a suspension;

Add amoxicillin at a mass ratio of 1/5 to 2/5 (the best ratio is 1/3), mix and grind thoroughly for 2 to 15 hours;

After cooling at 5°C for 12 hours, filter, take the solid and dry it to obtain the solid clathrate.

The method for further making the above-mentioned clathrate compound preparation is to increase the following steps:

The inclusion compound and potassium clavulanate are evenly mixed, sieved, dry granulated, pulverized and sieved to obtain a powdery semi-finished product compounded with β-cyclodextrin/amoxicillin inclusion compound and potassium clavulanate.

The semi-finished product is mixed with other auxiliary materials, granulated and then compressed into tablets or capsules.

More optimally and more specifically, the added steps are:

The clathrate and potassium clavulanate are evenly mixed, passed through an 80-mesh sieve, dry-granulated, crushed and passed through a 100-mesh sieve to obtain a powdery semi-finished pharmaceutical composition.

The semi-finished product is mixed with other auxiliary materials, dry granulated at 15°C-30°C, dried at 60°C for 4-20 hours, and then compressed into tablets or capsules.

Advantages of the present invention:

Enhance drug stability of amoxicillin and potassium clavulanate: After amoxicillin is prepared as an inclusion compound, the appearance is a white solid, and it is stored below 60°C for 72 hours without any decrease in drug content, decomposition and deterioration, and no change in the appearance of the solid. The DSC spectrum test proves that the volatilization of inclusion water and crystal water occurs at a temperature of 80°C to 105°C, and the decomposition of inclusion amoxicillin occurs above 300°C. The stability of the preparation potassium clavulanate meets the requirements of the Pharmacopoeia standard.

The inclusion compound has excellent dissolution properties, good machinability, and is easy to compound with clavulanate potassium to enhance the effect of clavulanate potassium. It has good compatibility with other pharmaceutical excipients and can be easily prepared into various solid oral preparations Such as tablets, capsules, dispersible tablets, sustained-release tablets, sustained-release capsules, granules, etc.

The dosage form prepared by the inclusion method is easy to disintegrate, the drug dissolution rate is fast, and the dissolution rate is high.

Easy to carry and easy to store: The prepared solid preparation has greatly improved pressure resistance, processability and appearance, easy to produce, easy to prepare, easy to pack, and no discoloration or cracking.

Detailed ways

Example 1, mix 100 ml of pure water with 100 g of β-cyclodextrin, add 33 g of amoxicillin at room temperature at 20°C, grind thoroughly for 8 hours, then place at 5°C for 12 hours; filter, and wash the solid with water 2 times. Vacuum-dry at 40°C for 12 hours to obtain a white solid clathrate. The solid clathrate is crushed through a 100-mesh sieve, mixed with 2.36 grams of potassium clavulanate, passed through an 80-mesh sieve twice, dry-granulated, and ground into a powder to obtain a pharmaceutical composition. In the composition, amoxicillin-clavulanate potassium The dose ratio is 14:1.

Embodiment 2: substantially the same as embodiment 1, but add 200 milliliters of pure water, fully grind for 5 hours.

Embodiment 3: substantially the same as embodiment 1, but add 20 grams of amoxicillin. The obtained white solid clathrate was mixed with 1.4 g of potassium clavulanate to prepare a powdery pharmaceutical composition.

Embodiment 4: substantially the same as embodiment 1, but add 40 grams of amoxicillin. The obtained white solid clathrate was mixed with 2.8 g of potassium clavulanate to prepare a powdery pharmaceutical composition.

Embodiment 5: It is basically the same as Embodiment 3, but 10 grams of clavulanate potassium is added and mixed with the clathrate to prepare a powdery pharmaceutical composition with a dosage ratio of amoxicillin-clavulanate potassium of 2:1.

Embodiment 6: It is basically the same as Embodiment 3, but 5 grams of potassium clavulanate is added and mixed with the clathrate to prepare a powdered pharmaceutical composition with a dose ratio of amoxicillin-potassium clavulanate of 4:1.

Embodiment 7: It is basically the same as Embodiment 3, but 4 grams of potassium clavulanate is added and mixed with the clathrate to prepare a powdered pharmaceutical composition with a dosage ratio of amoxicillin-potassium clavulanate of 5:1.

Embodiment 8: It is basically the same as Embodiment 4, but 5.7 g of clavulanate potassium is added and mixed with the clathrate to prepare a powdery pharmaceutical composition with a dosage ratio of amoxicillin-clavulanate potassium of 7:1.

Embodiment 9: It is basically the same as Embodiment 4, but 4 grams of potassium clavulanate is added and mixed with the clathrate to prepare a powdered pharmaceutical composition with a dose ratio of amoxicillin-potassium clavulanate of 10:1.

Claims (5)

1. A β-cyclodextrin/amoxicillin inclusion compound pharmaceutical composition, which comprises: amoxicillin and β-cyclodextrin, the mass ratio of which is 1:2.5-1:5. 2. The β-cyclodextrin/amoxicillin inclusion compound pharmaceutical composition according to claim 1, characterized in that: the composition also contains potassium clavulanate; the mass ratio of amoxicillin to potassium clavulanate is 14:1～2:1. 3. The β-cyclodextrin/amoxicillin inclusion complex pharmaceutical composition according to claim 1 or 2, characterized in that: the excipients in the composition are selected from: microcrystalline cellulose, corn starch, citric acid, Talc powder, sodium starch glycolate, stearic acid, calcium stearate, magnesium stearate, pregelatinized starch, lactose, mannitol, crospovidone, talc, macrogol 4000, low-substituted hydroxyl Propylene cellulose, micropowder silica gel, sodium starch glycolate or polyethylene glycol 6000. 4. A method for preparing the β-cyclodextrin/amoxicillin inclusion compound pharmaceutical composition according to claim 1, comprising the following steps: Mix β-cyclodextrin with water to make a suspension; Add amoxicillin with a mass ratio of 1/5 to 2/5, mix and grind thoroughly; Cool, filter, wash the solid with water and dry to obtain the solid clathrate. 5. According to the preparation method of the β-cyclodextrin/amoxicillin inclusion compound pharmaceutical composition according to claim 4, it is characterized in that the following steps are also provided: The solid clathrate is crushed through a 100-mesh sieve, mixed with clavulanate potassium, passed through an 80-mesh sieve twice, dry-granulated, and ground into a powder to obtain a pharmaceutical composition, wherein the dose ratio of amoxicillin-clavulanate potassium is 14: 1～2:1.