JP2003508419A - Co-compounding methods and their products - Google Patents

Abstract

(57) A co-formulation of an active substance (preferably pharmaceutically active, eg a COX-2 enzyme inhibitor) and an oligomer or polymer excipient, comprising at least 10% of the active substance, A co-formulation, of which 80 to 100% is amorphous. The amorphous phase is more stable than the crystalline phase when stored at 0-10 ° C. for at least 3 months after preparation. The present invention also provides a method for preparing such a co-formulation, preferably involving SEDS ™ particle formation.

Description

Detailed Description of the Invention

The present invention relates to a method for co-compounding an active substance and an oligomeric or polymeric excipient. The invention also relates to a granular product of such a method.

In particular, the invention relates to WO-95 / 01221 and (in a revised version) WO-96 /
00610, WO-98 / 36825, WO-99 / 44733 and W
O-99 / 59710 relates to a new application and product of the particle formation technology known as SEDS ™ (solution enhanced dispersion with supercritical fluids). It has been found that this technique can be used in particular to produce new co-formulated products with advantageous physicochemical characteristics of the pharmaceutically active ingredient and the oligomeric or polymeric excipient. It was

[0003] Highly soluble drugs have been modified to modify their solubility profile and thus, for example, improve the solubility of otherwise poorly soluble drugs, or to control their release after administration or reduce their toxicity. It is known to co-blend drugs with polymers to slow the dissolution.

Known techniques for making such drug / polymer co-blends include solvent evaporation and co-precipitation from drug and polymer mixtures in conventional solvent systems. However, these methods are difficult to manufacture, including solvent problems such as sieving, environmental constraints, the need for multi-solvent systems and the inevitable risk of phase separation, sufficiency, and scavenging required high levels of polymer. Limited by sex. Other major limitations can be aggregating and cumbersome, can contain unacceptable levels of residual solvent or heterogeneous drug distribution, and can suffer from poor chemical and physical stability. , And to a large extent tend to result from poor physical properties and processing characteristics of granular products, which are large particles that need to be further reduced in size before they can be processed into commercial products. It may also be difficult to control the drug form in the system, ie its relative proportions of crystalline and (more soluble and therefore generally preferred) amorphous phases.

Amorphous phase drugs also tend to be metastable as compared to crystalline phase, even in the presence of polymeric excipients. Over a long storage period, the amorphous drug can revert to its crystalline form with the inevitable change in its dissolution profile. The degree of instability depends on the storage temperature (especially the glass transition temperature of amorphous solids, T
g) and humidity, and the concentration of related drugs and excipients. It can also be influenced to a certain extent by the choice of excipients, as well as by the way in which the drug / polymer mixture is manufactured (see references [1]-[5]).

Active substances, such as drugs, should have stable properties under "normal" storage conditions, generally at room temperature over a shelf life of at least 2 years. Thus, criteria have been developed for drugs that require stability at 25 ° C for a reasonable period of time. Previous attempts to co-formulate drugs with excipients have generally failed to achieve an active amorphous phase with such high levels of stability; often on an hourly basis. Otherwise, recrystallization has been observed within a few days (above [1] to [5]
]).

[0007] Matsumoto and Zografi [6] have most recently claimed that polyvinylpyrrolidone (PVP) was used as a excipient to stabilize the amorphous phase of the drug indomethacin. They report storage times up to 20 weeks at 30 ° C. without recrystallization for co-formulations containing up to 95% indomethacin. The properties of the system are explained by hydrogen bonds between the drug and the polymer, which destroy the drug dimer associated with the crystalline phase.

The products according to the invention are co-formulations of active substances, generally pharmaceutically active substances, with oligomeric or polymeric materials. They can be much more stable than similar prior art co-blends and contain a significant amount of active material in amorphous form. They can be used in the design and manufacture of drug delivery systems, especially to control drug release and / or enhance bioavailability.

According to a first aspect of the invention, when stored at 0 ° C., conveniently at 6 ° C., it is amorphous compared to its crystalline form (s) for at least 3 months after its production. Co-formulation of active (preferably pharmaceutically active) substances with oligomeric or polymeric materials, wherein the phase active substance is stable, between 80 and 100% of the active substance is present in amorphous form as opposed to crystalline form Things are offered.

“Stable” means the X-ray diffraction (XRD) pattern of the co-formulation and its differential scanning calorimetry (DSC) profile, when appropriate (ie, when measurable), over a defined period of time. Means that there is no significant change in. Preferably,
There is no significant change in the dissolution profile of the co-formulated active substance. In other words, there is little or no detectable change in the amount of any crystalline form (s) present after the defined time period, preferably less than 10%, more preferably 1% compared to the initial amount.
% Variation, most preferably less than 0.1%. Even more preferably, the co-formulation contains no detectable crystalline active material both before and after storage.

For the purpose of assessing stability, the co-formulation may require storage in a protective atmosphere if it is particularly moisture sensitive. Low humidity levels, preferably a humidity-free environment or a relative humidity (RH) of at least 0-5%, can be achieved by conventional means, for example storage in moisture-resistant packaging or desiccators.

The amorphous phase active material is stable for at least 6 months, more preferably 9 or 12 months after its production, most preferably at least 18,
Stable for 24 or 36 months.

It is also preferably stable when stored at 25 ° C. and below 60% RH, over the period mentioned above.

Co-formulations according to the invention are generally homogeneous mixtures of active substances dispersed in a “matrix” of oligomeric or polymeric excipients in which the solubility properties of the active substances are modified by the presence of excipients. Is. Normally, the dissolution rate of the active substance will be increased by co-blending it, but in some cases (eg in the case of the use of "slow release" drug formulations) it can be suppressed.

The products according to the invention, when produced by the SEDS ™ process, have been modified according to the original conventional process, in particular a prior art containing amorphous activity or even semi-crystalline activity which may have particularly poor handling properties. Than similar co-blends produced by
In addition to being more stable, they generally tend to be less tacky, more fluid (having discrete particles) and easier to handle and process. The products of the invention can also be produced with particle sizes of between 0.1 and 1 μ, with a relatively narrow size distribution.

Another advantage of the products of the invention is that they can be prepared without the additional surfactants that many prior art co-formulations generally require as stabilizers. Also,
They usually contain significantly reduced levels of residual solvent. Moreover, because they precipitate rapidly from homogeneous active / excipient solutions, they tend to contain a more uniform activity distribution, a feature that is of particular importance when co-formulating low dose drugs.

The co-formulations of the present invention are preferably prepared by the SEDS ™ method from one or more “target solutions” containing the active substance and / or the oligomeric or polymeric material. SEDS ™ -co-blended products may contain even higher levels of amorphous phase activity than is possible using prior art manufacturing methods, and more importantly, the amorphous phase is traditionally It has been found to be more stable with respect to reversion to the crystalline phase than with co-formulations made in the manner. Although we do not wish to be bound by these theories, this may be due to increased homogeneity of the active agent / excipient mixture and / or reduced residual solvent levels. In some cases, the SEDS ™ method involves rapid particle formation such that neither the drug nor the excipient molecule can organize themselves to any extent in an orderly manner as they precipitate. possible. Slower prior art co-blending methods such as solvent evaporation and spray drying have been proposed to allow small seed crystals, which can act as nuclei sites for subsequent recrystallization,
It can lead to the formation of "microdomains". Co-blends have a significant number of these cores
When it contains a "seed", it necessarily reverts to a crystalline form for the most part within a short period of storage.

SEDS ™ can be used to make such co-blends:
This is surprising from previous literature on methods. WO-95 / 012
In No. 21, there are examples of drug / polymer co-blends (salmeterol cinnafoete and hydroxypropyl cellulose), but these clearly demonstrate a "hinder" of crystallization but in significant amounts of crystalline drug. Is still present from the accompanying DSC / XRD data. SE for producing crystalline materials anywhere in WO-95 / 01221 and WO-96 / 00610
Emphasis is placed on the capabilities of DS ™, their description and WO-98 / 3.
Most of the examples in 6825, WO 99/44733 and WO 99/59710 show highly crystalline products when SEDS ™ is used to process organic materials.

[0019] Thus, SEDS (trademark) is a rapid precipitation method that would have been expected to produce an amorphous solid separately, but in reality, most organic compounds are forced to be in a crystalline state. Has been shown. Polymer addition is WO-95 / 01221
Would be expected to reduce the crystallinity level as in Examples 10 and 16 of the publication, but especially at the relatively high drug loadings that now appear to be possible (in the past, high level polymer Achieving a 100% amorphous drug system would not have been expected to be achieved, with trends (> 80%) being seen to have been required to give any significant crystallinity reduction [2]). Furthermore, the products of the invention have significantly improved long-term stability (against active recrystallization), which could not be predicted from the prior art.

The “SEDS ™ method” refers to the extraction of a supercritical or subcritical (preferably supercritical) fluid antisolvent by dispersing a fluid vehicle from a solution or suspension of a target substance. WO-95 / 01221, WO-96 / 006, used simultaneously for both
No. 10, WO-98 / 36825, WO-99 / 44733 and / or WO-99 / 59710 means particle forming techniques. These techniques are better and more consistent with the physicochemical properties of the product (particle size and size distribution, particle morphology, etc.) than have been shown to be possible with co-formulations in the past. Can provide control.

SEDS ™ is also a one-step process; it is the same or separate “
It can be used to simultaneously precipitate both the active substance and the excipient from either the "target" solution or suspension, where the target solution (s) / suspension (s) is a poor solvent. Together, they are preferably introduced together into the particle formation vessel through coaxial nozzles having a suitable number of concentric passages.

As another advantage of the SEDS ™ method, the prior art, such as WO-95 / 01221, describes the ability to treat sensitive active substances, for example in a light-free and / or oxygen-free environment. .

The antisolvents used in the SEDS ™ method, although other (eg, as described in the SEDS ™ literature above) may be used instead or in addition,
Supercritical carbon dioxide is preferred.

The oligomer (including dimer) or polymer material may have any molecular weight, such as polyethylene glycol, hydroxypropylmethyl cellulose (HPMC).
) Or polyvinylpyrrolidone (PVP) or hydrophilic such as ethylcellulose (EC), or any suitable excipient for the active substance. It can be a biodegradable oligomer or polymer such as polylactide or glycolide or polylactide / glycolide. It can be crystalline, semi-crystalline or amorphous. It can be homo- or co-oligomer / polymer, synthetic or natural.

Examples of oligomeric or polymeric materials particularly suitable for co-formulation with pharmaceutically active substances include, but are not limited to: a) gum arabic, gum tragacanth, alginates (eg calcium alginate), alginates, starches. , Traditional a "natural" source materials such as agar, carrageenan, xanthan gum, chitosan, gelatin, guar gum, pectin, amylase or lecithin, their derivatives and their synthetic analogues, b) alkyls (eg methyl or ethyl). Cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose (H
PC), hydroxypropylmethylcellulose, sodium carboxymethylcellulose, cellulose and cellulose derivatives such as microcrystalline cellulose or microfine cellulose, c) homo- and co-polymers of hydroxy acids such as lactic acid and glycolic acid, d) "eudragit ( Eudragit) ™ polymers, acrylates and their derivatives such as methacrylic acid or methacrylates such as methyl methacrylate, e) Silicic acid such as bentonite or magnesium aluminum silicate, f) Polyvinyl chloride, polyvinyl Vinyl polymers such as alcohols, polyvinyl acetate, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, or carboxyvinyl copolymers, g) polyoxyethylene or polyoxypropyi Or a polymer surfactant such as polyalkylene oxide such as polyethylene oxide, h) phospholipid such as DMPC (dimyristoylphosphatidylcholine), DMPG (dimyristoylphosphatidylglycerin) or DSPC (distearylphosphatidylcholine), i) lactose, Carbohydrates such as dextran, cyclodextrins or cyclodextrin derivatives, j) dendritic polymers such as those based on 3,5-hydroxybenzyl alcohol, k) poly (ε-caprolactone), DL-lactide-co-caprolactone and their derivatives, And l) block polymers as described in U.S. Pat. No. 5,968,543 and U.S. Pat. No. 5,939,453, and derivatives of such polymers, as well as short chain .alpha.-hydro. Poly (orthoester) (s) and poly (orthoester) / poly (ethylene glycol) copolymers, including such polymers or glycol-co-lactic acid copolymers with xyacid incorporated esters.

Other suitable oligomers / polymers may be found in the literature on drug delivery systems, eg Broccini in World Markets Series “Bu.
thins briefing ", Drug Delivery Suppl
listed in the report by element [7].

The oligomeric or polymeric material is preferably EC, HPC or HPMC
Cellulosic materials such as (including cellulose derivatives), vinyl polymers such as polyvinylpyrrolidone, polyoxyalkylene (eg, polyoxyethylene or polyoxypropylene) polymers or copolymers or polylactides or glycolides (including lactide / glycolide copolymers) Is.

The active substance can be a single active substance or a mixture of two or more active substances. It can be monomeric or polymeric, organic (including organometallic) or non-metallic, hydrophilic or hydrophobic. It can be a small molecule, eg a synthetic drug such as paracetamol, or a larger molecule such as a (poly) peptide, enzyme, antigen or other biological material. It preferably comprises a pharmaceutically active substance, but many other active substances are not considered to be oligomeric or polymeric according to the invention whatever their intended function (eg, herbicide, insecticide, foodstuff, nutrient, etc.). It is possible to co-blend. In particular, the active agent can be a material with low aqueous solubility, which can be co-blended with an oligomeric or polymeric excipient to increase the aqueous dissolution rate and thus facilitate delivery.

In particular, surprisingly, even if their respective hydrophilicities differ significantly, SE
It has been found that DS ™ can be used to co-blend actives with oligomers or polymers. Such combinations have previously been considered incompatible with co-formulations. Examples include co-blends of relatively polar actives such as paracetamol, theophylline or ascorbic acid with hydrophobic polymers such as ethyl cellulose.

For some actives, SEDS ™ allows the production of co-formulations containing higher amorphous phase active loadings than previously possible.
Accordingly, a second aspect of the present invention provides a (i) an active substance selected from the group consisting of paracetamol, ketoprofen, indomethacin, carbamazepine, theophylline and ascorbic acid and (ii) an oligomer or a oligomer when the active substance is indomethacin or theophylline. Assuming that the polymeric material is not polyvinylpyrrolidone, between 80 and 100% of the active substance is present therein in amorphous form as opposed to crystalline form, in which the active substance is at least 10% of the co-formulation. Co-blends of oligomeric or polymeric materials exhibiting

In the co-formulation according to the invention, preferably between 80 and 100%, more preferably between 90 and 100% or between 95 and 100%, most preferably 100% of the active substance is in contrast to the crystalline form. It exists in an amorphous form. The active substance is preferably at least 1% of the system, more preferably at least 2% or 5% or 10%.
Or 20% or 25% or 30% or 35% or 40% or 50%
Or 60% or 70% or 80% or 90%. In other words, the products according to the invention contain high loadings of active substance, all or substantially all of which are present as a single amorphous phase.

[0032]   Concentration percentages are weight to weight unless otherwise noted.

When the active substance is indomethacin and the excipient is ethyl cellulose (EC), preferably between 95 and 100% of indomethacin is present in amorphous form, and indomethacin is at least 10% of the co-formulation, More preferably, it shows at least 20% or 25% or 30% or 35%.

When the active substance is indomethacin and the excipient is hydroxypropylmethylcellulose (HPMC), preferably between 95 and 100% of indomethacin is present in amorphous form and indomethacin is present in at least 10 of the co-formulation. %,
More preferably, it shows at least 20% or 25% or 30% or 35% or 40%.

When the active substance is indomethacin and the excipient is polyvinylpyrrolidone (PVP), preferably between 95 and 100% of indomethacin is present in amorphous form and indomethacin is at least 20% of the co-formulation. , More preferably at least 25% or 30% or 40% or 50% or 60% or 6
Indicates 5% or 70%.

When the active substance is carbamazepine and the excipient is EC, preferably 95-
Between 100% of the carbamazepine is present in amorphous form, and the carbamazepine is at least 10% of the co-formulation, more preferably at least 20% or 25.
% Or 30%.

When the active substance is carbamazepine and the excipient is HPMC, preferably 9
Between 5 and 100% carbamazepine is present in amorphous form, and carbamazepine represents at least 10% of the co-formulation, more preferably at least 20% or 25% or 30%.

When the active substance is theophylline and the excipient is EC, preferably 95-1
Between 00% of theophylline is present in amorphous form and theophylline represents at least 10% of the co-formulation, more preferably at least 20% or 25% or 28% or 30%.

When the active substance is theophylline and the excipient is HPMC, preferably 95
Between ~ 100% of theophylline is present in amorphous form, and theophylline represents at least 1% of the co-formulation, more preferably at least 2% or 5% or 8% or 10%.

When the active substance is ascorbic acid and the excipient is EC, preferably 95-
Between 100% of ascorbic acid is present in amorphous form, and ascorbic acid represents at least 1% of the co-formulation, more preferably at least 2% or 5% or 8% or 10% or 15%.

When the active substance is ascorbic acid and the excipient is HPMC, preferably 9
Between 5 and 100% ascorbic acid is present in amorphous form, and ascorbic acid represents at least 10% of the co-formulation, more preferably at least 20% or 25% or 30% or 35% or 40%.

[0042]   The active substance is a compound of formula (I):

[Chemical 2] ((Z) -3- [1- (4-chlorophenyl) -1- (4-methanesulfonyl) methylene] -dihydrofuran-2-one) and the excipient is hydroxypropylcellulose (HPC). , Preferably between 95 and 100% of compound (I
) Is present in amorphous form, and compound (I) is at least 5% of the co-formulation.
, More preferably at least 10% or 15% or 20% or 21%.

When the active substance is a compound of formula (I) and the excipient is a polyoxyalkylene polymer or copolymer such as a polyoxypropylene-polyoxyethylene copolymer, preferably between 95 and 100% of compound (I). Exist in amorphous form, and compound (I) represents at least 5%, more preferably at least 10% or 15% or 20% or 24% of the co-blend.

[0044]   The active substance is a compound of formula (II):

[Chemical 3] ((Z) -3- [1- (4-bromophenyl) -1- (4-methylsulfonylphenyl) methylene] -dihydrofuran-2-one), and when the excipient is HPC, preferably Between 95 and 100% of compound (II) is present in amorphous form, and compound (II) represents at least 5% of the co-formulation, more preferably at least 10% or 15% or 20% or 21%. .

In some cases, SEDS ™ results in the formation of the active substance in the amorphous phase (to the best of our knowledge) which was previously only produced in those crystalline phase (s). May be possible. One example of this is the production of a paracetamol / shaping agent co-blend. Accordingly, a third aspect of the invention is that between 80-100% of paracetamol is present in an amorphous form as opposed to a crystalline form, with paracetamol representing at least 1% of the co-formulation. Co-blends of paracetamol and oligomeric or polymeric materials are provided.

In such paracetamol co-blends, preferably between 90 and 100%, more preferably between 95 and 100%, most preferably 100% of paracetamol is present in its amorphous form. Paracetamol is at least 2%, more preferably at least 5%, most preferably at least 8% or 1 of the co-formulation.
0% or 20% or 25% or 28% or 30% or 35% or 4
Indicates 0% or 50% or 60%. The oligomeric or polymeric material is preferably hydrophobic; most preferably it is ethyl cellulose. The amorphous phase paracetamol, when stored between 0 and 10 ° C., compared to its crystalline form (s), is at least 3 months after its manufacture, preferably 6 months, more preferably 9 or 12 or 18. Or preferably stable for 24 or 36 months. It is preferably also stable over the same period when stored at 25 ° C, and more preferably at 40 ° C.

Aspects of the invention relate to the SEDS ™ process and SEDs for making co-blends.
The use of the S ™ method can also be leveraged to provide methods for making the above-described co-blends. In particular, the invention provides that between 80 and 100% of the active substance is present in an amorphous form as opposed to a crystalline form, and the amorphous phase active substance is 0% compared to its crystalline form (s). Provided is the use of the SEDS ™ process for producing a co-blend of an active substance and an oligomeric or polymeric material, which is stable in it for at least 3 months after its production when stored between -10 ° C. It is also
Co-formulation of active substance and oligomer or polymer material in which between 80 and 100% of the active substance is present in amorphous form as opposed to crystalline form, in which the active substance represents at least 10% of the co-formulation Providing the use of the SEDS ™ method for the manufacture of

Also provided is a pharmaceutical composition comprising a co-formulation according to the first, second or third aspect of the present invention.

The invention further provides that the difference between their respective total specific solubility coefficients, δ _S , is -5 to +.
Using the SEDS ™ method in which the active substances and excipients are selected such that they are between 5, preferably between −2 and +2 and more preferably at or near 0, the activity (preferably pharmaceutically) Methods are provided for the co-formulation of active) substances and hydrophobic oligomeric or polymeric excipients. The excipient is preferably cellulose or a cellulose derivative such as ethyl cellulose. The present invention provides products of such methods, and the use of the SEDS ™ method therein.

A further aspect of the present invention is anti-solvent derived particles in which, under the operating conditions used, the active substance is soluble in the selected “anti-solvent” but the excipient is not. A forming method (preferably the SEDS ™ method) is used to provide a method for making a co-blend of an active (preferably pharmaceutically active) substance and an oligomeric or polymeric excipient. The preferred "poor solvent" for this method is supercritical carbon dioxide. The active substance is preferably non-polar, eg the drug ketoprofen, and the excipient is preferably hydrophilic, eg HPMC. Again, the present invention provides products of such methods, and the use of the SEDS ™ method therein.

A still further aspect of the invention is a method of forming antisolvent-induced particles, preferably SEDS (
Method is used to provide a method for making a co-blend of indomethacin and polyvinylpyrrolidone. The present invention provides a product of such a method, and SEDS therein.
Provides use of the Trademarks Act.

In some cases, SEDS ™ is a sufficiently homogenous active agent / active agent capable of suppressing or even preventing the onset “burst” of drug release that is likely to occur during conventional dissolution profiles. It is believed that a excipient mixture can be produced. Thus, certain co-formulations according to the present invention can be used as slow-acting drug co-formulations that provide a more uniform drug release rate without the need for protective coatings or additional reagents. Examples include, inter alia, co-formulations of water-soluble active substances such as theophylline with relatively hydrophobic excipients such as ethyl cellulose.

This finding is particularly important as the co-formulation of the amorphous phase morphological active agent would normally be expected to increase its dissolution rate. Previous attempts to control dissolution have instead generally involved placing physical constraints on the active agent, such as by entrapping the particles in a two-phase polymer matrix.

Therefore, a further aspect of the invention is that between 80 and 100% of the active substance is present in an amorphous form as opposed to a crystalline form and the dissolution rate of the active substance in the aqueous medium is for the first 30 minutes. Co-formulation of an active (preferably pharmaceutically active) substance and an oligomeric or polymeric excipient, preferably comprising a homogeneous single phase mixture of the active substance which is not higher than the latter in the first 60 or 90 or 120 minutes. Provide things. Again, such co-blends are preferably made by the SEDS ™ method.

Yet another aspect of the invention provides the above co-formulation wherein the active agent is a COX-2 selective inhibitor. As used herein, the term “COX-2 selective inhibitor” refers to an organic compound or a pharmaceutically acceptable salt or a solvent thereof that can selectively inhibit the COX-2 enzyme over the COX-1 enzyme. Means Japanese.

The COX-2 selective inhibitor may be a diarylheterocycle. The term "diaryl heterocycle" as used herein is each directly attached to an adjacent atom in a 5- or 6-membered heterocycle, or both said phenyl rings are further said 5 or 6
Diaryl heterocycles (or pharmaceutically acceptable salts) containing two substituted or unsubstituted phenyl rings directly bonded to the same carbon atom of a C _1-3 alkylidene linking group that is bonded to one atom in a membered heterocycle Or a solvate thereof).

The COX-2 selective inhibitor may be a diarylfuranone. As used herein, the term "diarylfuranone" refers _to a C ₁ -C that is either directly bonded to an adjacent carbon atom in a furanone moiety or both phenyl rings are further bonded to a carbon atom in said furanone moiety _{. 3} means an organic compound of a diarylfuranone (or a pharmaceutically acceptable salt or solvate thereof) containing two substituted or unsubstituted phenyl rings, which are directly bonded to the same carbon atom of an alkylidene linking group.

The COX-2 selective inhibitor may alternatively be a diarylpyrazole. As used herein, the term "diarylpyrazole" refers to a C _1-3 alkylidene, each of which is attached directly to an adjacent atom in the pyrazole moiety or where both of the phenyl rings are further attached to one atom in the pyrazole moiety. By organic compounds of diarylpyrazoles (or pharmaceutically acceptable salts or solvates thereof) containing two substituted or unsubstituted phenyl rings, which are bonded directly to the same carbon atom of the linking group.

The COX-2 selective inhibitor may alternatively be an arylpyridylpyridine. The term "arylpyridylpyridine" as used herein, is each attached directly to an adjacent atom in the pyridine ring, or both the phenyl ring and the pyridyl moiety are further attached to an atom in the pyridine ring. Arylpyridylpyridines containing one substituted or unsubstituted phenyl ring and one substituted or unsubstituted pyridyl moiety directly bonded to the same carbon atom of a C _1-3 alkylidene linking group (
Or a pharmaceutically acceptable salt or solvate thereof).

The COX-2 selective inhibitor is preferably (Z) -3- [1- (4-bromophenyl) -1- (4-methylsulfonylphenyl) methylene] dihydrofuran-2.
-One, (Z) -3- [1- (4-chlorophenyl) -1- (4-methylsulfonylphenyl) methylene] dihydrofuran-2-one, 4- [5- (4-methylphenyl) -3- (Trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [4- (methylsulfonyl) phenyl] -3-phenyl-2 (5H) -furanone and compounds of formula (III):

[Chemical 4] Is selected from the group consisting of

(Z) -3- [1- (4-Bromophenyl) -1- (4-methylsulfonylphenyl) methylene] dihydrofuran-2-one and (Z) -3- [1- (4-
Chlorophenyl) -1- (4-methylsulfonylphenyl) methylene] dihydrofuran-2-one is a COX-2 selective inhibitor useful in the treatment of acute and chronic pain. See U.S. Pat. No. 5,807,873. Related application patents are incorporated herein by reference.

4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide was approved for the treatment of osteoarthritis and rheumatoid arthritis. COX-2 selective inhibitor, trade name CELEB
It is commercially available in the United States under the name REX® (celecoxib). See, eg, US Pat. No. 5,466,823 and US Pat. No. 5,563,165, incorporated herein by reference.

4- [4- (methylsulfonyl) phenyl] -3-phenyl-2 (5H) -furanone is approved for the treatment of osteoarthritis, the treatment of primary dysmenorrhea and the management of acute labor. COX-2 selective inhibitor, trade name VIOXX (registered trademark) (
Rofecoxib) is commercially available in the United States. See, eg, US Pat. No. 5,474,995, incorporated herein by reference.

The compound of formula (II) is a CO that has been developed for the treatment of acute and chronic pain.
It is an X-2 selective inhibitor. WO 99 / included herein by reference
See 15503 and related patent applications.

These and other COX-2 selective inhibitors, which fall within the scope of biaryl heterocycles or more specifically biaryl furanone and biaryl pyrazoles, appear to have low aqueous solubility and are suboptimal biological. Suggest availability. Their co-formulation with oligomeric or polymeric excipients according to the invention can be expected to enhance their bioavailability.

EXAMPLES The following experiments show the S for co-blending various drugs and polymers according to the present invention.
Demonstrate the use of the EDS ™ method. Physicochemical characteristics of the product, especially drug crystallinity (
In some cases) the stability of the amorphous phase and the relative concentrations of drug and polymer (ie drug “loading ratio”) were tested and manipulated by varying operating conditions and solvents present where possible. .

Drugs were selected to cover a wide range of polarities, including highly polar ketoprofen and from less polar to indomethacin, carbamazepine, paracetamol, theophylline and ascorbic acid. These agents were co-blended with both hydrophobic (EC) and hydrophilic (HPMC) polymers.

Ketoprofen was generally well soluble in supercritical carbon dioxide (selected antisolvent), yielding meaningful results even under mild processing conditions.
However, surprisingly, it could be retained to some extent when co-formulated with HPMC.

[0069]   In an additional study, PVP was co-formulated with the poorly water soluble drug indomethacin.

Further experiments (Examples II and III) showed that two cyclo-oxygenase-2 (COX-2) enzyme inhibitors were added to HPC and, in the case of Example II, polyoxypropylene-polyoxyethylene block co- -Polymer, Pluron
It was co-blended with ic® F87.

In Example IV, the drug glibenclamide was added to 75/25 DL-lactide-
Co-blended with co-caprolactone.

Experimental Details The method used was essentially the SEDS ™ method described in WO-95 / 01221. Documents, WO-96 / 00610, WO-98 / 3
6825, WO 99/44733 and / or WO-99 / 59710.
It is envisioned that a modification of SEDS ™ as described in the issue could have similar effects.

The device is shown diagrammatically in FIG. Wherein 1 is a particle formation tank; 2 is a device for holding the formed particles (eg a filter); 3 is an oven, 4 is a back pressure controller; and 5 is a tank 6 is a nozzle for co-introducing the supercritical poor solvent from 6 and the target solution from the tank 7 into the tank 1. Item number 8 is a pump;
9 is a cooler, 10 is a heat exchanger, and 11 is a pulse buffer. The recirculation system 12 is
Allows solvent recovery at 13 (via needle valve 14) while returning carbon dioxide to cooler 9 for reuse.

The nozzle used in 5 was a general form two-pass coaxial nozzle represented in FIG. 3 of WO-95 / 01221, the general dimensions being as described in that document. Supercritical carbon dioxide was the selected anti-solvent introduced into the 50 ml particle formation tank via the internal nozzle passage. The "target solution", ie the drug or polymer, or more commonly both solutions, was introduced through the outer nozzle passage.

In-situ mixing of the individual drug and polymer could be achieved using a nozzle with three or more coaxial passages that allowed the two solutions to merge at the nozzle outlet.

The choice of a suitable solvent was determined in particular by the properties of both the drug and the polymer, but because of the potential problems of processing polymer solutions and dispersions. The polymer dispersions can exhibit very high viscosities even when diluted, while in a "good" solvent the polymer matrix relaxes and relaxes to produce homogeneous drug / polymer mixtures and the SEDS ™ process, respectively. It enables both larger scale interactions and lower viscosities, which are important for the requirements [8].

[0077]   The analytical techniques used in the experiment were as follows.

Scanning Electron Microscopy (SEM) Particle size and morphology were examined using a Hitachi ™ S-520 Scanning Electron Microscope (Hitachi, Japan). An aluminum stub containing a small amount of sample microparticles was sputter coated with a gold layer to thickness of 300Å, visually inspected and photographed at various magnifications.

Differential Scanning Calorimetry (DSC) This technique was used to measure sample crystallinity, assuming that the lower the degree of the crystal lattice, the less energy is required to melt the sample. DSC
Was used to determine the thermal profile, monitor latent heat of fusion (ΔHf), identify any phase or polymorph transitions and desolvation phenomena, and measure melting points and glass transition temperatures. Perkin-Elmer ™ DSC7 (Perkin-Elmer Ltd,
UK) was used. A 1-5 mg sample was tested in a crimped aluminum pan with an ear hole under a nitrogen atmosphere. The analysis temperature range was determined according to the drug to be tested.
Theophylline was sublimed at temperatures just above its melting point, causing problems with endothermic peak scale measurements. This problem was overcome by adopting the closed pan method. The correlation between product crystallinity and parts by weight drug in the product was also investigated. The crystallinity was derived from the latent heat of fusion (ΔHf) using the following formula: Formula 1% crystallinity = ΔHf (co-blend) / ΔHf (100% crystal) X100 / parts by weight of drug.

X-Ray Diffraction (XRD) This was also used to give a quantitative assessment of crystallinity. The samples were analyzed on a D5000XRD (Siemens, Germany) between 5 and 30 ° 2θ.

UV Absorption Spectroscopy (Example I) The parts by weight of drug in the sample was taken from the reconstituted solution of the sample by Ultrospec ™
000 absorption spectrophotometer (Pharmacia Biotech, Cambridge)
GE, England). The absorption of the polymer was negligible at the wavelength used.

Dissolution Testing (Example I) Dissolution testing was performed using the stirred tank technique and UV analysis. The apparatus consisted of a 1 liter round bottom tank stirred at 60 rpm by a paddle and maintained near 37 ° C in a water bath. The medium was circulated through a 10 mm flow cell using a peristaltic pump. U
UV readings were taken every 30 seconds using an ltrospec (TM) 4000 absorption spectrophotometer (above) and analyzed between 30 and 60 minutes. Three lines were analyzed: paracetamol / HPMC, theophylline / EC and indomethacin / HPMC. The conditions for each system are: paracetamol / HPMC: 247 nm, 37 ± 0.5 ° C., 500 ml distilled water, theophylline / EC: 273 nm, 37 ± 1.0 ° C., 350 ml distilled water, indomethacin / HPMC: 235 nm, 37 ± 0. 0.5 ° C, 400 ml pH 7
． 00 ± 0.02 0.05M NaH ₂ PO ₄ aqueous buffer. Due to the poor water solubility of the drug, different media were needed for the indomethacin system. The medium of choice is provided as a compromise both in observing drug release within the time window and allowing sufficient discrimination to discern the actual dispersion. The release profile characteristics were compared to physical formulations to give an indication of polymer / drug interactions and possible complex formation. Physical formulations were made from pre-micronized drug dough (1 minute pestle and mortar) with the indicated polymers. Samples were transferred to a hard gelatin capsule (size 4 clear / clear, 60:40 tin / lead wire coil) for analysis. The capsules showed no significant absorption in the area of analysis.

Aerosizer-Aerodis
PERSER ™ particle size analyzer (Example II) Time-of-flight analyzer (Aerosizer ™ with Aerodisperser ™,
Particle size analysis was performed using TSI Inc, USA). 0 by this device
． Size analysis of dry powder samples over the range 2-700 μm is possible. The powder is dispersed in air and the air / particle suspension is expanded through a nozzle into a partial vacuum. The air / particle flow is accelerated through the measurement area where the particles pass through two continuous laser beams. Smaller particles experience more acceleration than the larger ones, and thus move faster between the two rays. From the measurement of the time required to travel between the rays and the known density of the material, Aerosizer ™ software calculates the average size distribution of the particles present in the sample. S from the data obtained
EM observation is supplemented. No sample preparation is necessary.

HELOS Sympatec ™ Particle Size Analyzer (Examples II and III) This instrument uses laser diffraction to measure the particle size distribution of solid particulate material. It can be measured over the particle size range 0.1-8750 μm. A dry powder sample is introduced into a dry dispersion unit via a vibrating conveyor feeder. The powder and any agglomerates present here are well dispersed in air. The dispersion of single particles is then driven by compressed air and the particle stream is fed through a measurement zone where it interacts with the monochromatic high-energy rays from the He-Ne laser. The laser beam is diffracted and detected by the multi-component photodetector. The intensity of the diffracted light is then converted into an electrical signal used to calculate the particle size distribution. Again, the data complement the SEM observations. No sample preparation is necessary.

High Performance Liquid Chromatography (HPLC) (Examples II and III) Compounds (I) and (II) loadings were measured by HPLC with UV detection. Then a single mobile phase (0.1% phosphoric acid: acetonitrile (62:38 v / v)
, Degassing for 20 minutes before use) was applied. Quantification was performed by external standardization. Two stock solutions of compound (I) at a concentration of 500 μg ml ⁻¹ were made in the mobile phase. Appropriate amounts were taken alternately and diluted with mobile phase to make a set of standard calibrators in the reference range 2-10 μg ml ⁻¹ . The prepared sample solution specimens were then diluted if necessary and subjected to HPLC analysis interspersed with calibration solutions. A chromatogram was created using the following standard conditions. Pump: 1.1 ml min- ¹ delivery possible Sample amount: 20 μl (ATI Unicam ™ automatic sampler) Column: 150 × 4.6 mm, ZORBAX ™, RX-C8
, 5 μm Column temperature: 30 ° C. Flow rate: 1.1 μg ml ⁻¹ Detector / wavelength: Jasco ™ UV-975 / 220 nm Peak reaction: Area Cycle time: generally 17 minutes All peak area measurements and calculations are Borwin. (Trademark) chromatography software version 1.22.01. Was carried out.

Example I The materials used in this series of experiments were as follows; their polarities and solubilities are shown in Table 1 below. Materials Supplier Quality L-Ascorbic acid Sigma Chemical Co, General laboratory reagents St Louis, Missouri, USA Carbamazepine Sigma Same as indomethacin Sigma Same as above Ketoprofen Sigma Same as paracetamol Sigma 99.0% + Theophylline Sigma anhydrous 99% + EC Colorcon, Dartford, 7 cps England HPMC Shin-Etsu Chemical Co., Ltd., Tokyo, 3 cps (603) Japan PVP Sigma Average molecular weight 10,000 dichloromethane BDH (Merck), Poole, AnalaR 99.5% + England chloroform BDH AnalaR 99.0-99.4% ethanol BDH AnalaR 99.7-100% ethanol Rathburn Chemicals HPLC Ltd, Walkerburn, Peebleshire, Scotland Methanol BDH AnalaR 99.8% + Dihydrogen orthophosphate Sigma 99.0% + Sodium (deionized water was obtained from Jencons Waterstil ™ 4000X).

[0087]   Material chemical structure

[Chemical 5]

[Chemical 6]

[Chemical 7]

[0088]

[Table 1]

In Table 1, δ _d , δ _p and δ _h are partial solubility coefficients showing dispersion, polarity and hydrogen bonding effects, respectively; δ _t is δ _t ² = δ _d ² + δ _p ² + δ _h ² . Is the total solubility coefficient; δ _S is the overall ratio (ie, polar and hydrogen bonding) solubility coefficient.

Manipulating the main operating conditions (temperature, pressure, fluid flow rate and nozzle orifice diameter),
Optimization was performed for each drug / polymer system. Different drug: polymer concentration ratios were also tested.

Temperatures in the range 34-50 ° C. and pressures between 80-100 bar have been found to be favorable for the treatment of these polymers. The poor solvent: target solution flow rate ratio (into the particle formation tank) was between 66: 1 and 200: 1. That is, the target solution flow rate is 0.1
When the flow rate of the poor solvent was 0.3 ml / min, 20 ml / min was used.

The nozzle outlet inner diameter was between 100 and 500 μm, with 100 μm being preferred over large ones exceeding 200 μm.

A 1: 1 mixture of ethanol and dichloromethane (or 1: 1 ethanol / chloroform for PVP) was used as the drug / polymer solvent. This produced a suitable low viscosity dispersion that allowed processing without large nozzle blockages. Similarly, ethanol was found to produce low viscosity dispersions for EC systems. A polymer concentration of 0.5% w / v provided a balance point between the ability to pump the solution with moderate back pressure and an acceptable high material throughput.

For ease of processing, the polymer used was a low molecular weight cut-3 cps HPMC.
, 7 cps EC and PVP with an average molecular weight of 10,000.

Results and Discussion Results of various experimental runs (especially yield, morphology and drug loading) are attached Table 2 (ascorbic acid), 3 (carbamazepine), 4 and 5 (indomethacin), 6 and 7 (ketoprofen). , 8 (paracetamol) and 9 (theophylline). The table also shows the operating conditions (temperature and pressure in the particle forming tank, fluid flow rate, target solution concentration and nozzle tip (outlet) diameter) in each operation.

The products took the form of finely dispersed granules; all were non-sticky free-flowing powders with good handling properties. Their morphology was evaluated using SEM and generally showed amorphous products as fine agglomerated coarse spherical particles of the order of 0.05-1 μm diameter. The homogeneity of the appearance of the particles suggested that they comprised molecular level dispersion. Above the amorphous boundaries detected, a mixture of such web structures with additional larger drug crystals was often observed.

2-5 are partial SEM photographs of the starting materials and products of the experiment. In particular, Figure 2 shows the indomethacin raw material (2000x magnification); Figure 3 shows the amorphous indomethacin / HPMC product of experimental run RASE21 (2000x magnification); Figure 4 shows the paracetamol raw material (200x magnification) and Figure 5 Experimental run RASF34 amorphous paracetamol / HPMC product is shown (1000x magnification).

Dissolution Tests FIGS. 6-8 show the three systems tested, namely paracetamol: HPMC (
6), theophylline: EC (FIG. 7) and indomethacin: HPMC (FIG. 8).
The dissolution profile for is shown. The symbols correspond to those used in Tables 2-9 for various experimental runs; X (%) is the maximum concentration of drug amorphous phase until crystals are detected. In all three systems, there is a significant difference in drug release rate between the SEDS ™ co-formulated product and the pure physical mixture of related drug and polymer, which indicates that the product of the invention is homogeneous in drug in the polymer matrix. It was suggested that it was formed as a dispersion on the molecular level. For example, theophylline release is significantly suppressed by co-blending it with EC according to the invention, that of paracetamol also HPMC.
Slightly suppressed by the co-blend with, while the dissolution rate of indomethacin was HP
Increased by co-formulation with MC (including one sample on the amorphous detection border).

Crystallinity A plot of drug crystallinity (as measured by DSC) versus drug parts by weight is shown in FIGS.
Shown in. The illustrated systems are ascorbic acid / EC, ascorbic acid /
HPMC, carbamazepine / EC, carbamazepine / HPMC, indomethacin / EC, indomethacin / HPMC, indomethacin / PVP, paracetamol / EC, paracetamol / HPMC, theophylline / EC and theophylline /
HPMC.

It depends largely on the drug and the polymer involved, but in general SEDS
It has been found that the ratio of amorphous drug to crystalline drug present in the ™ product is higher than that achieved using conventional processing techniques such as evaporation and co-precipitation from solvent systems. [1]. For example, the maximum amorphous phase concentration for indomethacin is 25 ± 5% by EC, 35 ± 5% by HPMC and 6 by PVP.
It was 0 ± 5%. Up to 10-15% amorphous ascorbic acid was achieved in co-formulation with EC and up to 35-40% with HPMC (Figures 9 and 10).
). (Note that the drug concentration range is estimated by the limit of the crystallinity quantification method by DSC and the boundary limit of the amorphous / crystalline state due to the limitation of the number of data points near the phase change concentration)

These results are especially important for poorly water-soluble drugs, where the amorphous form is generally preferred due to its excellent dissolution rate.

Physical and Chemical Stability The media for long term storage stability of some Example I products was investigated. In all cases, the physical properties of the samples did not change even after storage up to 24 months; the samples remained free-flowing and easy to handle.

Chemical stability (in terms of amorphous phase contents) was evaluated using DSC. Looking first at the indomethacin / PVP system, the drug in its crystalline form shows a scan rate of 20 ° C.
When analyzed in 1 / min, it shows a peak in the DSC profile at 150-165 ° C. This peak shifts to lower temperatures in the co-blended indomethacin / PVP system. 20 and 21 show the crystal raw material and the experimental run RA, respectively.
3 shows the DSC profile for the indomethacin / PVP system made in SE64. The peak at 139 ° C in Figure 20 indicates the presence of crystalline indomethacin in the sample (the sample contained 30% crystallinity 78% w / w indomethacin).

Experimental Runs RASE70, RASE69, RASE62, RASE66 and R
Indomethacin / PVP samples made in ASE63 (containing 16, 20, 48, 51 and 62% indomethacin respectively) were evaluated in a desiccator between 2-8 ° C. initially and after both 12 and 24 months storage. did. DS
The C results showed no crystallinity in any of the samples even after 24 months. An example DSC profile for the RASE63 sample at 24 months is shown in FIG. 22; the absence of the 139 ° C. peak indicates the absence of crystalline indomethacin.

Three theophylline / EC systems were also tested without desiccator after storage at room temperature. 2 for products of run RASH6, LSDA52 and RASH14 (100% amorphous in each case, containing 9,17 and 27% theophylline respectively)
The DSC profile obtained after 4 months again lacked a distinct peak and showed no detectable drug crystallinity. An example DSC profile for the RASH14 sample is shown in FIG.

In a similar experiment, the stability of four paracetamol / HPMC products was tested over a 24 month storage period. Storage conditions were the same as for the theophylline / EC system. Experimental run RASF31, RASF27, RASF97 and RAS
The 24-month DSC profile for the product of F40 (100% amorphous in each case, containing 19, 20, 21 and 29% paracetamol respectively) showed the absence of crystals. FIG. 24 is an example DSC profile for the RASF40 sample.

Therefore, the co-formulations according to the invention produced by the SEDS ™ method appear to have excellent long-term storage stability, both with regard to their physical properties and active substance recrystallization.

With respect to the stability data above, it is important that many systems tested were close to the inflection point on the crystallinity versus drug loading graph. In other words, they were the systems containing the highest possible drug loading prior to the onset of crystallization. Other products of the invention containing lower drug loadings would rather be more stable under the same storage conditions.

Solubilizing effect In a system containing the hydrophobic polymer ethylcellulose, the amorphous phase drug concentration and the total specific solubility coefficient of the reagents δ _S (δ _S = (δ _p ² + δ _h ² ) ^1/2 ) See Table I There was a correlation between As deduced from the systems studied, the trend is to the maximum concentration of the amorphous phase (and thus also to the maximum drug: polymer interaction) achieved when the δ _{S of the} drug and polymer are equivalent or substantially so. It was going.

Drug / polymer dispersion, and intermolecular / interpolymer chain mixing and interactions are (
δ _S ^d −δ _S ^p ) can be maximized by choosing reagents such that δ _S ^d −δ _S ^p ) is 0 or close to 0, where δ _S ^d and δ _S ^p are the total ratios (eg, polar and Hydrogen bond) indicates the solubility coefficient). These systems would be expected to contain the maximum amount of amorphous phase drug, and lower amorphous phase levels would occur as positive or negative values (δ _S ^d −δ _S ^p ).

Table 10 shows (δ _S ^d − for the systems studied with X% (midpoint and range) values.
List the calculated values of δ _S ^p ).

[Table 2]

[0112]   The data in Table 10 are plotted in Figures 25 and 26. Paracetamol / EC
With the exception, the maximum amorphous phase content found for the drug / EC system is δ_S ^d −δ_S ^p = 0, the maximum amorphous content was about 27%, which seems to be inferred (Fig. 2).
5). On the contrary, for the drug / HPMC system (FIG. 26), paracetamol /
The polymer system deviates from the trend, but a minimum is seen at the zero point.

Systems containing paracetamol deviate from the trends exhibited by other drugs. Polar systems have a greater tendency to exhibit disordered solution behavior. Furthermore, if the molecule contains at least two active groups with different hydrogen-bonding capacities, this can also lead to anomalous dissolution behavior. Commonly referred to as the "chameleon effect," it is a combined effect of solubility coefficient and solute-solvent and solvent-solvent hydrogen bonding. Paracetamol is known to form disordered solutions in polar solvents [10-12] and contains functional groups -OH and -NH- which lead to a change in behavior depending on the solvent environment.

Although this is attributed to the high crystallinity and crystal energy of the drug, it is important that attempts to form amorphous paracetamol using conventional particle formation techniques have clearly been unsuccessful. However, SEDS ™ can be used to co-formulate paracetamol with HPMC, for example, to produce a granular product containing between 25 and 35% amorphous drug.

Example II This series of experiments uses the SEDS ™ to cyclo-oxygenase-2 (COX-2) inhibitors of formula (I):

[Chemical 8] ((Z) -3- [1- (4-chlorophenyl) -1- (4-methanesulfonyl) methylene] -dihydrofuran-2-one) and: (a) Hydroxypropylcellulose (HPC): Structural formula:

[Chemical 9] (Wherein R is H or _{[-CH 2 -CH (CH 3)} -] is a _m H) and: (b) Pluronic (Pluronic) formula HO also known as (TM) F87 (C ₂ H ₄ O ) ₆₄ (C ₃ H ₆ O) ₃₇ (C ₂ H ₄ O) ₆₄ H polyoxypropylene-polyoxyethylene block copolymer, “Poloxamer
Amer) 237 "(P-237).

The reagents used in the experiments were analytical or HPLC grade. For (a), the solvent used is DC which can dissolve both drug and polymer.
It was a mixture of M and ethanol (1: 1). (HPC + drug) concentration is 0.5-
Varying between 4.5% w / v, the DCM: ethanol ratio was modified to increase solution saturation when appropriate. Ethanol served to reduce the viscosity of the HPC dispersion.

The operating conditions for (a) were 90 bar and between 50 and 70 ° C. Higher temperatures facilitated solvent extraction. A CO ₂ flow rate of 20 ml / min or less was used and the target solution flow rate was as low as 0.1 ml / min. The conditions for each experimental run are summarized in Attachments 11 and 12.

For (b) the operating temperature was 35 ° C. (due to the relatively low melting point of the polymer) and the pressure varied between 75 and 100 bar. DCM was used as the solvent for both compound (I) and the polymer together and the solution concentration was between 1-3% w / v. CO ₂ poor solvent is flowed at 18 ml / min, and the target solution flow rate is 0.1 to 0.2 ml / min.
It was between minutes. Table 13 (attached) summarizes the operating conditions for each operation.

In both experimental sets, nozzle outlet diameters of 100, 200, 400 and 750 μm were used, with either 50 ml or in some cases a 500 ml particle formation tank.

Results and Discussion-Compound (I) and HPC results are shown in attached Tables 11 and 12. The best yields and particle sizes are compound (
I) Obtained in run 14 with 85% w / w-this has a mean diameter of 3.8 μm
95 of free-flowing circular / dish-like particles (Fig. 27, SEM at 4000x magnification).
% Yield was given. At 30% w / w HPC (Run 17) a 96% yield was obtained, but the particles were more flaky and agglomerated, their average size was 13.1 μm.
Met. HPC concentrations of 50-80% w / w produced large (20.7 μm) coral-like aggregates (Run 21 (FIG. 28, SEM at 2000 × magnification) and 22). In all runs, the recovery of compound (I) was over 90%.

In general, nozzle clogging was reduced at lower concentrations of compound (I) (eg, about 80% w / w or less). For some runs, the 50 ml tank was immediately clogged with precipitated solids; the 500 ml tank was replaced to eradicate this problem.

Particle agglomeration (and thus large particle size) is generally reduced by reducing the process throughput, eg by decreasing the concentration and / or flow rate of the drug / polymer solution (while still maintaining the solution near saturation). I was able to do it.

Results and Discussion-Compound (I) and P-237 Results are shown in Appendix Table 13. The smallest particles of pure compound (I) have a flow rate of 0.15 ml.
Produced in run 38 with 2% w / v target solution / min. These conditions were used to make co-formulations for dissolution testing and control batches of pure compound (I). In all the samples, the recovery rate of compound (I) was 100%.

Crystallinity The product was subjected to DSC analysis to determine the crystallinity present in compound (I).
The results are shown in Table 1 below as a function of drug concentration for the HPC and P-237 systems, respectively.
4 and 15 and graphically illustrated in FIGS. 29 and 30, respectively.

[Table 3]

[Table 4]

The results for both systems show that the crystallinity decreases significantly with increasing polymer content. The decrease is almost linear for the P-237 system, but
For HPC, a polymer content of at least 20% w / w is required before the crystallinity level begins to decrease. 20% w for 100% amorphous product for both systems
It was achieved at a drug compounding rate of less than / w.

Physical and Chemical Stability A representative sample containing 20% w / w Compound (I) and 80% w / w P-237 prepared using the SEDS ™ method described above was darkened. Under room temperature (10-27
C.) in a screw-capped glass jar for 13 months. At the end of this storage period, the sample was found to retain its starting physical properties. That is, it was a free flowing, easily handleable powder that still contained discrete particles. It also retained its 100% amorphous character (assessed using DSC).

Example III This series of experiments was carried out using SEDS ™, a COX-2 inhibitor of formula (II):

[Chemical 10] Demonstrate the co-formulation of ((Z) -3- [1- (4-bromophenyl) -1- (4-methylsulfonylphenyl) methylene] -dihydrofuran-2-one) with HPC.

An apparatus similar to that used in Examples I and II, but scaled up 10-fold, was used to perform SEDS ™ particle formation. Both compound (II) and HPC (as used in Example II) were dissolved in acetone at an optimal concentration of 2.0% w / v. The preferred operating temperature was 60 ° C. and a pressure of 120 bar. The optimum target solution flow rate is 1.0 ml / min and 2 for supercritical carbon dioxide poor solvent.
It was 00 ml / min. Products containing 10%, 20%, 30%, 50% and 70% w / w of compound (II) were prepared using these conditions and the exact conditions for each run are summarized in Table 16 below.

Low molecular weight of HPC (80,000) for some runs as shown in the table.
Grade was used.

The experiment was also carried out using DCM: ethanol (35:65 v / v) as solvent, solution concentration 1.0% v / v, operating temperature and pressure 50 ° C. and 90 bar, respectively.
The target solution flow rate was 1.0 ml / min and the supercritical carbon dioxide flow rate was 200 ml / min. The operating conditions for each operation are summarized in Attachment 17; 90% w / w compound (I
A product containing I) was successfully manufactured.

Results and Discussion The results are shown in attached Tables 16 and 17. Sample crystallinity was evaluated by DSC in each case; the results are shown in Table 18 below and presented graphically in Figure 31 (crystallinity versus drug loading).

[Table 5]

As a result, products containing 20% w / w or less of compound (II) (Run Nos. 10, 13 and 25) had a crystallinity of 0%. After storage in glass bottles with screw caps for about 3 months at room temperature (10-27 ° C.) in the dark, these samples were found to retain their 100% amorphous character. They were also powders that were free-flowing and easy to handle, even as they started.

Example IV This series of experiments was performed using SEDS ™, glibenclamide (1- {
4- [2- (5-chloro-2-methoxybenzamido) ethyl] benzenesulfonyl} -3-cyclohexylurea, an antidiabetic drug and 75/25 DL-lactide-co-caprolactone (Birmingham Polymers, Engl).
Demonstrate co-formulation with and).

Supercritical nitrogen was used as the anti-solvent because supercritical carbon dioxide would plasticize the amorphous polymeric excipient. Gleebenclamide was dissolved in methylene chloride. The antisolvent flow rate was between 15 and 25 liter min ^{−1 and} the flow rate for the drug solution was between 0.05 and 0.1 ml min ⁻¹ . A 500 ml particle formation tank was used with an operating temperature between 35 and 60 ° C. and a pressure of 100 bar.

Results and Discussion Co-blends with drug: polymer ratios between 1: 1 and 9: 1 were successfully prepared under the conditions described above. Glebenclamide raw material is crystalline, but all SED
The S ™ product was confirmed by XRD analysis to contain 100% amorphous phase drug.

For all co-blends, residual solvent levels (measured using Headspace Gas Chromatography (Varian ™)) account for supercritical nitrogen, which has poor mass transfer properties compared to supercritical carbon dioxide. It was surprisingly low, less than 300 ppm.

The above Tables 2-9 (Example I), 11-13 (Example II) and 16 and 17 (Example III) are attached below.

[0138]

[Table 6]

[0139]

[Table 7]

[0140]

[Table 8]

[0141]

[Table 9]

[0142]

[Table 10]

[0143]

[Table 11]

[0144]

[Table 12]

[0145]

[Table 13]

[0146]

[Table 14]

[0147]

[Table 15]

[0148]

[Table 16]

[0149]

[Table 17]

[0150]

[Table 18]

[0151]

[Table 19]

[0152]

[Table 20]

[Brief description of drawings]

1 is a schematic illustration of a device that can be used to carry out the method according to the invention and obtain a product.

[Fig. 2]   3 is a scanning electron micrograph of some starting materials and products of Example I.

[Figure 3]   3 is a scanning electron micrograph of some starting materials and products of Example I.

[Figure 4]   3 is a scanning electron micrograph of some starting materials and products of Example I.

[Figure 5]   3 is a scanning electron micrograph of some starting materials and products of Example I.

[Figure 6]   3 shows solubility profiles for three of the systems investigated in Example I.

[Figure 7]   3 shows solubility profiles for three of the systems investigated in Example I.

[Figure 8]   3 shows solubility profiles for three of the systems investigated in Example I.

FIG. 9 shows a plot of crystallinity versus drug parts by weight for the system investigated in Example I.

FIG. 10 shows a plot of crystallinity versus drug parts by weight for the system investigated in Example I.

FIG. 11 shows a plot of crystallinity versus drug parts by weight for the system investigated in Example I.

FIG. 12 shows a plot of crystallinity versus drug parts by weight for the system investigated in Example I.

FIG. 13 shows a plot of crystallinity versus drug parts by weight for the system investigated in Example I.

FIG. 14 shows a plot of crystallinity versus drug parts by weight for the system investigated in Example I.

FIG. 15 shows a plot of crystallinity versus drug parts by weight for the system investigated in Example I.

FIG. 16 shows a plot of crystallinity versus drug parts by weight for the system investigated in Example I.

FIG. 17 shows a plot of crystallinity versus drug parts by weight for the system investigated in Example I.

FIG. 18 shows a plot of crystallinity versus drug parts by weight for the system investigated in Example I.

FIG. 19 shows a plot of crystallinity versus drug parts by weight for the system investigated in Example I.

FIG. 20 is a DSC (Differential Scanning Calorimetry) trace for each crystalline indomethacin and a number of co-formulations prepared in Example I containing 24 months of storage.

FIG. 21 is a DSC (Differential Scanning Calorimetry) trace for each crystalline indomethacin and a number of co-formulations prepared in Example I containing 24 months of storage.

FIG. 22 is a DSC (Differential Scanning Calorimetry) trace for each crystalline indomethacin and a number of co-formulations prepared in Example I including 24 months storage.

FIG. 23 is a DSC (Differential Scanning Calorimetry) trace for each crystalline indomethacin and a number of co-formulations prepared in Example I including 24 months storage.

FIG. 24 is a DSC (Differential Scanning Calorimetry) trace for each crystalline indomethacin and many co-formulations prepared in Example I including 24 months storage.

To some of systems was investigated in [25] Example ^{_{I, (δ S d -δ S}} p) vs. X (Table 1
(See 0).

To some of systems was investigated in [26] Example ^{_{I, (δ S d -δ S}} p) vs. X (Table 1
(See 0).

FIG. 27   It is a SEM photograph of some products of Example II.

FIG. 28   It is a SEM photograph of some products of Example II.

FIG. 29   9 is a plot of crystallinity versus parts by weight of drug for the product of Example II.

FIG. 30   9 is a plot of crystallinity versus parts by weight of drug for the product of Example II.

FIG. 31   3 is a plot of crystallinity versus drug parts by weight for the product of Example III.

[Procedure amendment]

[Submission date] March 7, 2002 (2002.3.7)

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be amended] Claims

[Correction method] Change

[Contents of correction]

[Claims]

[Chemical 1] 8. The co-formulation of claim 7, selected from the group consisting of:

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/375 A61K 31/375 31/40 31/40 31/444 31/444 31/522 31/522 31 / 55 31/55 45/00 45/00 47/30 47/30 47/32 47/32 47/34 47/34 47/38 47/38 A61P 15/06 A61P 15/06 19/02 19/02 25 / 04 25/04 29/00 101 29/00 101 43/00 111 43/00 111 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, K E, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, Z, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP , KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (71) Applicant Bristol-Myers Squibb Campany BRISTOL-MYERS SQUIB B COMPANY USA United States New York 10154 New York Park Ave 345 (72) Inventor York, Peter United Kingdom, Ilkley Els 299 Pearl, Parish Gildrive 47 (72) Inventor Wilkins, Simon Anthony United Kingdom, Leeds Els 28 5B, Farsley , Beckberg Street 8 (72) Inventor Stori, Richard Anthony UK, Kent Seaty 47 TJ, Canterbury, Chartham, Laural Way 18 (72) Inventor Walker, Stephen Ernest UK, West Yorkshire Hardy 17 7 JX, Shipley, Baildon, Roundwood Road, Roundwood Grange (72) Inventor Harland, Ronald Scott USA, Pennsylvania 19 067, Yardley, Harlow Court 1F Term (reference) 4C076 AA29 EE01 EE02 EE24 EE31 FF63 4C084 AA16 BA44 MA05 MA41 NA03 ZA08 4C086 AA01 BA03 BA18 BC15 BC17 BC56 CB07 MA05 MA41 NA03 ZA08 ZC80 DAMA25A05 MA05A05 MA08A05C08 4MA05A01

Claims (31)

[Claims] 1. Between 80-100% of the active substance is present in an amorphous form as opposed to a crystalline form, provided that the polymer is not polyvinylpyrrolidone when the active substance is indomethacin, and the amorphous phase activity is A co-blend of the active substance and the oligomeric or polymeric material, which is stable for at least 3 months after its production when the substance is stored between 0 and 10 ° C. compared to its crystalline form (s). 2. Between 80 and 100% of the active substance is present in an amorphous form as opposed to a crystalline form, and the amorphous phase active substance is 0 compared to its crystalline form (s). A co-blend of the active substance and the oligomeric or polymeric material which is stable for at least 6 months after its manufacture when stored between -10 ° C. 3. A co-formulation according to claim 1 or claim 2 wherein the amorphous phase active material is stable for at least 24 months after its manufacture when stored between 0-10 ° C. 4. The co-formulation of claim 1, claim 2 or claim 3 wherein the amorphous phase active material is stable for a specified storage period when stored at 25 ° C. 5. Co-formulation according to any of the preceding claims, wherein the active substance comprises a pharmaceutically active substance. 6. The co-formulation according to claim 5, wherein the active substance is selected from the group consisting of paracetamol, ketoprofen, indomethacin, carbamazepine, theophylline and ascorbic acid. 7. The co-formulation of claim 5, wherein the active substance is a COX-2 selective inhibitor. 8. The COX-2 selective inhibitor is a diarylheterocycle.
The co-formulation described in. 9. A COX-2 selective inhibitor is (Z) -3- [1- (4-bromophenyl) -1- (4-methylsulfonylphenyl) methylene] dihydrofuran-.
2-one, (Z) -3- [1- (4-chlorophenyl) -1- (4-methylsulfonylphenyl) methylene] dihydrofuran-2-one, 4- [5- (4-methylphenyl) -3. -(Trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [4- (methylsulfonyl) phenyl] -3-phenyl-2 (5H) -furanone and a compound of formula (III): Chemical 1] 8. The co-formulation of claim 7, selected from the group consisting of: 10. Polyvinylpyrrolidone is an oligomeric or polymeric material, wherein (i) an active substance selected from the group consisting of paracetamol, ketoprofen, indomethacin, carbamazepine, theophylline and ascorbic acid and (ii) the active substance is indomethacin or theophylline. Oligomer or polymer in which between 80 and 100% of the active substance is present in an amorphous form as opposed to a crystalline form, in which the active substance represents at least 10% of the co-formulation. Co-blend of materials. 11. A prior claim, wherein the oligomeric or polymeric material is selected from the group consisting of cellulosic materials (including cellulose derivatives), vinyl polymers, polylactic or glycolic acids (including lactide / glycolide copolymers), and mixtures thereof. A co-formulation according to any of the clauses. 12. Coformulation according to any of the preceding claims, wherein the active substance is a polar substance and the oligomeric or polymeric material is hydrophobic. 13. Coformulation according to any of the preceding claims, wherein 100% of the active substance is present in amorphous form as opposed to crystalline form. 14. A co-formulation according to any of the preceding claims, wherein the active substance represents at least 20% of the co-formulation. 15. Any of the preceding claims comprising a homogeneous single phase mixture of active and oligomeric or polymeric material in which the rate of dissolution of the active in the aqueous medium is not higher than in the first 30 minutes. The co-formulation described in. 16. The co-formulation according to claim 15, wherein the dissolution rate of the active substance in the aqueous medium is not higher than that of the latter in the first 60 minutes. 17. Between 80-100% of paracetamol is present in an amorphous form as opposed to a crystalline form, wherein paracetamol is at least one of the co-formulations therein.
% Of paracetamol with oligomeric or polymeric materials. 18. The co-formulation of claim 17, wherein 100% paracetamol is present in amorphous form. 19. A co-formulation according to claim 17 or claim 18, wherein paracetamol represents at least 25% of the co-formulation. 20. The amorphous phase paracetamol is stable for at least 3 months after its manufacture when stored between 0-10 ° C. compared to its crystalline form (s). A co-blend as described in any one. 21. A co-formulation according to any of the preceding claims, which has been produced by the SEDS ™ method. 22. The active agent and oligomer of any one of claims 1, 2, 10 or 17, wherein the active agent is substantially as described herein in connection with the accompanying illustrations. Or a co-blend with a polymeric material. 23. A pharmaceutical composition containing a co-formulation according to any of the preceding claims. 24. A method of making a co-formulation according to any of claims 1 to 22 which involves the use of the SEDS ™ process. 25. Active substance and oligomer, wherein between 80 and 100% of the active substance is present in an amorphous form as opposed to a crystalline form, in which the active substance represents at least 10% of the co-formulation. Or S for producing co-blends with polymeric materials
Use of the EDS ™ method. 26. Using the antisolvent derived particle formation method, wherein the active substance is soluble in the selected "anti-solvent" but the oligomeric or polymeric material is not soluble under the operating conditions used. , A method for producing a co-blend of an active substance with an oligomeric or polymeric material. 27. The method of claim 26, wherein the particle forming method is the SEDS ™ method. 28. The method according to claim 26 or 27, wherein the poor solvent is supercritical carbon dioxide. 29. The method according to claim 26, wherein the active substance is ketoprofen. 30. The method according to any of claims 26-29, wherein the oligomeric or polymeric material is hydroxypropyl methylcellulose. 31. A method for making a co-blend of an active agent and an oligomeric or polymeric material, the method being substantially as described herein in connection with the accompanying illustrations.