ULTRASOUND-ASSISTED COMPACTION PROCESS WITH A COMPACTION DEVICE MADE OF COUPLED PLASTIC-METAL MATERIALS FIELD OF INVENTION
The present invention relates to an ultrasound-assisted compaction process of powders mixtures. PRIOR ART
The formulation and administration of drugs which are slightly soluble or insoluble is one of the major problems that arises in pharmaceutical research. Slightly soluble or insoluble drugs often present insufficient absorption in the gastrointestinal tract, and consequently a low level of bioavailability. As a result, pharmaceutical formulations must contain large amounts of such drugs, and need to be administered repeatedly during the day, in order to maintain a plasma concentration with therapeutic efficacy. The factors that influence the solubility and dissolution rate of molecules in water are associated with their chemical-physical properties such as crystalline form, particle size, surface area and wettability.
A way to enhance the solubility of poorly soluble or insoluble drugs is to thermodynamically activate them by forming an amorphous phase and/or nanocrystalline structures from the original crystalline state. This results in drug solubilisation kinetic, having dissolution rate and supersaturation concentrations, that is much higher than that obtainable with differently formulated drug in crystalline state. As a consequence, a strong increase of the drug effects "in vivo" is allowed by enhancing the bioavailability, reducing the onset of action (tmaχ) and decreasing the variability between subjects. A technique to enhance the solubility of poorly soluble or insoluble drugs of reduced particle size consists in incorporating them into water-swellable but insoluble polymer by means of polymer swelling with a solution of the drug in a solvent; the solvent is thus removed and the drug precipitates in small particles within the polymer network. An example of this processes is described in US 5,225,192, which deals with the loading of thermodynamically activated drug into particles of inert crosslinked polymers.
The mechanochemical activation by high-energy, co-grinding of crystalline drugs with inert substances (carriers) is a technique that allows modification of the chemical-physical properties of drugs by destructuring of the crystal and forming an amorphous phase and/or nanocrystalline structures inside the carrier (Nakai et al. Chem. Pharm. Bull. 25, 3340, 1977) and consequently improves the drug solubility in water. Mechanochemical activation offers the advantage of carrying out the process in solid state, avoiding the use of solvents with the related limitations (e.g. residual amount of solvents in the final product, drug degradation in a liquid state). Ultrasounds or other heat treatments by means of waves can also be used to produce solid dispersions of thermodynamically activated drugs. US 6,462,093 deals with a process for producing solid dispersion of sparingly water soluble drugs comprising an amorphous state-inducing agent and an amorphous state-stabilising agent. The sparingly water soluble drug is converted in an amorphous state by means of a high-frequency heating (microwaves), carried out at a temperature lower than that of conventional methods. The solid dispersion of the amorphous drug have improved biopharmaceutical properties (e.g. bioavailability) . The possibility of converting an active drug from crystalline to amorphous state exploiting ultrasounds is also reported in literature (Sancin et al. Eur. J. Pharm. Sci. 7, 207, 1999). This article describes the preparation of tablets containing amorphous active drugs by means of an ultrasound-assisted tabletting machine. The tablets obtained in this way do not present noticeable decomposition of the drug at the end of the process. Homogeneous physical mixtures comprising a crystalline drug and a suitable carrier have been treated according to US 5,662,935 by means of an ultrasound- assisted tabletting machine, equipped with a compaction device (die chamber and punch) in stainless steel. The mixture of the drug and one or more excipients is exposed to mechanical or electromechanical actions of frequency between 1 kHz and 2MHz . Depending on the selected excipients, the obtained controlled release forms have a delayed or rapid release. This ultrasound-assisted compaction has shown to bring improvements in the compacting of pharmaceutical solids with
respect of the classical compaction processes such as reducing the energy required for compaction, increasing the efficiency in the control of release, improving the uniformity of the original mixture in the obtained tablets. This notwithstanding, the process is unsatisfactory since the ultrasound-induced amorphisation of the drug is not homogeneously accomplished throughout the matrix. In fact, different content of amorphous drug are present in different sampling points of the tablet, while the total drug (chemical assay) in any thermodynamic state, crystalline and amorphous, is homogeneously present in the tablet maintaining the homogeneity of the original physical mixture. Therefore this method gives rise to considerable problems. As a consequence, the ultrasound-assisted process of the prior art cannot be used for the thermodynamic activation of drugs, since the final product is not homogeneous and the resulting properties are not repeatable. DESCRIPTION OF THE FIGURES FIGURE 1. shows the scheme of the ultrasound-assisted tabletting machine. FIGURE 2 shows the scheme of the compaction device. FIGURE 3. show sampling spots on the tablet. SUMMARY OF THE INVENTION The present invention relates to an improved process for preparing a compacted matrix comprising one or more amorphous active compounds by means of ultrasound-assisted compaction. This invention aims to achieve an improvement in both the homogeneity of the dispersion of the amorphous active compound and in the percentage of amorphisation of the active compound by modifying the known process. These goals have surprisingly and unexpectedly been attained by using an ultrasound-assisted compaction device whose die chamber and punch are made of a different material one from the other, chosen from plastic and metal. DETAILED DESCRIPTION OF THE INVENTION
Ultrasound-assisted compaction is a technique that uses ultrasounds that are sound waves with high frequency (from 16 KHz up to 200 MHz ) usually generated exploiting the inverse piezoelectric effect of special materials such as quartz or ceramics. The application of a voltage between the faces of a piezoelectric crystal causes a mechanical distortion of the material. If the frequency of the applied
voltage is equal to the typical frequency to whom the crystal is distorted, the result is a sound wave. The ultrasonic wave is therefore generated by a piezoelectric transducer. Then, it passes through a horn (or booster), where the original amplitude of the wave is amplified, and is addressed to the powder material to be compressed. The ultrasound-assisted machine combines the actions of pressure and ultrasounds to generate compacted matrices having throughout dispersed the active compound in a thermodynamically activated form (amorphous form). The compaction pressure is lower than that normally required in standard compaction machines (e.g. roll compactors, tabletting machines), since the ultrasounds enhance the compaction of the powder bed by means of their energy.
Hence, the present invention provides an improved process for preparing a compacted matrix containing an amorphous active compound comprising the step of compacting a powder mixture comprising one or more active compounds and one or more inactive components in a modified ultrasound-assisted compacting device whose die chamber and punch made of a different material one from the other, chosen from plastic and metal.
The active and the inactive compounds are mixed my means of conventional methods and the obtained physical mixture is then exposed to ultrasound-assisted compaction. The mixing is preferably carried out in the absence of any solvents so as to obtain a dry physical mixture.
According to the present invention, by "active compound" it is meant any compound that is endowed with a biological activity. According to a preferred embodiment of the invention the active component is a drug and the inactive component is an excipient. The active component is preferably a substance which is more efficacious in its amorphous form than in its crystalline form or it is a substance that provides for the desired performances when it is in this form. A typical example is given by poorly soluble or insoluble drugs that have higher solubility in the amorphous state than in the crystalline state. Therefore, according to a further preferred embodiment of the present invention the active compound is a poorly soluble or insoluble drug. The final product obtained with the process herein described is a matrix comprising at least one homogeneously distributed active compound and
possessing reproducible properties from lot to lot. Moreover, also an increase in the amount of the amorphous form in the matrix has been observed when the compaction device of the invention, made of coupled metal-plastic parts, is used for the preparation of the matrix, compared to when conventional devices with parts made of the same material are used. Conventional devices are usually made either of metal or plastic parts.
This ultrasound-assisted compaction device suitable for carrying out the compaction process of the invention constitutes a further object of the present invention. The compaction device is made of a compaction die which is formed by a die chamber, where the powder mixture is loaded, and a punch which presses the powder against the ultrasound generator. The device of the invention works essentially according to usual practice of ultrasound-assisted devices but its die chamber and punch are made of a different material one from the other, chosen from plastic and metal, contrary to the normally employed devices whose die chamber and punch are made of the same material. The die chamber of the apparatus of the present invention may be made of metal and the punch of plastic material. As an alternative, the die chamber may be made of plastic material and the punch of metal. Preferably, the metal material is chosen form the group consisting of stainless steels, in their different types and forms (e.g. AISI 304, AISI 316), cast irons, aluminium and bronze, titanium.
Preferred plastic materials are DELRIN®, an acetal resin trademark of DuPont Co., fluoropolymer resins (TEFLON®), polybutylene terephtalate resins as CRASTIN®, polyamide resins as ZYTEL®, polyethylene terephtalate, or glass reinforced copolyesther resins as THERMX®. Other plastic materials having high toughness and chemical resistance can also be used.
According to a preferred embodiment of the invention, the plastic material is an acetal resin and the metal is stainless steel. The ultrasound-assisted compaction device can be applied to any ultrasound- assisted compactor such as a tabletting machine or a roll compactor.
Tablets, mono or multilayered films, rod-shaped matrices are easily produced, but more complicated geometries can also be prepared.
The basic operation conditions of the compactor comprising the device of the invention correspond to usual practice.
The physical mixture is preferably exposed to the ultrasound-assisted compaction process of the invention at the frequency of the ultrasounds ranging from 16 to 100 KHz, more preferably from 20 to 60KHz and at a range of amplitude of the ultrasonic waves ranging preferably from 10 to 100 μm, more preferably from 15 to 40 μm. The ultrasound action on the powder bed is preferably applied for a brief period of time, usually from 0.1 to 100 seconds, more preferably from 0.2 to 10 seconds. The total amount of energy supplied to the powder is usually between 10 and 10000 J, preferably from 100 to 2000 J.
When the compaction device of the invention is used in an ultrasound-assisted tabletting machine, then the resulting compacted matrix is a tablet. Prefarably said tablet has a diameter from 2 to 25 mm or a mono or multi layered film having a size from 4 to 50 cm and thickness from 0.1 to 20 mm. According to a preferred embodiment of the present invention, the powder mixture to be compacted by means of the process of the present invention is a pharmaceutical powder mixture comprising at least one drug and at least one excipient. Preferably said drug is a poorly water-soluble or water-insoluble drug. Illustrative examples of therapeutic classes to which said drug may belong are antibiotics, diuretics, sedatives, analgesics, bronchodilators, beta-blockers, anti- inflammatories, anti-depressants, anti-diabetics, anti-hyperlipidemic agents, anti- hypertensives, vasodilators, vasoconstrictors, hormones, steroids, anti-histamines, anti-pyretics, anti-microbial agents, amphetamines, barbiturates, anti-Parkinson agents, anti-spastics, ophthalmic drugs, anti-cancer drugs, immunosuppresants, anti-HIV agents, anti-psoriasis.
Preferred drugs according to the present invention are nimesulide, piroxicam, naproxene, ketoprofen, ibuprofen, diacereine, griseofulvin, itraconazole, fluconazole, miconazole, ketonazole, zafrilukast, salbutamol, beclomethasone, flunisolide, clenbuterol, salmeterol, budesonide, estradiol, estriol, progesterone, megestrol acetate, medroxyprogesterone acetate, nefedipine, nicergoline, nicardipine, lisinopril, enalapril, nicorandil, celiprolol, verapamil, temazepam,
diazepam, lorazepam, fluidiazepam, medazepam, oxazolam, zolmitriptan, sumatriptan, fenofibrate, lovastatin, atorvastatin, fluvastatin, simvastatin, tosufloxacin, ciprofloxacin, ritonavir, saquinavir, nelfinavir, acyclovir, indinavir, tacrolimus, rapamycine, didanisine, loratadine, etoposide, bicalutamide, tamoxifen, docetaxel, paclitaxel, risperidone, raloxifene, carbamazepin, phenytoin, oxycodone, hydrocodone, morphine, butorpanol, tinazadine, famotidine. The inactive compounds forming the matrix can be chosen among the different excipients used in pharmaceutical preparations, such as polymers, organic compounds (sugars, fatty acids, organic salts, surfactants, etc.) and inorganic compounds.
Preferably, the matrix of the present invention contains as an excipient at least one pharmaceutically acceptable polymer .
Particularly preferred polymers, which can be utilised alone or any mixture thereof, comprise cellulose and derivatives thereof such as methyl cellulose, ethyl cellulose, hydroxylpropyl cellulose, hydroxylpropylmethyl cellulose and sodium crosscarmellose, starch and derivatives thereof such as pre-gelatinised starch and sodium starch glycolate, linear and crosslinked polyvinylpyrrolidones, cyclodextrins such as alpha-, beta- and gamma-cyclodextrin, polysaccharides such as carrageenans, alginates, pectates, hyaluronates, chitosan, chitin, scleroglucans, dextrans and beta-glucans, acrylic polymers such as polymethacrylates as Eudragit L, S, RL, RS, polyethylene glycols, polyvinylpyrroline, polyvinylacetate, polylactic and polyglycolic polymers.
A further object of the present invention are also compacted matrices obtained with the process of the invention. Preferably, said matrices are in the form of a tablet.
According to a preferred embodiment, the matrices of the invention contain at least one drug and at least one excipient.
The obtained matrices can be subjected to further treatments, such as size reduction, encapsulation, coating, pelletization for the manufacture of different pharmaceutical forms or compositions, and pharmaceutical forms prepared with said matrices.
A further object of the present invention is a method to increase the amorphous fraction of a water insoluble or slightly soluble drug characterised in that a powder mixture comprising said drug is compacted in a device according to the invention. The present invention is not restricted to the used active compounds or inactive ingredients described in the examples below.
EXAMPLES AND METHODS
The equipment is a Saitec (Castelguelfo (BO), Italy) ultrasound-assisted tabletting machine (Figure 1) having the compaction device reported in Figure 2. The compaction die chamber is loaded with the powder (that has been previously homogeneously obtained by mixing the drug and excipient) and the punch presses the powder against the horn. Unlike traditional tabletting machines, the punch pressure is very low (20-80 kg/cm2) . The ultrasonic wave is generated by a piezoelectric transducer and then passed through the horn (or booster) where the original amplitude of the wave is amplified. The simultaneous action of pressure and ultrasounds shapes the tablet and activates the drug inside it. A Teflon® sheet avoids sticking of tablets on the horn , so tablets can be easily ejected.
The assay of the amount of drug sampled in the different parts (bottom, centre, periphery) of the matrix is determined by means of a HPLC method. The sampling spots in the matrix are performed according to the scheme reported in Figure 3.
The amount of amorphous drug present in the different spots (bottom, centre, periphery) of the matrix is determined, as a complementary part of the crystalline form of the drug, by means of Differential Scanning Calorimetry (DSC). The fraction of crystalline form is determined by comparing the enthalpy relative to the melting of the crystals in the polymer (ΔHmeιting) to that of pure drug (ΔH0). The ΔHmeiting/ΔHo ratio, normalized in accordance with the drug assayed in the polymer, is then considered equal to the fraction of crystalline form. The amount of amorphous form is then:
Amorphous % = 100 % - Crystalline form %
The lower is the amount of crystals (lower crystallinity), the higher the amount of amorphous drug (higher thermodynamic activation). The sampling spots in the matrix are performed according to the scheme reported in Figure 3.
Example 1A (ret) Drug Nimesulide (Tm = 145°C) Powder mixture Nimesulide/crosslinked polyvinylpyrrolidone 1:2 w/w
Amplitude 27 μm
Compaction device Die chamber: stainless steel Punch: stainless steel
Results: Table 1A
Example 1B
Drug Nimesulide (Tm = 145°C)
Powder mixture Nimesulide/crosslinked polyvinylpyrrolidone 1 :2 w/w
Amplitude 27 μm
Compaction device Die chamber: Stainless steel Punch: Delrin®
Table 1B
Example 1C (ret) Drug Nimesulide (T
m = 145°C) Powder mixture Nimesulide/crosslinked polyvinylpyrrolidone 1 :2 w/w
Amplitude 27 μm
Compaction device Die chamber: stainless steel internally coated with Teflon1 Punch: stainless steel internally coated with Teflon®
Results: Table 1C Pp def mi |ιri Matrix Js Assay (mg/g) 30.09 ± 0.5 30.08 ± 0.4 Crystallinity (%) 100 35 ± 11 Average amorphous (%) 0 68
Example 2A (ret)
Drug Itraconazole (Tm = 165°C)
Powder mixture Itraconazole/sodium crosscarmellose 1 :3 w/w
Amplitude 36 μm
Compaction device Die chamber: stainless steel Punch: stainless steel
Results:
Example 2B
Drug Itraconazole (Tm = 165°C)
Powder mixture Itraconazole/sodium crosscarmellose 1 :3 w/w
Amplitude 36 μm
Compaction device Die chamber: Teflon® Punch: stainless steel
Table 2B Test Powder mixture I M- Matri Assay (mg/g) 24.7 ± 0.3 25.0 ± 0.4 Crystallinity (%) 100 33 ± 3 Average amorphous (% 0 67
Example 3A (ret)
Drug Pi roxicam (Tm = 200°C)
Powder mixture Piroxicam/β-cyclodextrin 1:3 w/w
Amplitude 36 μm
Compaction device Die chamber: stainless steel Punch: stainless steel
Results: Table 3A tTesfr; Pawl©** ftιj$$ϋι% jMMtftk Assay (mg/g) 25.1 ± 0.3 24.8 ± 0.4 Crystallinity (%) 100 30 ± 15 Average amorphous (% 0 70
Example 3B
Drug Pi roxicam (Tm = 200°C)
Powder mixture Piroxicam/β-cyclodextrin 1 :3 w/w
Amplitude 36 μm
Compaction device Die chamber: stainless steel Punch: glass reinforced copolyesther resin
Table 3B
The illustrative examples show an increase of homogeneity of the distribution of the amorphous form (complementary to crystalline form) in the matrices compressed in the coupled plastic-metal parts of the compaction device. In fact, the standard deviation values of the crystallinity are much lower in samples compressed in devices made of coupled plastic and metal parts (examples B) compared to those of samples compressed either in metal (reference examples A) or in plastic (reference example C) parts.
Moreover, the amount of amorphous drug in the samples compressed in devices made of coupled plastic and metal parts (examples B) is higher.