2.3.
De conclusies van EP 092 luiden in de oorspronkelijke Engelse taal als volgt.
1. A free drug particulate form of a compound having a formula
and pharmaceutically acceptable salts and solvates thereof in which the compound is present as solid particles not intimately embedded in a polymeric co-precipitate, wherein at least 90% of the particles have a particle size of less than about 40 microns.
2. The free drug particulate form of claim 1 wherein at least 90% of the particles have a particle size of less than about 25 microns.
3. The free drug particulate form of claim 1 wherein at least 90% of the particles have a particle size of less than about 15 microns.
4. The free drug particulate form of claim 1 wherein at least 90% of the particles have a particle size of less than about 10 microns.
5. A pharmaceutical composition comprising:
(a) a free drug form of a compound having the formula
and pharmaceutically-acceptable salts and solvates thereof in which the compound is present as solid particles not intimately embedded in a polymeric co-precipitate, wherein at least 90% of the particles have a particle size of less than about 40 microns; and
(b) one or more pharmaceutically-acceptable carriers, diluents, or excipients ,
6. The pharmaceutical composition of claim 5 wherein the compound is present entirely as solid particles not intimately embedded in a polymeric copreciptate.
7. A pharmaceutical composition according to claim 5, wherein at least 90% of the particles have a particle size of less than about 10 microns.
8. A pharmaceutical composition comprising:
(a) a free drug form of a compound having the formula
and pharmaceutically-acceptable salts and solvates thereof, in which the compound is present as solid particles not intimately embedded in a polymeric co-precipitate; and
(b) one or more pharmaceutically-acceptable carriers, diluents, or excipients,
wherein the composition exhibits a Cmax of 180 to 280 micrograms/liter or an AUC (0-24) of 2280 to 3560 microgram . hour/liter, measured using a 10 miligram dose of the compound.
9. The composition of claim 8 wherein the composition exhibits a Cmax of about 180 to about 280 micrograms/liter and an AUC (0-24) of 2280 to 3560 microgram . hour/liter.
10. A method of manufacturing the free drug particulate form of claim 1 comprising:
(a) providing a solid, free form of the compound in which the compound is present as solid particles not intimately embedded in a polymeric co-precipitate, and
(b) comminuting the solid free form of the compound to provide particles of the compound wherein at least 90% of the particles have a particle size of less than about 40 microns.
11. The method of claim 10 further comprising the step of admixing the particles of step (b) with one or more pharmaceutically-acceptable carriers, diluents, or excipients.
12. A free drug particulate form according to any one of claims 1 to 4 for use in a method of treatment.
13. Use of particles of a free drug particulate form according to any one of claims 1 to 4 or a pharmaceutical composition according to any one of claims 5 to 7 for the manufacture of a medicament for the treatment of sexual dysfunction.
14. The use of claim 13 wherein the sexual dysfunction is male erectile dysfunction.
15. The use of claim 13 wherein the sexual dysfunction is female sexual arousal disorder.
16. Use of a pharmaceutical composition according to claim 8 or 9 for the manufacture of a medicament for the treatment sexual dysfunction.
17. The use of claim 16 wherein the sexual dysfunction is male erectile dysfunction.
18. The use of claim 16 wherein the sexual dysfunction is female sexual arousal disorder.
19. The use of anyone of claims 13 to 18, wherein the medicament is formulated for oral administration up to a maximum daily dose of 20 mg per day.
2.4.
In de onbestreden Nederlandse vertaling luiden deze conclusies:
1. Vrij geneesmiddel deeltjesvormige vorm van een verbinding
met een formule
en farmaceutisch aanvaardbare zouten en solvaten daarvan, waarbij de verbinding aanwezig is als vaste deeltjes die niet innig zijn ingebed in een polymeer samen neergeslagen product, waarbij ten minste 90% van de deeltjes een deeltjesgrootte bezit van minder dan ongeveer 40 micron.
2. Vrije geneesmiddel deeltjesvormige vorm volgens conclusie 1, waarbij ten minste 90% van de deeltjes een deeltjesgrootte bezit van minder dan ongeveer 25 micron.
3. Vrije geneesmiddel deeltjesvormige vorm volgens conclusie 1, waarbij ten minste 90% van de deeltjes een deeltjesgrootte bezit van minder dan ongeveer 15 micron.
4. Vrije geneesmiddel deeltjesvormige vorm volgens conclusie 1, waarbij ten minste 90% van de deeltjes een deeltjesgrootte bezit van minder dan ongeveer 10 micron.
5. Farmaceutische samenstelling die omvat:
(a) een vrije geneesmiddelvorm van de verbinding met de
formule
en farmaceutisch aanvaardbare zouten en solvaten daarvan, waarbij de verbinding aanwezig is als vaste deeltjes die niet innig zijn ingebed in een polymeer samen neergeslagen product, waarbij ten minste 90% van de deeltjes een deeltjesgrootte bezit van minder dan ongeveer 40 micron; en
(b) één of meer farmaceutisch aanvaardbare dragers, verdunningsmiddelen of hulpmiddelen.
6. Farmaceutische samenstelling volgens conclusie 5, waarbij de verbinding volledig aanwezig is als vaste deeltjes die niet innig ingebed zijn in een polymeer samen neergeslagen product.
7. Farmaceutische samenstelling volgens conclusie 5, waarbij ten minste 90% van de deeltjes een deeltjesgrootte bezit van minder dan ongeveer 10 micron.
8. Farmaceutische samenstelling die omvat:
(a) een vrije geneesmiddelvorm van de verbinding met de
formule
en farmaceutisch aanvaardbare zouten en solvaten daarvan, waarbij de verbinding aanwezig is als vaste deeltjes die niet innig zijn ingebed in een polymeer samen neergeslagen product; en
(b) één of meer farmaceutisch aanvaardbare dragers, verdunningsmiddelen of hulpmiddelen,
waarbij de samenstelling een Cmax van 180 tot 280 microgram/liter of een AUC (0-24) van 2280 tot 3560 microgram • uur/liter, gemeten met een dosis van 10 mg van de verbinding, bezit.
9. Samenstelling volgens conclusie 8, waarbij de samenstelling een Cmax van ongeveer 180 tot ongeveer 280 microgram/liter en een AUC (0-24) van 2280 tot 3560 microgram • uur/liter bezit.
10. Werkwijze voor het bereiden van de vrije geneesmiddel deeltjesvormige vorm volgens conclusie 1, welke werkwijze omvat:
(a) ter beschikking stellen van een vaste, vrije vorm van de verbinding waarbij de verbinding aanwezig is als vaste deeltjes die niet innig ingebed zijn in een polymeer samen neergeslagen product, en
(b) verkleinen van de vaste vrije vorm van de verbinding zodat deeltjes worden verkregen van de verbinding waarbij ten minste 90% van de deeltjes een deeltjesgrootte bezit van minder dan ongeveer
40 micron.
11. Werkwijze volgens conclusie 10 die bovendien het mengen van de deeltjes van stap (b) met één of meer farmaceutisch aanvaardbare dragers, verdunningsmiddelen of hulpmiddelen omvat.
12. Vrije geneesmiddel deeltjesvormige vorm volgens één van de conclusies 1 tot 4 voor toepassing bij een behandelingsmethode.
13. Toepassing van deeltjes van een vrije geneesmiddel deeltjesvormige vorm volgens één van de conclusies 1 tot 4 of een farmaceutische samenstelling volgens één van de conclusies 5 tot 7 voor het
bereiden van een geneesmiddel voor het behandelen van seksueel disfunctioneren.
14. Toepassing volgens conclusie 13, waarbij het seksueel disfunctioneren erectiel disfunctioneren bij mannen is.
15. Toepassing volgens conclusie 13, waarbij het seksueel disfunctioneren de verstoring van seksuele prikkeling bij vrouwen is.
16. Toepassing van een farmaceutische samenstelling volgens conclusie 8 of 9 voor het bereiden van een geneesmiddel voor het behandelen van seksueel disfunctioneren.
17. Toepassing volgens conclusie 16, waarbij het seksueel disfunctioneren erectiel disfunctioneren bij mannen is.
18. Toepassing volgens conclusie 16, waarbij het seksueel disfunctioneren de verstoring van seksuele prikkeling bij vrouwen is.
19. Toepassing volgens één van de conclusies 13 tot 18, waarbij het geneesmiddel geformuleerd is voor orale toediening tot een maximale dagelijkse dosis van 20 mg per dag.
2.5.
De beschrijving van het octrooi houdt onder meer het volgende in:
[0002] The present invention relates to the fields of pharmaceutical and organic chemistry, and to a
-carboline compound which is useful for the treatment of various medical indications where inhibition of type 5 cGMP-specific phosphodiesterase (PDE5) is desired. More particularly the present invention provides a free drug form of -carboline particles in a size range allowing for uniform formulation of stable pharmaceutical compositions, especially compositions providing desired bioavailability properties heretofore not provided in the art.
BACKGROUND OF THE INVENTION
(…)
[0004] Daugan U.S. Patent No. 5,859,006 discloses a class of -carboline compounds, and pharmaceutical compositions containing the -carbolines, which are useful in the treatment of conditions wherein inhibition of PDE5 is desired. PCT publication WO 97/03675 discloses use of this class of -carboline compounds in the treatment of sexual dysfunction.
[0005] The poor solubility of many -carboline compounds useful as PDE5 inhibitors prompted the development of coprecipitate preparations, as disclosed in PCT publication WO 96/38131 and Butler U.S. Patent No. 5,985,326. Briefly, coprecipitates of a -carboline with polymeric hydroxypropylmethylcellulose phthalate, for example, were prepared, milled, mixed with excipients, and compressed into tablets for oral administration. Studies revealed, however, that difficulties arose in generating precisely reproducible lots of coprecipitate product, which makes use of coprecipitates less than ideal in pharmaceutical formulations.
[0006] Additionally, clinical studies involving administration of coprecipitate tablets preliminarily revealed that maximum blood concentration of the -carboline compound is achieved in 3 to 4 hours, with the average time for onset of therapeutic effect not yet precisely determined. In the treatment of sexual dysfunction, such as male erectile dysfunction or female sexual arousal disorder, however, a more rapid achievement of maximum blood concentration, along with a greater prospect for rapid onset of therapeutic effect, frequently is sought by individuals desiring more immediate and/or less prolonged effects. Accordingly, a need in the art continues to exist for orally administrable
-carboline compounds and -carboline-containing pharmaceutical compositions having an ability to provide a therapeutic effect within a desirable, or at least acceptable, time frame.
[0007] The present invention provides particulate preparations of a free drug form of a -carboline compound having specific and defined particle size characteristics. The defined particle size permits a uniform formulation of stable pharmaceutical compositions. In particular, the present invention provides compositions that exhibit a rapid achievement of maximum blood concentration of PDE5 inhibitor and/or a rapid onset of a therapeutic PDE5 inhibitory effect.
[0008] The present invention provides a compound having the formula (I)
and pharmaceutically acceptable salts and solvates thereof, wherein the compound is a free drug in particulate form, and wherein at least 90% of the particles have a particle size of less than about 40 microns, and preferably less than 30 microns. Highly preferred particulate forms of the -carboline compound (I) have at least 90% of the particles less than 25 microns in size. Most preferred forms of the free compound (I) are those wherein 90% of the particles are less than 10 microns in size.
[0009] The present invention provides, therefore, a free form of a -carboline compound, and compositions containing the -carboline compound, which can be used in an effective therapy for conditions wherein inhibition of PDE5 provides a benefit. The free form of -carboline compound (I) has a particle size such that the onset of beneficial effects of PDE5 inhibition are exhibited in a relatively short time after oral administration.
(…)
[0012] Alternatively stated, the present invention provides for the use of the above-described particulate forms of compound (I) for the manufacture of medicaments for the treatment of sexual dysfunction. Specific conditions that can be treated by the compound and compositions of the present invention include, but are not limited to, male erectile dysfunction and female sexual dysfunction, for example, female arousal disorder, also known as female sexual arousal disorder.
(…)
DETAILED DESCRIPTION OF THE INVENTION
(…)
[0024] The term "free drug" refers to solid particles of compound (I) not intimately embedded in a polymeric coprecipitate.
(…)
[0031] It has been found that by processing (6R-trans)-6-(1,3-benzodioxo1-5-y1)-2,3,6,7,12,12a-hexahydro-2-methylpyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione, alternatively named (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylene-dioxyphenyl)pyrazino[2',1':6.1]pyrido[3,4-b]indole-1,4-dione, as disclosed in Daugah U.S. Patent No. 5,859,006, and represented by structural formula (I) [structuurformule weggelaten - rechtbank] to bring the particle size within a particular narrow range, manufacturing capability is enhanced, and pharmaceutical compositions can be prepared that exhibit an improved bioavailability of the active ingredient, i.e., compound (I).
(…)
[0036] The compound of the structural formula (I) can be made according to established procedures, such as those detailed in U.S. Patent No. 5,859,006, incorporated herein by reference. The preparation of the compound of structural formula (I) is specifically provided in U.S. Patent No. 5,859,006.
(…)
[0039] After being characterized for size in its raw state, the free drug compound then is milled, for example using a pin mill under suitable conditions of mill rotation rate and feed rate, to bring the particle size value within the above mentioned limits of the present invention. (…)
(…)
[0050] A compound (I)/hydroxypropylmethylcellulose phthalate coprecipitate was manufactured generally by the method set forth in Butler U.S. Patent No. 5,985,326. (…) Applicants found that the coprecipitate contained a portion of the free drug form of compound (I) not embedded in the coprecipitate polymer. In clinical studies (see Example 2), applicants further discovered that the blood levels of compound (I) within thirty minutes of administration was attributable to the free drug present in the coprecipitate compositions.
(…)
[0061] In vitro dissolution tests were performed using compound (I) which had been processed by milling from its raw state particulate form (d90=75-200 microns) into particulate preparations having d90 (microns) values as follows: Lot 1, d90=4; Lot 2, d90=22; Lot 3, d90=55; Lot 4, d90=65; Lot 5, d90=73; and Lot 6, d90=116. (…)
[0062] Lots were evaluated in vitro by accurately weighing approximately 10 mg of bulk drug into a test tube, adding 1 mL of purified water, and soni-cating for up to 2 minutes to ensure the powder was wetted. The drug slurry was subsequently transferred to a dissolution apparatus vessel containing 1000 mL of aqueous 0.5% sodium lauryl sulphate at 37C. The test tube was rinsed with multiple aliquots of warmed dissolution medium and added back into the dissolution vessel. The paddle speed was 50 rpm and samples were taken at 5, 10, 20, and.30 minutes and subsequently analyzed by HPLC. The results are illustrated in Figure 1 and demonstrate improved in vitro dissolution occurs with smaller particle sizes of compound (I).
[0063] The improvement in bioavailability and reproducibility of pharmaceutical compositions made available by the present invention is demonstrated in vivo in humans. The following Table 1 demonstrates the pharmaceutical compositions prepared as in Examples 4 and 5 with particulate free drug having a d90 of 8.4 microns compared to composition incorporating the coprecipitate of compound (I) with hydroxypropylmethylcellulose phthalate (coprecipitate). In each instance, the tableted composition was designed to deliver a 10 mg dose of compound (I).
[0064] The composition incorporating a particulate free drug form having a d90 of 8.4 demonstrated. significantly improved Tmax over a composition containing the coprecipitate (Tmax is a measure of the time to achieve peak blood levels of a drug, and is indicative of improved onset of action). The particulate free drug formulation correspondingly provided a more rapid rate of absorption of compound (I) into plasma, providing a geometric mean plasma level at 30 minutes of 51 ng/ml (nanograms per milliliter) as compared to 29 ng/ml for the coprecipitate formulation.
[0065] A study was conducted to determine the bioequivalence of tablets containing compound (I) in different particle sizes. The tablets contained compound (I) in a particle size of d90=8.4 (micron), d90=20, or d90=52.
(…)
[0071] The following table summarizes various pharmacokinetic parameters of compound (I) following oral administration of a single 10 mg dose of the d90 52, 20, and 8.4 particle size formulations.
[0072] This study showed that reducing the particle size of compound (I) in accordance with the present invention has an impact on the in vivo rate of absorption of compound (I) from a solid dosage form, and, hence, on the bioavailability of compound (I). For example, from the statistical analysis, tmax for the 52 formulation occurred significantly (i.e., 1 hour) later than for the 8.4 formulation. There was no significant difference in tmax between the 20 and 8.4 formulations. Accordingly, onset of a therapeutic benefit attributed to compound (I) after administration is significantly faster for the 8.4 and 20 formulations compared to the 52 formulation.
2.7.
De navolgende publicaties behoren voor het octrooi tot de stand van de techniek.
2.7.1.
Internationale octrooiaanvrage PCT/EP95/00183, op 27 juli 1995 gepubliceerd als WO 95/19978, heeft geleid tot Europees octrooi EP 0 740 668, eveneens van Icos, voor de stof tadalafil, de in EP 092 vermelde compound I. EP 0 740 668 is inmiddels geëxpireerd, maar Icos heeft een aanvullend beschermingscertificaat verkregen dat zal verlopen op 11 november 2017.
2.7.2.
De in paragraaf 0004 van het octrooi genoemde internationale octrooiaanvrage PCT/EP96/03024, gepubliceerd op 6 februari 1997 als
WO 97/03675, betreft ‘Use of CGMP-phosphodiesterase inhibitors to treat impotence’ (verder: WO 675). Deze octrooiaanvrage openbaart tadalafil en het gebruik daarvan voor de behandeling van erectiestoornissen bij mannen.
2.7.3.
De in paragraaf 0005 van het octrooi genoemde internationale octrooiaanvrage PCT/EP96/02299, gepubliceerd op 5 december 1996 als WO 96/38131, betreft een ‘Method of producing a solid dispersion of a poorly water soluble drug’ (verder: Butler). Butler openbaart tadalafil in een zogenaamde
co-precipitaatformulering. De beschrijving houdt onder meer het volgende in:
(…)
The present invention relates to the field of solid dispersions of poorly water
soluble drugs, to processes for their preparation and their use in pharmaceutical compositions. More particularly the present invention relates to solid dispersions in the form of co-precipitates of poorly water soluble drugs and their compositions with a pharmaceutically acceptable carrier or excipient therefor.
(…)
Co-precipitation is a recognised technique for increasing the dissolution of
poorly water soluble drugs, such as griseofulvin, ketoprofen, sulphathiazide,
spirinolactone, tolbutamide and nifedipine, so as to consequently improve
bioavailability thereof. Techniques such as solvent deposition, lyophilization,
solvate formation and solid dispersion (of which co-precipitation is an example as described above) have therefore been developed to try to overcome the problem of poor water solubility and resultant low bioavailability.
(…)
In general terms, problems which can be associated with known co-precipitation techniques can include excess solvent usage, identifying carrier/drug combinations which can be effectively precipitated and enhance bioavailability, the use of heat to effect solution which may detrimentally affect the drug, and the like. Co-precipitation techniques are however attractive for the preparation of solid dispersions, in that less solvents and heat are employed when compared to techniques such as co-evaporation and solvent removal may therefore be facilitated.
We have now developed a co-precipitation technique which alleviates the
above described disadvantages associated with known techniques, and have
also found that co-precipitation offers an advantageous preparation route for
solid dispersions of poorly water soluble drugs.
(…)
2.7.4.
In H.A. Lieberman e.a. (red.), ‘Pharmaceutical dosage forms: tablets’, (volume 1, tweede editie), New York: Marcel Dekker Inc. 1989, is het volgende vermeld (pagina 5 en 6):
It is now generally recognized that poorly soluble drugs showing a
dissolution rate-limited step in the absorption process will be more readily
bioavailable when administered in a finely subdivided state than as a coarse
material. (...) Because of these significant roles, it is important to decide on a
desired size range, and thence to maintain and control it. It is probably safest
to grind most new drugs having particles that are above approximately 100 m
in diameter. If the material consists of particles primarily 30 m or less in
diameter, then grinding is unnecessary, except if the material exists as needles
- where grinding may improve flow and handling properties, or if the material
is poorly water-soluble where grinding increases dissolution rate. Grinding
should reduce coarse material to, preferably, the 10- to 40-m range.
2.7.5.
In M. Gibaldi, ‘Biopharmaceutics and Clinical Pharmacokinetiks’, (vierde editie), Philadelphia / Londen: Lea & Febiger 1991, is het volgende vermeld (pagina 51):
A drug dissolves more rapidly when its surface area is increased. This is usually
accomplished by reducing the particle size of the drug. Many poorly soluble,
slowly dissolving drugs are marketed in micronized or microcrystalline form.
Particle size reduction usually results in more rapid and complete absorption.
2.7.6.
In R.A. Gennaro (red.), ‘Remington: The Science and Practice of Pharmacy’, (19e editie), Easton, Pennsylvania: Mack Publishing Company 1995, is het volgende vermeld (pagina 1449):
Gastrointestinal absorption of a poorly soluble drug may be affected by the
particle size distribution. If the dissolution rate of the drug is less than the
diffusion rate to the site of absorption and the absorption rate itself, then the
particle size of the drug is of great importance. Smaller particles should
increase dissolution rate and, thus, bring about more rapid gastrointestinal
absorption. One of the first observations of this phenomenon was made with sulfadiazine. Blood-level determinations showed that the drug in suspension containing particles 1 to 3 m in size was absorbed more rapidly and more efficiently than from a suspension containing particles 7 times larger. Maximum blood levels were about 40% higher and occurred 2 hours earlier. Increased bioavailability with
particle-size reduction also has been observed with griseofulvin. The extent of absorption of an oral dose increased 2.5 times when the surface area was increased approximately sixfold. Micronized griseofulvin permits a 50% decrease in dosage to obtain a satisfactory clinical response.
2.7.7.
J.C. Chaumeil, ‘Micronization, A Method of Improving the Bioavailability of Poorly Soluble Drugs’, Meth Find Exp Clin Pharmacol 1998, 20(3), vermeldt het volgende (pagina 211):
For poorly soluble drugs, the digestive absorption depends on their rate of dissolution. Decreasing the particle size of these drugs improves their rate of dissolution. Fine grinding mills are use to micronize powders: either jar mills or fluid energy mills. Theses processes were applied to griseofulvin, progesterone, spironolactone and diosmin. For each drug, micronization improved
their digestive absorption, and consequently their bioavailability and clinical efficacy.
(…)
The bioavailability of a drug is classically defined as the fraction of the administered dose that reaches the systemic circulation of a living organism, and the rate at which it does so. The first, and often only, parameter that can improve the bioavailability of a poorly soluble drug is its rate of dissolution in the digestive fluids.
.jpg?width=50&height=55)
.jpg?width=50&height=55)
