HK1080720B - A process for the preparation of piroxicam:b-cyclodextrin inclusion compounds - Google Patents

Description

Process for preparing piroxicam beta-cyclodextrin inclusion compound

Technical Field

The invention relates to a preparation method of piroxicam and beta-cyclodextrin inclusion compound.

In more detail, according to the preparation method of the present invention, the aqueous solutions of the two components are subjected to a freezing treatment at an extremely high speed before being dried. The products obtained have physico-chemical characteristics and technical and biopharmaceutical properties which are more advantageous than those obtained by the processes according to the prior art. The resulting product is suitable for the preparation of pharmaceutical compositions for oral administration.

Technical Field

Piroxicam is a non-steroidal anti-inflammatory drug (NSAIDs) compound widely used in rheumatoid arthritis, osteoarthritis, acute pain in musculoskeletal disorders, post-operative and post-traumatic pain, and dysmenorrhea.

Piroxicam is poorly soluble in water (0.003% at pH5, 37 ℃) and exhibits low surface wettability (water contact angle 76 ℃) and a high crystal lattice, as evidenced by its melting point (198-.

Since the molecule exhibits good membrane penetration properties, its low solubility is responsible for its low dissolution rate in gastrointestinal fluids, which in turn leads to slow absorption and a delay in onset time.

Slow dissolution may also exacerbate local side effects associated with the drug (e.g., gastric irritation).

The handling of piroxicam is complicated by its possible tautomeric transformations and polymorphism. The molecules do exist in two polymorphs, a and β, with the same intramolecular structure eze (i) and different intramolecular and intermolecular hydrogen bonding interactions; it may also exist as a pseudopolymorph, which is the zwitter-ionic hydrate ZZZ, one of its possible resonance forms being represented by formula (II) (Reck et al Pharmazie 1988, 43, 477; Bordner et al acta crystallogr 1984, C40, 989).

An effective solution to the problems associated with the low solubility of piroxicam consists in the preparation of cyclodextrin inclusion complexes, as claimed in EP 153998. Hereinafter, the terms "complex", "inclusion complex" and "clathrate" are used equivalently.

Cyclodextrins (CDs) are natural cyclic oligosaccharides with a receptacle-like macrocyclic shape obtained by enzymatic degradation of starch. The three major cyclodextrins are composed of 6 (. alpha.), 7 (. beta.), or 8 (. gamma.) (1 → 4) D-glucopyranose units. Among them, β CD has proved to be the most useful compound piroxicam.

Preclinical and clinical studies have demonstrated that piroxicam: beta-cyclodextrin inclusion compounds (hereinafter referred to as P beta CD) are characterized by a faster and more efficient oral absorption than piroxicam alone (Derouba ix et al Eur J Clin Pharmacol 1995, 47, 531). In particular, the bioavailability of the active ingredient is greatly increased in terms of speed and extent of absorption over the first two hours. As far as stoichiometry is concerned, inclusion complexes in a molar ratio of 1: 2.5 are preferred over complexes in a 1: 1 or 1: 4 ratio (Acerbi, Drug Invest1990, 2(4), 42).

The formation of the inclusion complex results in a much faster dissolution and absorption rate of piroxicam than any of the crystal forms known so far for technical modification (Acerbi et al: A piroxicam reactant simple administration of inhibition: beta-cyclic inhibition of complex catalysis, of inhibition of expression of the 8th international cyclic inhibition of Symposium, Budapest, March 30-April 2, 1996; Wangd et al J in clinical 2000, 40(11), 1257-1266).

The faster onset of action makes P β CD particularly effective as an analgesic, i.e., for treating diseases such as toothache, post-traumatic pain, headache, and dysmenorrhea.

The successful results obtained by the use of cyclodextrins depend on the fact that by complexation it is possible to obtain a stable amorphous structure, since the amorphous form has a larger surface area, its lattice energy is much lower than that of the crystalline form, and both the wettability and the water solubility of piroxicam are increased. Amorphous piroxicam like this is indeed a metastable form that crystallizes in less than a few hours (Redenti et al Int J Pharm 1996, 129, 289).

Furthermore, raman studies have also demonstrated that piroxicam in the β -cyclodextrin inclusion complex exhibits a positively and negatively switched zwitterionic structure, undergoing electron shifts similar to this structure of the hydrated pseudopolymorph (II). This structure is stable due to chemical interactions with β -cyclodextrin through electrostatic and hydrogen bonds. The bipolar character of the zwitterionic structure increases the solubility and dissolution rate of piroxicam, thereby increasing its absorption rate (Bertoluzza et al J Mol Struct1999, 480-.

Therefore, in order to ensure the best performance of dissolution rate and absorption rate, which are important for analgesic effect, the process of preparation of P β CD should not only reach the completion of the inclusion reaction, but also the complete amorphization of the whole product. Moreover, since the solubility aspects are strictly dependent on the intramolecular structure assumed by piroxicam in the inclusion complex, the preparation process should be able to achieve complete conversion of piroxicam into the zwitterionic form.

A1: 2.5 molar ratio of amorphous P β CD clathrate, wherein piroxicam is completely in the form of zwitterions, can be characterized by its Raman spectrum, X-ray powder diffraction pattern, and thermodynamic behavior.

The FT-raman spectrum obtained by simply filling the powder into a measuring cup is disclosed in fig. 1. It is at 1650-^-1The following main peaks are shown in the range (accuracy. + -. 1 cm)^-1)：

1613cm^-1(sh)，1593(s)，1578(sh)，1561(w)，1525(br)，1519(br)，1464(m)，1436(m)，1394(s)，1331(brm)/1306(sh)，1280(w)，1260(w)，1234(w)，1217(vw)，1186(w)，1158(m)，1119(m)，1083(w)，1053(w)，1036(w)，992(w)，947(brw)。

Description of the symbols: sh is acromion; s is a strong peak; m is a middle peak; w is weak peak; vw is a very weak peak; br ═ broad peak.

The thermal profile of the Differential Scanning Calorimetry (DSC) analysis does not show any endothermic melting peaks at 190-200 ℃ typical of crystalline piroxicam. A typical DSC curve is shown in figure 2. The situation is as follows: the initial temperature was 20 ℃, the scanning speed was 10 ℃/min and the final temperature was 250 ℃.

In general, cyclodextrin inclusion complexes can be prepared based on liquid, solid or semi-solid reactions between components. The cyclodextrin and drug are first dissolved in a suitable solvent, followed by isolation of the solid complex by crystallization, evaporation, spray drying (Tokomura et al Yakuzaigaku 1985, 45, 1) and lyophilization (Kurozumi et al Chem Pharm Bull 1975, 23, 3062).

In the semi-solid state, the two components are kneaded together in the presence of a small amount of a suitable solvent, and the resulting complex is vacuum dried, sieved and homogenized (Torricelli et al Int JPharm 1991, 75, 147). In the solid state process, the two components are optionally sieved to uniform particle size and thoroughly mixed, and then they are ground in a high energy mill, optionally heated, sieved and homogenized.

The method is also useful for the preparation of inclusion complexes consisting of piroxicam (P) and Cyclodextrins (CDs).

For example, EP 153998 discloses that complexes of P and CDs in a molar ratio of between 1: 1 and 1: 10 can be prepared in different ways:

a) crystallization from an aqueous or organic/aqueous solution containing two components;

b) evaporating the water/ammonia solution;

c) freeze-drying or atomizing (spray-drying) the water/ammonia solution in an air stream.

All examples refer to 1: 2.5P β CD formulations on a laboratory scale (from mg to g).

EP 449167 discloses the preparation of P: a method of forming a CD complex, characterized in that two components, both in solid powder form, are mixed together and then co-milled together in a high energy mill in a milling chamber which has been saturated with water vapour.

In this case, the 1: 2.5P β CD formulation with the best performance was also obtained on the gram scale.

In example 2 of EP 449167, the dissolution rate of tablets prepared according to the process of claim containing 1: 2.5P β CD as active ingredient was compared with the dissolution rate of similar pharmaceutical compositions obtained by different methods containing the same active ingredient, as well as commercially available piroxicam compositions in the form of capsules. The conditions of the dissolution test are not specified.

In this experiment, all formulations including the capsules achieved a dissolution of piroxicam of > 90% within ten minutes (600 "), although the dissolution rate of piroxicam of the inclusion complex obtained according to the patented method was the highest.

The technical problem faced by the present invention is that, when changing from laboratory to industrial scale, tablets prepared with the complex are obtained that exhibit good performance in terms of dissolution rate,

according to the invention, 1: 2.5P β CD can be obtained by freeze-drying (lyophilization) on an industrial scale. Lyophilization is a process in which water is removed from the product by sublimation, i.e., at a product temperature below its eutectic temperature. This operation is carried out with a freeze-drying apparatus (freeze-dryer) consisting of a drying chamber equipped with temperature-controlled shelves, a condenser to capture the water removed from the product, a cooling system to refrigerate the shelves and condenser, a vacuum system to reduce the pressure in the chamber and a condenser to facilitate the drying process.

In the case of 1: 2.5P β CD, the lyophilization process of the present invention comprises the following steps:

i. dissolving piroxicam and beta-cyclodextrin in hot water in the presence of ammonium hydroxide;

adjusting the solution to a temperature of at least about-10 ℃ in order to achieve complete freezing;

further reducing the temperature of the frozen solution, i.e. to a temperature below the eutectic temperature of the product (-18 ℃), i.e. at least-20 ℃, preferably between-30 ℃ and-40 ℃;

vacuum drying the frozen solution.

It has been found that this is also a first aspect of the invention, in order to obtain a 1: 2.5P β CD, characterized in that: i) the inclusion reaction is complete; ii) completely amorphous; iii) complete conversion of piroxicam to the zwitterionic form, it is necessary to cool the solution as quickly as possible, in any case at a rate equal to or greater than about 1 deg.C/min, to the temperature at which complete freezing occurs.

A rapid cooling rate is required to "freeze" and maintain the same structure in the solid state as the inclusion complex in solution, where piroxicam is the zwitterionic form.

The inventors have indeed found that if the cooling operation is carried out at a very low rate, the β -cyclodextrin starts to recrystallize before the solution is completely frozen, after which piroxicam decomplexes, partially losing the zwitterionic structure.

The rapid cooling of the solution may be performed by dividing the solution into portions and placing the portions in trays which are placed on a temperature controlled shelf of a freeze dryer. To cool the solution at a rate equal to or greater than about 1 deg.C/minute, the temperature control rack should be pre-cooled to a temperature of at least-30 deg.C, preferably-40 deg.C.

In another embodiment, to further speed up the cooling operation, the product solution may be frozen outside the freeze-dryer, for example by pouring it into a dewar filled with liquid nitrogen, and then, once recovered, subjecting the resulting product to a drying operation in the freeze-dryer.

In fact, it has been found that, in a further aspect of the invention, the result of freezing with liquid nitrogen is the formation of a product in the form of solid particles. And the solid particles have an increased sublimation surface than the layer-shaped powder obtained by cooling the solution on a temperature-controlled shelf, thereby shortening the drying time and increasing the yield.

None of the prior art documents mentions a critical freezing rate to obtain a 1: 2.5 molar ratio of lyophilized ptcd that meets the above requirements, namely: i) the inclusion reaction is complete; ii) completely amorphous; iii) complete conversion of piroxicam to the zwitterionic form. However, there are mentioned the benefits that can be obtained in terms of improved yields by subjecting the solution containing the complex to a pre-freezing treatment in liquid nitrogen.

Example 4 of EP 153998 indicates the preparation of P β CD by lyophilization, the state of the clear solution being poured into a freeze-dryer pre-cooled to-20 ℃. None mention the importance of the cooling rate of the solution, a temperature of-20 ℃ is not sufficient to guarantee a cooling rate of the hot solution equal to or greater than 1 ℃/minute.

In the paper of Acerbi et al (Drug Invest1990, 2, supply.4, 29-36), a flow chart showing the process of preparation of P β CD is outlined. As far as lyophilization is concerned, only the temperature of the frozen solution (-40 ℃) prior to drying is mentioned.

In this paper, no critical conditions are reported regarding the freezing step, in particular no cooling rate is reported.

Detailed Description

The features of the method of the present invention for preparing P β CD clathrates will become more apparent from the detailed description below.

The method of the invention consists in a lyophilization process. Freeze dryers of various sizes and configurations may be used. In a first step, piroxicam and β -cyclodextrin in appropriate molar ratios and ammonium hydroxide are added to a water tank equipped with a tap containing water at a temperature higher than 60 ℃, preferably higher than 70 ℃, more preferably between 70 and 75 ℃, and then mixed until dissolved. In a second step, the hot solution is poured through a tap onto a temperature-controlled rack pre-cooled to at least-30 ℃ in such a way that: the temperature of complete freezing (-10 ℃) is reached within not more than 90 minutes (speed ≈ 1 ℃/min), preferably within less than 60 minutes (speed ≈ 1.5 ℃/min). More preferably, the shelves are pre-cooled to-40 ℃ to reach the initial freezing temperature (about-5 ℃) in about 30 minutes. In a third step, the temperature is further lowered to at least-20 ℃ in about 120 minutes, preferably to a temperature between-30 ℃ and-40 ℃, i.e. to a temperature below the eutectic temperature (-18 ℃) of the product (total freezing time: 210 minutes). The frozen product is then subjected to a vacuum drying stage by adjusting the temperature of the shelves to 50-60 c, preferably 55 c. The drying stage can be carried out in one or two stages, and the product can be dried a second time, keeping the shelf temperature at the same temperature of 50-60 ℃, to further reduce the residual water content of the complex.

Alternatively, the hot solution is poured through a tap into a dewar filled with liquid nitrogen, in such a way that: almost immediately (speed greater than 1 ℃/min) to a temperature below the eutectic temperature (-18 ℃).

The frozen product is reconstituted and subjected to a drying stage on the shelves of the freeze-dryer described above.

According to the invention, piroxicam and beta-cyclodextrin are used in a molar ratio of 1: 1 and 1: 4, preferably 1: 2.5.

In the first step of the procedure, concentrated ammonium hydroxide is advantageously used, preferably at a concentration of 28-30% w/w, in a ratio of 1: 1w/w with respect to piroxicam.

The P β CD complexes obtained with the process of the present invention can be advantageously used for the preparation of pharmaceutical compositions for oral, rectal and topical administration having analgesic, anti-inflammatory and antirheumatic activity, preferably in the form of tablets, effervescent tablets or oral sachets.

Advantageously, the oral tablets contain per unit dose between 40mg and 200mg of the 1: 2.5 complex, preferably 95.6mg or 191.2mg (corresponding to 10 and 20mg of piroxicam, respectively), and as excipients lactose, crospovidone, sodium starch glycolate, silicon dioxide, starch and magnesium stearate.

The following examples better illustrate the invention.

Detailed Description

Example 1 lyophilization preparation of 1: 2.5P β CD

About 50 liters of water was poured into a water tank and heated to a temperature of 70-73 c. 8.6kg (7.57 mol) of beta-cyclodextrin, 1kg (3.02 mol) of piroxicam and 1kg of 28% ammonium hydroxide were added successively and the mixture was stirred for 30 minutes. The solution was poured through a tap onto a temperature-controlled shelf of a freeze-dryer pre-cooled to-40 ℃. After 210 minutes the frozen product reached a temperature of-30 ℃ and therefore the residual water content was reduced by adjusting the shelf temperature to 50-60 ℃ and performing a first drying stage under vacuum and then a second drying stage at the same temperature.

The 1: 2.5P β CD product was collected from the plate in layers.

The raman spectrum and the thermal curve of the resulting product are shown in fig. 1 and 2, respectively. Powder X-ray analysis shows a typical diffuse diffraction pattern for the amorphous product.

EXAMPLE 2 dissolution Rate of tablets

Tablets containing 1: 2.5P β CD prepared according to the method of example 1 as the active ingredient were prepared by direct compression according to the following composition units.

Composition (I)	Mass (mg/tablet)
		1∶2.5 PβCD	191.2
Lactose monohydrate	102.8
		Crospovidone	50
Sodium starch glycolate	20
		Colloidal hydrated silica	20
Pregelatinized starch	10
		Magnesium stearate	6
In all	400

The parameters used to perform dissolution testing are known to be quite stringent, which can greatly affect dissolution performance. For the differences between the different inclusion complexes, dissolution tests were performed according to the USP paddle method with the following modifications: six tablets were dissolved in 300ml of water at 37 ℃ at 125 r.p.m; after 10 minutes an aliquot was taken and the content of piroxicam was measured by spectrophotometric analysis.

To obtain the required absorption curve, the dissolution specification requires that the amount of dissolved piroxicam within 10 minutes is > 90%.

The tablets containing the 1: 2.5P β CD complex obtained according to the process of the invention (example 1) meet such a specification, whereas the tablets containing the same complex prepared according to the prior art process do not.

Claims (11)

1. A process for the preparation of piroxicam in a molar ratio of 1: 2.5: the freeze drying method of the beta-cyclodextrin inclusion compound comprises the following steps:

a) dissolving piroxicam and beta-cyclodextrin in a molar ratio of 1: 2.5 in water at a temperature of at least 60 ℃ in the presence of ammonium hydroxide;

b) cooling the hot solution to-10 ℃ of full freezing;

c) further reducing the temperature of the frozen solution of step b) to at least-20 ℃; and

d) vacuum drying the frozen solution;

characterized in that the hot solution of step a) is brought to a fully frozen-10 ℃ at a cooling rate equal to or greater than 1 ℃/minute.

2. Method according to claim 1, characterized in that the complete freezing temperature of the hot solution is obtained in a time not exceeding 90 minutes.

3. Method according to claim 2, characterized in that the complete freezing temperature of the hot solution is obtained in less than 60 minutes.

4. A method according to claim 3, characterized in that the cooling rate is 1.5 ℃/min.

5. The process according to claim 1, characterized in that the hot solution of step a) is placed on a temperature-controlled shelf of a freeze-dryer pre-cooled to at least-30 ℃ in order to obtain a cooling rate equal to or greater than 1 ℃/min.

6. A method according to claim 5, characterized in that the temperature-controlled shelves of the freeze-dryer are pre-cooled to at least-40 ℃.

7. The method according to claim 1, characterized in that the hot solution of step a) is poured into a dewar filled with liquid nitrogen.

8. Method according to claim 1, characterized in that said temperature of the frozen solution of step b) is lowered to between-30 ℃ and 40 ℃.

9. The process according to any one of claims 1 to 7, characterized in that the drying of step d) is carried out at a temperature of 50 to 60 ℃.

10. A method according to any one of claims 1 to 7, characterized in that ammonium hydroxide is used in a concentration of 28-30% and in a ratio to piroxicam of 1: 1 w/w.

11. Piroxicam prepared according to the process of any of claims 1 to 10, in a molar ratio of 1: 2.5: a β -cyclodextrin inclusion compound characterized in that it has a raman spectrum as shown in fig. 1.