HK1079992B - Process for preparation of inclusion compounds between a non-steroidal anti-inflam-matory drug and betacyclodextrin by microwave treatment - Google Patents

Description

Method for preparing inclusion compound of non-steroidal anti-inflammatory drug and beta-cyclodextrin through microwave treatment

Technical Field

The present invention relates to a novel process for the preparation of inclusion compounds of a drug with a cyclodextrin.

In accordance with the present invention, the powdered ingredients are mixed to form a suitable aqueous or alcoholic suspension. Subjecting the suspension to microwave treatment, the resulting product having physical, process and biopharmaceutical properties suitable for the preparation of solid pharmaceutical preparations, wherein said product contains a drug predominantly or exclusively in amorphous form.

In particular, the methods of the invention can produce inclusion complexes of a drug with a cyclodextrin that are more wettable and more balanced in dissolution than crystalline drugs, and dissolve more rapidly in aqueous media. This means more favorable pharmacokinetic properties and may therefore have better therapeutic effects.

Background

Many substances used as active ingredients (drugs) are characterized by their low ability to interact with water, in particular by poor wettability, low solubility and slow dissolution rate. These properties can adversely affect the bioavailability of a drug when it is not administered systemically. In fact, after oral or rectal administration of a drug whose gastrointestinal mucosa absorbs slowly and variably, the blood concentration of the drug fluctuates up and down, and the blood peak is delayed. As a result, the therapeutic efficacy of the drug is reduced and/or exhibits significant inter-and intra-individual variation after absorption. This behavior can also increase deleterious side effects such as gastric damage caused by prolonged contact of poorly soluble drugs with the mucosa in the presence of acidic drugs. Sufficient solubility in water is also a prerequisite for the preparation of liquid formulations in solution.

In view of the above problems, it is very advantageous to employ a method capable of improving the dissolution property of a drug which is hardly soluble in water by itself.

The lower ability of a substance to interact with water depends primarily on the chemical nature of the substance and also on its physicochemical properties, such as the crystalline or amorphous structure of the substance and its particle size.

Some examples of modifications of the chemical properties of poorly soluble drugs to increase their solubility have been reported in the pharmaceutical industry, for example by salt formation (Berge et al J Pharm Sci1977, 66, 1-19; Ceppi Monti et al Arzneimittel Forschung 1992, 42, 556-.

Micronization processes may also be used to increase the surface area of the drug, thereby increasing the surface area in contact with the solvent. However, while this method may increase the dissolution rate in some cases, it does not always increase the solubility.

An interesting way to increase the solubility and dissolution rate of poorly soluble active ingredients is to form complexes with cyclodextrins, i.e. cyclic oligosaccharides obtained by hydrolysis of starch and enzymatic cyclization. Natural cyclodextrins (α, β and γ) are formed primarily from six, seven and eight glucopyranose molecules, respectively, which are linked by α -1, 4 linkages to form a ring. Hundreds of semisynthetic derivatives have also been produced.

The techniques invented to prepare these complexes can be applied to solutions or solid phases so far.

The method for preparing the complex in solution requires the preparation of an aqueous solution of the cyclodextrin to which the drug to be included can be added directly or as a solution. The suspension (or solution) thus obtained is continuously stirred to equilibrium, followed by filtration and removal of the solvent by evaporation (for example by spray drying, Tokomura et al Yakuzaigaku 1985, 45, 1-6) or sublimation (freeze drying, Kurozumi et al Chem Pharm Bull 1975, 23, 3062-3068) to give a complex. For example, EP 153998 filed by the applicant of the present application describes the preparation of piroxicam/β -cyclodextrin complexes by freeze-drying an aqueous solution containing piroxicam/β -cyclodextrin in a molar ratio of 1: 2.5.

Coprecipitation is the most common method used in small scale production of composites. A hot aqueous cyclodextrin solution is prepared, the appropriate amount of "guest molecule" (the substance to be included) is added, and the mixture is then cooled to room temperature. The solid composite precipitates during cooling.

The "kneading" process requires effective mixing of the cyclodextrin with the drug and a small amount of a suitable solvent, which can be removed when the mixture is dried. For example, patent application WO95/32737 filed by SAD discloses a method of preparing a complex product of a non-steroidal anti-inflammatory drug with beta-cyclodextrin by preparing a paste and drying it to make an inclusion complex.

Alternatively, as already mentioned, the composite can also be prepared without solvent, for example by co-milling. A physical mixture of the drug and cyclodextrin was prepared and milled with a high energy mill under controlled humidity conditions (RH 60-75%), with or without heat. Amorphous composites can generally be formed.

For example, EP 449167, also filed by the applicant of the present application, discloses the preparation of piroxicam: a process for beta-cyclodextrin complexes wherein two ingredients in powder form are pre-mixed, followed by co-milling in steam with a high energy mill.

While many of these techniques have been used on an industrial scale, they typically involve time-consuming preparation methods and large amounts of solvents; in addition, a continuous process is not possible. Therefore, there is a need for a process for preparing cyclodextrins on an industrial scale that is faster and more convenient.

Disclosure of Invention

Analysis of the methods described in the cited documents shows that modification of the physicochemical properties of poorly soluble active ingredients by complexation with cyclodextrins can lead to better results in terms of the biopharmaceutical behaviour of said ingredients. In particular, the increased dissolution rate over pure drugs may improve the bioavailability of the product, which may result in better therapeutic effects.

There is also a need for a process for preparing cyclodextrin complexes on an industrial scale that is faster and more convenient.

Microwaves are electromagnetic waves similar to radio waves, and have a frequency of 300MHz to 300 GHz.

The operating frequencies for industrial, scientific and national purposes are 915 and 2450 MHz. For example, the frequency maximum is used to perform the drying process under vacuum (Waldrom et al, PharmEng 1988, 8, 9-13).

When a substance is placed in an electric field in the presence of radio waves or microwaves, it is uniformly heated due to the polarization of individual molecules.

The dielectric heating method is based on the principle that energy is absorbed by a permanent inductive dipole. As a result of this absorption, the molecules begin to vibrate and their friction generates heat (Vromans et al Eur J Pharm Biopharm 1994, 40, 333-.

Not all molecules have a structure suitable for this energy absorption. In general, polar materials with high dielectric constants can absorb more energy than non-polar materials. However, the intensity of the generated vibrations also depends in part on the structure (shape and size) of the molecules, the viscosity of the material, the temperature, and the intermolecular bonds.

The use of microwaves in various industrial fields has increasingly attractive advantages due to their potential for energy saving, environmental protection and cost saving. More reasonable use of energy means lower cost and higher production efficiency.

Industrial process in the food field this energy source was first used in 1960 to dry potato chips. The use of microwaves in continuous production can improve productivity and can reduce the number of production, the space required for production, and the energy cost.

By 1986, more than 130 food manufacturers used microwaves (for drying dough, sanitizing yogurt, etc.) during their production.

Microwaves are only later introduced into the general chemical industry, in particular the pharmaceutical industry, but their use is rapidly expanding; they include some advantageous applications in the fields of extraction, evaporation, proteolysis, determination of the percentage of water content, thermolysis, polymerization, catalysis and combinatorial chemistry, which have great advantages in terms of speed of operation, possibility of automatic sampling, interfaces in analytical systems, etc.

The present invention relates to a method for preparing inclusion complexes with advantageous biopharmaceutical and technological properties by subjecting a mixture of a drug and a natural or semi-synthetic cyclodextrin in an aqueous or alcoholic suspension to microwave treatment.

The method of the invention can produce inclusion complexes that are predominantly or entirely in dissolved form with better dissolution kinetics, the chemical purity of which remains unchanged. The formation of inclusion complexes can be determined by the disappearance of the melting peak of the active ingredient in the thermal analysis (Frmming & Szejtli, cyclodextrins in Pharmacy, Kluwer Academic Publishers, 1994). It is preferable to use cyclodextrin having an initial water content of more than 4% because an initial water content of less than 4% by weight makes it difficult to completely complex the drug. The time and maximum power of irradiation may be adjusted as set forth in detail below to promote formation of the inclusion complex and to ensure that the chemical (and physical) stability of the components is not affected. Since cyclodextrins are carbohydrates, they are prone to thermal degradation processes (caramelization) and in some cases can accelerate the degradation rate of the active ingredients contained therein (Backensfeld et al Int J Pharm 1991, 74, 85-93; Glass et al 8. conference record of International Cyclodextrin monograph, 1996, Kluwer academic publishers, pp 287-290).

WO 97/06781 of the Nissan Chemical application relates to a high frequency mechanical/Chemical heating process (e.g. microwave oven) useful for preparing solid dispersions of drugs, which are poorly soluble in water or characterized by low dissolution kinetics, in the presence of reagents such as polymers and cyclodextrins capable of stabilizing the amorphous state. The product thus prepared is characterized by a faster rate of transmucosal absorption, which makes it possible to increase the bioavailability of the drug. Some examples of solid dispersions obtained by treatment with 500 or 700W microwaves have been reported, but none of them uses cyclodextrins.

Kerc J et al (Drug Dev Ind Pharm 1998, 24, 359-363) describe the preparation of solid dispersions of the poorly soluble Drug felodipine in water-soluble carriers such as porous (amorphous) SiO2 or NaCl (crystalline) by mixing and at different times in a vacuum dryer (at 100 ℃ and 0.01X 10⁵Pa) or in a microwave oven with maximum power (500W).

Bettinetti et al, World Meet. Pharm, Biopharm Pharm Technol591-2, 1995, describes the use of microwaves (energy ═ 500W) for alpha-cyclodextrins, but this application is only for the elimination of residues and/or water of crystallization.

As can be observed, none of these references describe inclusion complexes, and they also make little reference to specific operating conditions that aid in the complexation and prevent the above-described degradation process.

Another aspect of the invention relates to a pharmaceutical composition comprising the drug obtained by the claimed method in association with a cyclodextrin inclusion complex and additives and/or excipients commonly used in the pharmaceutical industry.

Detailed Description

The properties of the process of the invention, the resulting product and the corresponding pharmaceutical composition will be described in the following detailed description.

The method is based on rapid drying under controllable vacuum conditions caused by the thermal effect of microwave radiation.

In the first stage, the drug in fine powder form is mixed with cyclodextrin and a small amount of water or an aqueous solution of an alcohol (preferably ethanol), an acid (preferably HCl) or a base (preferably ammonium) using a vortex mixer such as an Ultraturrax.

By "small amount" of water or solution we mean from 20% to 80%, preferably from 40% to 60% by weight of the drug in admixture with the cyclodextrin.

In the second stage, the resulting mixture is treated in a microwave oven. In the third stage, the product obtained is dried in vacuo at room temperature or with slight heating.

For each drug/cyclodextrin mixture, the maximum time of irradiation and maximum power that can be administered must be determined experimentally. Typically the treatment is carried out with radiation having a radiation power of from 100 to 800W, preferably from 400 to 600W, even more preferably 450W. The treatment may be carried out for 1 to 60 minutes, preferably 2 to 10 minutes. Drying is carried out at below 50 ℃ for 2 to 60 minutes, preferably 5 to 30 minutes.

Preferred active ingredients are drugs that are poorly soluble in water or that are characterized by slow dissolution kinetics. Examples of poorly soluble drugs that can increase bioavailability by forming inclusion complexes are nonsteroidal anti-inflammatory drugs such as piroxicam, ibuprofen, ketoprofen, calcium antagonists such as nifedipine and nicardipine, anticonvulsants such as carbamazepine and phenytoin, and oral hypoglycemic agents such as tolbutamide and glyburide.

Any natural cyclodextrin, such as alpha-, beta-or gamma-cyclodextrin, preferably beta-cyclodextrin or a semi-synthetic cyclodextrin such as hydroxypropyl-beta-cyclodextrin, can be used. Preferably the cyclodextrin should have an initial moisture content of 4% by weight or more.

The molar ratio of drug to cyclodextrin is 10: 1 to 1: 100, preferably 5: 1 to 1: 50, more preferably 1: 1 to 1: 5.

The inclusion complex obtained by the method of the present invention can be prepared into solid or liquid preparations, preferably tablets, using additives and excipients commonly used in the pharmaceutical field.

The invention is further illustrated by the following examples.

Example 1-piroxicam: beta-cyclodextrin inclusion complexes

Preparation of the physical mixture

About 10g of Piroxicam (PRX) and 92g of beta-cyclodextrin (beta CD) were precisely weighed out in a molar ratio of 1: 2.5.

The two powders were combined and mixed thoroughly to ensure a uniform particle distribution.

After addition of water (ca. 70ml) and 28% aqueous ammonia (1.5ml), the physical mixture was mixed with an Ultraturrax vortex mixer at 9500 rpm for 5 minutes.

Microwave treatment

From each of the resulting paste, about 25 g portions of each sample were removed. The sample was placed in a crystallizer, covered with a glass fibre plate to prevent it from spilling in a heating oven, and subjected to microwave treatment according to the following operating protocol:

TABLE 1 with three PRX-beta CD-H copies₂O-NH₃Parameters relating to microwave treatment of mixture samples

PRX:βCD	Time of day	Power (W)	Vacuum pressure (mbar)
				First stage	5 minutes and 30 seconds	450	～250
Second stage	5 points of	0	～190

The second stage, also known as the "dry period", has a vacuum pressure of 190mbar and no microwave radiation. These conditions, along with the residual heat, allow for rapid removal of residual water from the sample.

The microwaved samples were weighed and their weight loss averaged about 40%.

The microwave treated samples were followed by thermodynamic analysis showing that the melting peak of piroxicam disappeared at about 200 ℃.

The solid recovered from the crystallizer was additionally ground in a mortar to examine the stability of the composite to mechanical stress. The traces indicated that the resulting composites did not differ prior to milling.

Determination of the dissolution Rate of piroxicam in the solid phase obtained

The dissolution rate of the samples studied was determined by the dispersion method in USP 25, NF 20, 2002. Each test sample was transferred to a container containing 1 liter of distilled water.

The test was carried out while keeping the temperature of the dissolution tank at 37 ℃ and the rotation speed of the slurry at 50 rpm.

The concentration of the drug in the solution was determined spectrophotometrically every 2 minutes.

Samples containing equal amounts of PRX (about 20mg) were analyzed:

a PRX sample (about 20mg), labeled PRX;

a sample of a physical mixture with a molar ratio of PRX- β CD of 1: 2.5 (about 200mg), labeled m.f.;

3. a sample of the mixture obtained after the microwave treatment (about 200mg) was labelled PROD.

Each sample was analyzed in triplicate.

The amount eluted and the corresponding percentage compared to the initial dose of PRX in the sample are given in table 2.

As can be appreciated, piroxicam dissolves out more quickly and in greater quantities from the inclusion complex obtained by the microwave treatment.

TABLE 2

T minutes	PROD dissolution (mg)	M.f. dissolution (mg)	PRX dissolution (mg)	PROD% dissolution	M.F% dissolution	PRX% dissolution
							0	0	0	0	0	0	0
2	6.376	0.793	0.011	26.778	3.324	0.052
							4	8.437	1.881	0.054	35.436	7.885	0.245
6	10.218	3.063	0.100	42.915	12.841	0.451
							8	11.764	4.563	0.137	49.408	19.129	0.619
10	13.135	6.161	0.189	55.168	25.826	0.851
							20	17.481	10.916	0.455	73.421	45.759	2.051
30	19.998	13.198	0.741	83.991	55.324	3.340
							40	21.315	15.119	1.042	89.522	63.377	4.694
50	21.701	16.734	1.351	91.145	70.145	6.087
							60	21.810	17.991	1.695	91.602	75.414	7.635

Example 2-ketoprofen: beta-cyclodextrin inclusion complexes

Preparation of the physical mixture

About 2g of ketoprofen (keto) and 9.960g of beta-cyclodextrin were weighed out exactly in a molar ratio of 1: 1.

The two powders were mixed thoroughly to ensure uniform dispersion.

After addition of water (. about.8 ml), the physical mixture was mixed with an Ultraturrax vortex mixer at 8000 rpm for 3 minutes.

Microwave treatment

About 5 grams of each sample was taken in triplicate and the samples were placed in a crystallizer and treated with microwaves. Since the amount of the substance to be dried is directly proportional to the time of irradiating the microwave, when the amount of the substance in each sample is reduced, the heating time can also be reduced.

The following methods are summarized in table 3.

TABLE 3. and triplicate Keto- β CD-H₂O-NH₃Parameters relating to microwave treatment of mixture samples

Keto:βCD	Time of day	Power (W)	Vacuum pressure (mbar)
				First stage	2 minutes and 30 seconds	450	～250
Second stage (drying)	3 points of	0	～190

The microwaved samples were weighed and their weight loss averaged about 44%.

Calorimetric analysis of the dried sample showed that the melting peak of ketoprofen disappeared at about 96 ℃.

Example 3-ketoprofen: hydroxypropyl-beta-cyclodextrin inclusion complexes

Preparation of the physical mixture

About 2g of ketoprofen (keto) and 10.5g of cyclodextrin were weighed out exactly in a molar ratio of 1: 1.

Mixing the two powders until uniformly dispersed; water (. about.5.5 ml) was added to the dispersion and the resulting mixture was mixed with an Ultraturrax vortex mixer at 8000 rpm for 3 minutes.

Microwave treatment

Three samples, each about 4 grams, were taken from the resulting mixture and the samples were microwaved using the method described herein.

TABLE 4 parameters relating to the microwave treatment of three samples of ketoprofen/hydroxypropyl-beta-cyclodextrin-mixture

Keto/HPβCD	Time of day	Power (W)	Vacuum pressure (mbar)
				First stage	2 minutes and 30 seconds	450	～250
Second stage (drying)	3 points of	0	～190

After this operation, the weight loss of the sample averaged about 30%. And the melting peak of the active ingredient disappears again.

Example 4-ibuprofen: beta-cyclodextrin inclusion complexes

Preparation of the physical mixture

About 2g of ibuprofen (Ibu) and 19.1g of beta-cyclodextrin were weighed out exactly in a corresponding molar ratio of 2: 3.

Mixing the powders; about 13ml of water was then added to the physical mixture, followed by mixing with an Ultraturrax vortex mixer at 9500 rpm for 4 minutes.

Microwave treatment

Samples of about 6 grams each were taken in triplicate, placed in a crystallizer, covered with plates, and subjected to microwave treatment.

TABLE 5 parameters associated with microwave treatment of triplicate Ibu- β CD-H2O sample mixtures

Ibu:βCD	Time of day	Power (W)	Vacuum pressure (mbar)
				First stage	2 minutes and 30 seconds	450	～250
Second stage	3 points of	0	～190

The weight loss of the samples after this operation averaged 35%.

The results of the thermal analysis showed that the melting peak of the active ingredient disappeared at about 76 ℃.

Example 5-carbamazepine: beta-cyclodextrin inclusion complexes

Preparation of the physical mixture

About 2g of Carbamazepine (CBZ) and 11.3g of beta-cyclodextrin were precisely weighed in a molar ratio of 1: 1.

About 10ml of water was added to the resulting physical mixture, followed by mixing for 2 minutes at 9500 rpm using an Ultraturrax vortex mixer.

Microwave treatment

Three samples of about 5 grams each of the resulting mixture were placed in a crystallizer and subjected to microwave treatment as described in table 6.

TABLE 6 with triplicate CBZ-beta CD-H₂Parameters relating to microwave treatment of O-mixture samples

CBZ:βCD	Time of day	Power (W)	Vacuum pressure (mbar)
				First stage	2 minutes and 30 seconds	450	About 250 f
Second stage (drying)	2 is divided into	0	About 190

The weight loss of the samples after this operation averaged 47%.

The results of thermal analysis show that both melting peaks of both polymorphic forms of carbamazepine are significantly reduced, although trace amounts of crystalline active ingredient are still present.

Claims (7)

1. A method of preparing an inclusion complex of a drug and a cyclodextrin, comprising the steps of:

a) mixing a drug in the form of a fine powder with a cyclodextrin in a molar ratio of 1: 1 to 1: 5 in the presence of water or an aqueous solution comprising an alcohol, an acid or a base in an amount of 20% to 80% by weight of the total amount of the drug and cyclodextrin mixture;

b) exposing the resulting mixture to microwave radiation;

c) the obtained product is dried in vacuum at a heating temperature of less than 50 ℃,

wherein the drug is selected from piroxicam, ibuprofen, ketoprofen or carbamazepine,

characterized in that the microwave oven radiation of step b) is carried out at a radiation power of 100 to 800W and the exposure time is 1 to 60 minutes.

2. The method according to claim 1, characterized in that the amount of said water or aqueous solution of step a) is between 40% and 60% by weight of the total amount of said drug and cyclodextrin mixture.

3. A method according to claim 1 or 2, characterized in that the radiation power is 400 to 600W.

4. A method according to claim 3, characterized in that the radiation power is 450W.

5. A method according to claim 1 or 2, characterized in that the exposure time is 2-10 minutes.

6. Method according to claim 1 or 2, characterized in that the cyclodextrin is selected from the group consisting of α -, β -, γ -cyclodextrin or hydroxypropyl- β -cyclodextrin.

7. Method according to claim 1 or 2, characterized in that said drug is piroxicam, said cyclodextrin is β -cyclodextrin and said molar ratio is 1: 2.5.