U.S. patent application number 10/490089 was filed with the patent office on 2004-12-16 for pharmaceutical compositions comprising colloidal silicon dioxide.
Invention is credited to Haeberlin, Barbara, Heuerding, Silvia, Kramer, Andrea.
Application Number | 20040254210 10/490089 |
Document ID | / |
Family ID | 9922916 |
Filed Date | 2004-12-16 |
United States Patent
Application |
20040254210 |
Kind Code |
A1 |
Haeberlin, Barbara ; et
al. |
December 16, 2004 |
Pharmaceutical compositions comprising colloidal silicon
dioxide
Abstract
A pharmaceutical composition comprising a macrolide solid
dispersion, a disintegrant and colloidal silicon dioxide, wherein
the composition comprises 1 to 5% colloidal silicon dioxide by
weight.
Inventors: |
Haeberlin, Barbara;
(Munchenstein, CH) ; Kramer, Andrea; (Reute,
DE) ; Heuerding, Silvia; (Basel, CH) |
Correspondence
Address: |
NOVARTIS
CORPORATE INTELLECTUAL PROPERTY
ONE HEALTH PLAZA 430/2
EAST HANOVER
NJ
07936-1080
US
|
Family ID: |
9922916 |
Appl. No.: |
10/490089 |
Filed: |
July 30, 2004 |
PCT Filed: |
September 27, 2002 |
PCT NO: |
PCT/EP02/10890 |
Current U.S.
Class: |
514/291 ;
514/183 |
Current CPC
Class: |
A61P 17/00 20180101;
A61P 37/08 20180101; A61K 9/2009 20130101; A61P 19/02 20180101;
A61P 25/00 20180101; A61P 25/28 20180101; A61K 9/2077 20130101;
A61P 5/14 20180101; A61K 31/435 20130101; A61P 11/00 20180101; A61P
13/12 20180101; A61P 21/04 20180101; A61P 19/08 20180101; A61P
31/00 20180101; A61K 9/2027 20130101; A61P 1/04 20180101; A61K
31/445 20130101; A61P 35/00 20180101; A61K 9/0056 20130101; A61P
17/14 20180101; A61P 11/06 20180101; A61P 3/10 20180101; A61K 9/145
20130101; A61P 9/08 20180101; A61P 5/00 20180101; A61P 17/04
20180101; A61P 31/10 20180101; A61P 27/14 20180101; A61P 29/00
20180101; A61P 17/02 20180101; A61P 17/08 20180101; A61P 37/06
20180101; A61P 37/02 20180101; A61P 17/06 20180101; A61P 7/06
20180101; A61P 1/16 20180101; A61P 27/02 20180101; A61K 9/146
20130101 |
Class at
Publication: |
514/291 ;
514/183 |
International
Class: |
A61K 031/4745; A61K
031/33 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 28, 2001 |
GB |
0123400.4 |
Claims
1. A pharmaceutical composition comprising a macrolide solid
dispersion, a disintegrant and colloidal silicon dioxide, wherein
the composition comprises 1 to 5% colloidal silicon dioxide by
weight.
2. A pharmaceutical composition according to claim 1, wherein 250
mg of the composition, when compressed using a force of 8 to 11 kN
with a 9 mm die and standard flat punches, forms a tablet having a
hardness of 35 to 80 N and a disintegration time of 3 minutes or
less.
3. A composition according to claim 1, wherein the composition is
in the form of a dispersible tablet.
4. A composition according to claim 3, wherein the tablet has a
disintegration time of 90 seconds or less.
5. A composition as claimed in claim 1, wherein the macrolide is
rapamycin, ascomycin or a derivative thereof.
6. A composition as claimed in claim 1, wherein the derivative of
rapamycin is 40-O-(2-hydroxy)ethyl-rapamycin.
7. (canceled)
8. A method of administering a pharmaceutical composition of claim
1 to a subject in need of such therapy which comprises (i)
contacting the composition with an aqueous solution (ii) allowing
the composition to disperse in the aqueous solution to form a
dispersed mixture and (ii) ingesting the dispersed mixture.
9. (canceled)
10. A process for producing a macrolide-containing dispersible
tablet, comprising preparing a macrolide solid dispersion, mixing
the macrolide solid dispersion with a disintegrant and colloidal
silicon dioxide to form a pharmaceutical composition and
compressing the pharmaceutical composition to form the dispersible
tablet.
Description
[0001] This invention relates to novel oral pharmaceutical
compositions comprising a macrolide, e.g. rapamycin or a derivative
thereof or an ascomycin, in a solid dispersion.
[0002] The term "macrolide" as used herein, refers to a macrocyclic
lactone, for example a compound having a 12-membered or larger
lactone ring. Of particular interest are the "lactam macrolides",
i.e., macrocyclic compounds having a lactam (amide) bond in the
macrocycle in addition to a lactone (ester) bond, for example the
lactam macrolides produced by microorganisms of the genus
Streptomyces such as rapamycin, ascomycin, and FK-506, and their
numerous derivatives and analogues. Such lactam macrolides have
been shown to have interesting pharmaceutical properties,
particularly immunosuppressive and anti-inflammatory
properties.
[0003] Rapamycin is an immunosuppressive lactam macrolide that is
produced by Streptomyces hygroscopicus. The structure of rapamycin
is given in Kesseler, H., et al.; 1993; Helv. Chim. Acta; 76: 117.
See, e.g., McAlpine, J. B., et al., J. Antibiotics (1991) 44: 688;
Schreiber, S. L., et al., J. Am. Chem. Soc. (1991) 113: 7433; U.S.
Pat. No. 3,929,992. Rapamycin is an extremely potent
immunosuppressant and has also been shown to have antitumor and
antifungal activity. Its utility as a pharmaceutical, however, is
restricted by its very low and variable bioavailability. Moreover,
rapamycin is highly insoluble in aqueous media, e.g. water, making
it difficult to formulate galenic compositions. Numerous
derivatives of rapamycin are known. Certain 16-O-substituted
rapamycin derivatives are disclosed in WO 94/02136, the contents of
which are incorporated herein by reference. 40-O-substituted
rapamycin derivatives are described in, e.g., U.S. Pat. No.
5,258,389 and WO 94/09010 (O-aryl and O-alkyl rapamycin
derivatives); WO 92/05179 (carboxylic acid esters), U.S. Pat. No.
5,118,677 (amide esters), U.S. Pat. No. 5,118,678 (carbamates),
U.S. Pat. No. 5,100,883 (fluorinated esters), U.S. Pat. No.
5,151,413 (acetals), U.S. Pat. No. 5,120,842 (silyl ethers), WO
93/11130 (methylene rapamycin and derivatives), WO 94/02136
(methoxy derivatives), WO 94/02385 and WO 95/14023 (alkenyl
derivatives) all of which are incorporated herein by reference.
32-O-dihydro or substituted rapamycin derivatives are described,
e.g., in U.S. Pat. No. 5,256,790, incorporated herein by
reference.
[0004] Further rapamycin derivatives are described in PCT
application EP96/02441, for example 32-deoxorapamycin is described
in Example 1, and 16-pent-2-ynyloxy-32(S)-dihydrorapamycin is
described in Examples 2 and 3. The contents of PCT application
EP96/02441 are incorporated herein by reference.
[0005] Rapamycin and its structurally related derivatives are
termed collectively as "rapamycin and rapamycin derivatives".
[0006] The ascomycin class, of which FK-506 and ascomycin are the
best known members, comprise another class of lactam macrolides,
many of which have potent immunosuppressive and anti-inflammatory
activity. FK-506 is a lactam macrolide immunosuppressant that is
produced by Streptomyces tsukubaensis No 9993. The structure of
FK506 is given in the appendix to the Merck Index, 11th ed. (1989)
as item A5. Ascomycin is described, e.g., in U.S. Pat. No.
3,244,592. Many derivatives of ascomycin and FK-506 have been
synthesized, including halogenated derivatives such as
33-epi-chloro-33-desoxy-ascomycin described in EP 427 680.
Ascomycin, FK-506 and their structurally similar analogues and
derivatives are termed collectively "ascomycin and ascomycin
derivatives".
[0007] On oral administration to humans, solid rapamycin or
rapamycin derivatives, may not be absorbed to any significant
extent into the bloodstream. PCT application WO 97/03654, the
contents of which are incorporated herein by reference, describes
pharmaceutical compositions in the form of a solid dispersion
comprising a macrolide, e.g. a rapamycin, ascomycin or a derivative
thereof, and a carrier medium. These compositions provide improved
bioavailability of drug substance, are convenient to administer,
and are stable.
[0008] However for certain groups of patients, oral administration
of medicaments in solid tablet form is either undesirable or
impractical. In particular, children and elderly patients may be
unable to swallow such tablets conveniently. For these patients, it
is typically more desirable to provide a tablet which can first be
dispersed in an ingestible liquid, before consumption by the
patient.
[0009] For administration to children and elderly patients, it
would be highly desirable to provide a tablet which disperses
rapidly in an ingestible liquid such as water. A problem with the
prior art macrolide formulations is that, because they do not
necessarily disperse rapidly in aqueous solutions, it may be
inconvenient and time-consuming to prepare a sufficiently dispersed
liquid preparation before administration to the patient. One
particular difficulty in the formulation of a macrolide solid
dispersion composition in the form of a dispersible tablet is the
high amount of carrier used in solid dispersion compositions,
acting as a binder in tablet formulations.
[0010] It is known that a more rapidly disintegrating tablet can be
produced by using a lower compaction force during the tablet
manufacturing process. However, this typically results in a tablet
which has inferior mechanical properties. In particular, weakly
compressed tablets show insufficient hardness and are liable to
crumble, chip or disintegrate before this is desired (i.e. during
packaging, transit, storage or at any time before addition of the
tablet to an ingestible liquid for consumption).
[0011] The present invention aims to provide a pharmaceutical
composition which alleviates the problems of the prior art
compositions. Accordingly, the present invention provides a
pharmaceutical composition comprising a macrolide solid dispersion,
a disintegrant and colloidal silicon dioxide, wherein the
composition comprises 1 to 5% colloidal silicon dioxide by
weight.
[0012] The present invention is based on the surprising finding
that a particularly rapidly-dispersing composition comprising a
macrolide solid dispersion can be provided by using colloidal
silicon dioxide to promote disintegration. Colloidal silicon
dioxide is known from the prior art primarily as a lubricant or
flow-regulating agent in pharmaceutical compositions. Where it is
used for such purposes, silicon dioxide typically comprises around
0.5% by weight of the composition. According to the present
invention, the inclusion of 1 to 5% by weight of colloidal silicon
dioxide has been found to be particularly effective in promoting
disintegration of a macrolide solid dispersion in an aqueous
solution, when combined with another disintegrant.
[0013] Furthermore, the compositions of the present invention show
high stability and physical integrity, e.g. during storage,
handling, packaging and the like, without limiting the
disintegration performance of the composition. The inclusion of
colloidal silicon dioxide in a suitable amount is additionally
advantageous because it results in a composition which, when
compressed into a tablet, possesses enhanced mechanical properties.
In particular, tablets formed from compositions according to the
present invention possess a surprising combination of rapid
disintegration in aqueous solutions with mechanical stability. For
a given level of hardness, the inclusion of silicon dioxide results
in tablets having a faster disintegration rate. Alternatively, for
a given disintegration rate, silicon dioxide containing tablets
according to the present invention are harder than tablets which do
not contain silicon dioxide.
[0014] The compositions of the present invention comprise one or
more disintegrants. Examples of disintegrants include crosslinked
polyvinylpyrrolidone, e.g. as commercially available as
Crospovidone.RTM. or Polyplasdone.RTM. (Handbook of Excipients, p.
143-144) available from ISP; sodium starch glycolate available from
Generichem; and crosscarmelose sodium, e.g. as commercially
available as Ac-di-sol.RTM. from FMC Corporation. Preferably the
disintegrant comprises crosslinked polyvinylpyrrolidone.
[0015] Crospovidone.RTM. is preferably included in the composition
of this invention in an amount of up to about 50% by weight, e.g.
10 to 30%, more preferably in an amount of about 20%, all weights
based on the total weight of the composition.
[0016] The compositions of the present invention comprise 1 to 5%
by weight of colloidal silicon dioxide in addition to a
disintegrant as defined above. Colloidal silicon dioxide may be
obtained commercially available as Aerosil.RTM.. Colloidal silicon
dioxide, is included in the composition of this invention in an
amount from 1 to 5% of the total weight of the composition,
preferably in an amount of 2 to 5% of the total weight of the
composition. More preferably, the composition comprises 2 to 4% and
still more preferably 2.5 to 3.5% of colloidal silicon dioxide
based on the total weight of the composition. Most preferably the
composition comprises about 3% of colloidal silicon dioxide by
weight.
[0017] Preferably, a mixture of colloidal silicon dioxide and
crosslinked polyvinylpyrrolidone, may be used e.g. in a ratio of
from 1:1 (such as from 1:3) to 1:50 (such as from 1:10).
[0018] The macrolide used in the solid dispersion of this invention
may be rapamycin or any derivative thereof, e.g. an O-substituted
derivative in which the hydroxyl group on the cyclohexyl ring of
rapamycin is replaced by --OR.sub.1 in which R.sub.1 is
hydroxyalkyl, hydroxyalkoxyalkyl, acylaminoalkyl or aminoalkyl;
e.g. as described in WO 94/09010, for example
40-O-(2-hydroxyethyl)-rapamycin, 40-O-(3-hydroxypropyl)-rapamycin-
, 40-O-[2-(2-hydroxyethoxy)ethyl]-rapamycin, and
40-O-(2-acetaminoethyl)-r- apamycin. The rapamycin derivative may
be a 26- or 28-substituted derivative. The rapamycin derivative may
be an epimer of a derivative mentioned above, particularly an
epimer of a derivative substituted in position 40, 28 or 26, and
may optionally be further hydrogenated, e.g. as disclosed in WO
95/14023 and 99/15530, e.g. ABT578, or may be a rapalog as
disclosed e.g. in WO 98/02441 and WO01/14387, e.g. AP23573.
[0019] Preferred rapamycin derivatives for use in this invention
include rapamycin, 40-O-(2-hydroxy)ethyl rapamycin,
32-deoxorapamycin and 16-pent-2-ynyloxy-32(S)-dihydrorapamycin. A
more preferred compound is 40-O-(2-hydroxy)ethyl rapamycin.
[0020] Numbering of rapamycin derivatives as used herein refers to
the structure disclosed as Formula A at page 4 of PCT WO 96/13273,
incorporated herein by reference.
[0021] Examples of compounds of the ascomycin class are those
mentioned above, e.g FK-506, ascomycin and other naturally
occurring compounds, or synthetic analogues thereof.
[0022] A preferred compound of the ascomycin class is disclosed in
EP 427 680, Example 66a, also known as
33-epi-chloro-33-desoxy-ascomycin. Other preferred compounds are
disclosed in EP 465 426, and in EP 569 337 (Example 71).
Particularly preferred is 33-epi-chloro-33-desoxy-ascomycin- .
[0023] The macrolide (e.g., rapamycin or a derivative thereof such
as 40-O-(2-hydroxyethyl) rapamycin or an ascomycin such as
33-epi-chloro-33-desoxy-ascomycin or FK-506) is preferably present
in the composition in an amount of about 0.01 to about 30%, more
preferably 0.1 to 20% by weight based on the total weight of the
composition. In particular a rapamycin derivative, e.g.
40-O-(2-hydroxy)ethyl rapamycin, may be present in the composition
in an amount of 0.1% by weight.
[0024] The macrolide used in this invention, may be in crystalline
or amorphous form prior to formation of the solid dispersion. An
advantage, therefore, of this invention is that the macrolide need
not be crystalline. Thus, the macrolide may be used directly in
combination, for example with a solvent, and does not have to be
isolated in advance. Another advantage of the invention is that
dissolution rates of the solid dispersion are higher than
dissolution rates found for a crystalline macrolide or an amorphous
macrolide in a simple mixture.
[0025] The carrier medium for the preparation of the solid
dispersion preferably comprises a carrier, e.g. a water-soluble
polymer, for example one or a mixture of the following polymers may
be used:
[0026] hydroxypropylmethylcellulose (HPMC). Good results may be
obtained using HPMC with a low apparent viscosity, e.g. below 100
cps as measured at 20.degree. C. for a 2% by weight aqueous
solution, e.g. below 50 cps, preferably below 20 cps, for example
HPMC 3 cps. HPMC is well-known and described, for example, in the
Handbook of Pharmaceutical Excipients, pub. Pharmaceutical Society
of Great Britain and American Pharmaceutical Association, 1994, pp.
229 to 232, the contents of which are incorporated herein by
reference. HPMC, including HPMC 3 cps, is available commercially
under the name Pharmacoat.RTM. 603 from the Shinetsu company;
[0027] hydroxypropylmethylcellulose phthalate (HPMCP), e.g. as
commercially available as HPMCP HP50 or HPMCP HP55;
[0028] polyvinylpyrrolidone (PVP), e.g. PVP K30 or PVP K12. PVP is
available commercially, for example, as Povidone.RTM. (Handbook of
Pharmaceutical Excipients, p. 392-399) from the BASF company. A PVP
having an average molecular weight between about 8,000 and about
50,000 Daltons is preferred, e.g. PVP K30;
[0029] poly(meth)acrylates, e.g. a copolymer which is resistant to
gastric juice and soluble in intestinal juices, e.g. a copolymer
formed from monomers selected from the group consisting of
methacrylic acid, methacrylic acid esters, acrylic acid and acrylic
acid esters, such as those known and commercially available as
Eudragit.RTM. from Rohm Pharma GmbH. An especially preferred
polymer is the 1:1 or 1:2 copolymer formed from monomers selected
from the group consisting of methacrylic acid and methacrylic acid
lower alkyl esters, such as the 1:1 or 1:2 copolymer formed from
methacrylic acid and methyl methacrylate. The 1:1 copolymers are
available as Eudragit.RTM. L, the 1:2 copolymers are available as
Eudragit.RTM. S. A particularly preferred polymer is the 1:1
copolymer of methacrylic acid and acrylic acid ethyl ester,
commercially as Eudragit.RTM. L 100-55;
[0030] hydroxypropylcellulose (HPC) or a derivative thereof.
Examples of HPC derivatives include those having low dynamic
viscosity in aqueous media, e.g. water, e.g. below about 400 cps,
e.g. below 150 cps as measured in a 2% aqueous solution at
25.degree. C. Preferred HPC derivatives have a low degree of
substitution, and an average molecular weight below about 200,000
Daltons, e.g. between 50,000 and 150,000 Daltons. Examples of HPC
available commercially include Klucel.RTM. LF, Klucel.RTM. EF and
Klucel.RTM. JF from the Aqualon company; and Nisso.RTM. HPC-L
available from Nippon Soda Ltd;
[0031] a polyethylene glycol (PEG). Examples include PEGs having an
average molecular weight between 1000 and 9000 Daltons, e.g.
between about 1800 and 7000, for example PEG 2000, PEG 4000, or PEG
6000 (Handbook of Pharmaceutical Excipients, p. 355-361);
[0032] a saturated polyglycolised glyceride, available for example,
as Gelucire.RTM., e.g. Gelucire.RTM. 44/14, 53/10, 50/13, 42/12, or
35/10 from the Gaftefoss company; or
[0033] a cyclodextrin, for example a .beta.-cyclodextrin or an
.alpha.-cyclodextrin. Examples of suitable .beta.-cyclodextrins
include methyl-.beta.-cyclodextrin; dimethyl-.beta.-cyclodextrin;
hydroxyproypl-.beta.-cyclodextrin; glycosyl-.beta.-cyclodextrin;
maltosyl-.beta.-cyclodextrin; sulfo-.beta.-cyclodextrin; a
sulfo-alkylethers of .beta.-cyclodextrin, e.g.
sulfo-C.sub.1-4-alkyl ethers. Examples of .alpha.-cyclodextrins
include glucosyl-.alpha.-cyclod- extrin and
maltosyl-.alpha.-cyclodextrin.
[0034] The carrier medium of the solid dispersion is present in an
amount of, e.g., 0.1 to 99.99% by weight, for example 0.1 to 99.9%,
e.g. 1 to 95%, e.g. 5 to 95%, e.g. 10 to 90% based on the total
weight of the solid dispersion.
[0035] In one embodiment of this invention, the solid dispersion
composition comprises 2% by weight of rapamycin or a derivative
thereof, e.g. 40-O-(2-hydroxy)ethyl rapamycin, and 80% by weight
HPMC 3 cps.
[0036] The carrier medium for the preparation of the solid
dispersion may further comprise one or a combination of a
water-soluble or water-insoluble sugar or other acceptable carrier
or filler such as saccharose, lactose, amylose, dextrose, mannitol,
inositol, and the like, preferably lactose; or microcrystalline
cellulose, e.g. commercially available as Avicel.RTM.,
Pharmacel.RTM., Emcocell.RTM., and Vivapur.RTM., from FMC
Corporation (Handbook of Pharmaceutical Excipients, p. 84-87).
Preferably, lactose may be used.
[0037] A filler, if present, may be generally present in an amount
of up to about 50% by weight, e.g. from about 0.01 to about 50%,
e.g. from about 0.5 to about 40%, preferably from about 5 to about
35%, in particular about 20%, based on the total weight of the
solid dispersion.
[0038] The carrier medium may further comprise one or more
surfactants, for example a nonionic, ionic, or amphoteric
surfactant. Examples of suitable surfactants include:
[0039] polyoxyethylene-polyoxypropylene co-polymers and block
co-polymers, commercially available as Pluronic.RTM. or
Poloxamer.RTM., e.g. as described in H. Fiedler, "Lexikon der
Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete",
Editio Cantor Verlag Aulendorf, Aulendorf, 4th revised and expanded
edition (1996), the contents of which are hereby incorporated by
reference. A preferred polyoxyethylene-polyoxypropylene block
co-polymer is Poloxamer.RTM. 188, commercially available from the
BASF company;
[0040] ethoxylated cholesterins, commercially available as
Solulan.RTM., for example Solulan.RTM. C24, from the Amerchol
company;
[0041] vitamin derivatives, e.g. vitamin E derivatives such as
tocopherol polyethylene glycol succinate (TPGS), available from the
Eastman company;
[0042] sodium dodecylsulfate or sodium laurylsulfate;
[0043] a bile acid or salt thereof, for example cholic acid,
glycolic acid or a salt, e.g. sodium cholate; or
[0044] lecithin, e.g. soy bean phospholipid, e.g. commercially
available as Lipoid.RTM. S75 from Lipoid; or egg phospholipid, e.g.
as commercially available as Phospholipon.RTM. 90 from
Nattermann.
[0045] If present, the surfactant(s) may generally be present in an
amount from about 0.01% to about 30% by weight, e.g. 1 to 20%, e.g.
1 to 15%, all weights based on the weight of the solid dispersion.
Applicants have obtained good results using surfactant-free solid
dispersions.
[0046] In another embodiment, the carrier medium for the
preparation of the solid dispersion may comprise further additives
or ingredients, e.g. an antioxidant and/or a stabilizer for
example, in an amount of up to about 5% by weight, for example
about 0.05 to 5% by weight, e.g. 0.05 to 1%, in particular about
0.2%, all weights based on the total weight of the solid dispersion
composition. Examples of antioxidants include butylated
hydroxytoluene (BHT), butyl hydroxy anisole (BHA),
DL-.alpha.-tocopherol, propyl gallate, ascorbyl palmitate, and
fumaric acid. Preferably, butylated hydroxytoluene may be used.
Malonic acid may be an appropriate stabiliser.
[0047] The 40-O-(2-hydroxy)ethyl rapamycin may be especially
admixed with a stabilizer e.g. butylated hydroxytoluene, e.g in a
ratio of from 5:1. to 20:1.
[0048] The carrier medium may further include antimicrobial agents,
enzyme inhibitors, and preserving agents.
[0049] In another aspect, the present invention relates to a
process for producing a macrolide-containing pharmaceutical
composition, comprising preparing a macrolide solid dispersion and
mixing the macrolide solid dispersion with a disintegrant and
colloidal silicon dioxide to form the pharmaceutical
composition.
[0050] In the above process, the macrolide solid dispersion is
first prepared. The term solid dispersion as used herein means a
preparation in which the macrolide is in an amorphous or
substantially amorphous form and is dispersed in a carrier medium.
For instance, the solid dispersion may be a co-precipitate or
co-evaporate of the macrolide with the carrier medium. The solid
dispersion may be a composition which is adapted for further
processing to an administrable formulation.
[0051] A. In one embodiment, the solid dispersion may be obtained
by dissolving or suspending the macrolide and carrier medium, e.g.
comprising a water-soluble polymer, a filler and an antioxidant, in
a solvent or solvent mixture. The solvent may be a single solvent
or mixture of solvents, and the order of dissolution and suspension
of the macrolide with the carrier medium in the solvent may be
varied. Solvents suitable for use in preparing the solid dispersion
may be organic solvents such as an alcohol, for example methanol,
ethanol, or isopropanol; an ester, e.g. ethylacetate; an ether,
e.g. diethylether; a ketone, e.g. acetone; or a halogenated
hydrocarbon, e.g. dichloroethane. Preferably a solvent mixture of
ethanol/acetone having a weight ratio of ethanol:acetone of between
about 1:10 to about 10:1, e.g. 1:5 to 5:1 may be used. Typically
the macrolide and carrier medium are present in a ratio by weight
with the solvent of 1:0.1 to 1:20. The solvent may be evaporated
and the macrolide co-precipitated with the carrier medium.
[0052] B. In another embodiment, the solid dispersion may be
prepared by melting the carrier medium to form a melt, and
combining the melt with the macrolide, e.g. by stirring, optionally
in the presence of a solvent or solvent mixture as described
herein. The resulting mixture may be granulated with a filler, e.g.
lactose or mannitol.
[0053] C. In another embodiment the solid dispersion may be
prepared by dissolving or suspending the macrolide and carrier
medium in a solvent or solvent mixture as described above, and
granulating the resulting solution/dispersion with a filler, e.g.
lactose.
[0054] D. The solid dispersion may be prepared by spray-drying
techniques as described, for example, in Theory and Practice of
Industrial Pharmacy, Lachmann et al., 1986. A solution/dispersion
of the macrolide and carrier medium in a solvent or solvent mixture
as described above is dispersed through a nozzle into a chamber
maintained at, e.g. 20 to 80.degree. C., and a spraying pressure of
e.g. 3 bar. The solvent is evaporated through the nozzle and finely
dispersed particles are collected.
[0055] E. In a further embodiment the solid dispersion may be
prepared by spray granulating the solution/dispersion of the
macrolide and carrier medium in a solvent or solvent mixture as
described above onto a filler, e.g. lactose, or microcrystalline
cellulose, or a mixture thereof, in a fluid bed.
[0056] In accordance with the present invention the
macrolide-containing solid dispersion as described above is further
processed to a pharmaceutical composition in the form of a
dispersible tablet. The dispersible tablet preferably has a
disintegration time of 3 minutes or less.
[0057] In an alternative aspect of this invention the solid
dispersion composition as described above may be further processed
to a rapidly disintegrating powder or granules which may be filled
into e.g. sachets or gelatin capsules.
[0058] The resulting residues of each of the processes A to B
described above may be sieved and milled to particles, e.g. having
a mean particle size of less than about 0.9 mm, e.g. less than
about 0.8 mm, for example less than about 350 microns. Preferably
the particle size is at least about 5 microns, e.g. about 200 to
300 microns.
[0059] The (milled) solid dispersion may be combined with colloidal
silicon dioxide, one or more disintegrants such as
Crospovidone.RTM., and other excipients, such as a filler, e.g.
lactose, and blended, sieved and combined with a lubricant, e.g.
magnesium stearate, blended, and, for example, compressed to obtain
a dispersible tablet, or filled into sachets or gelatin
capsules.
[0060] One or more lubricants, such as magnesium stearate, may
further be included in the composition of this invention. Magnesium
stearate may be included in an amount from 0.5 to 2% by weight,
preferably, about 0.5%, all by weights based on the total weight of
the composition.
[0061] In a particularly preferred embodiment, the pharmaceutical
composition further comprises a lubricant and a filler.
[0062] It may be advantageous to include one or more sweetening or
flavoring agents in the compositions of this invention, e.g. in an
amount of about 2.5 or 5% by weight based on the total weight of
the composition.
[0063] In another embodiment of this invention a water-soluble or
water-insoluble sugar or other acceptable filler such as saccharose
lactose, or microcrystalline cellulose (e.g., as available as
Avicel.RTM., from FMC Corporation) may be included in the
compositions of this invention. Preferably lactose, in particular
anhydrous lactose, may be used, e.g. in an amount of up to about
90% by weight, e.g. 20 to 80%, preferably from about 50 to about
72%, all weights based on the total weight of the composition.
[0064] The rapidly disintegrating compositions of this invention
may be administered in any convenient form, for example in tablet,
capsule, granule, or powder form, e.g. in a sachet. Preferably, the
formulation is in the form of a tablet. Whereas hereinafter the
compositions of the invention are described with particular
reference to tablets other types of dosage forms may be produced
and are encompassed within the scope of this invention.
[0065] Tablets may be produced from the compositions of the present
invention using any suitable apparatus or procedure. Typically a
tablet press is used to compress the compositions. Varying amounts
of the compositions may be compressed in order to produce tablets
of different weights. In preferred embodiments, 50 to 500 mg of the
composition is compressed into each tablet. More preferably,
tablets are produced having a weight of about 100 mg or about 250
mg.
[0066] The force used to compress the present compositions may be
varied in order to vary the hardness and disintegration time of the
resulting tablets. Use of a higher compression force results in
harder tablet with a longer disintegration time. For a dispersible
tablet, it is important that the disintegration time is
sufficiently short so that the tablet can be conveniently dispersed
in an aqueous solution before consumption. Therefore it is
necessary to select an appropriate compression force in order to
achieve the desired disintegration time.
[0067] However, it is also important that tablets have a sufficient
degree of mechanical strength. The present compositions are
advantageous because for a given compression force, the resultant
tablets disintegrate more rapidly in an aqueous solution than prior
art tablets. Even so, the tablets of the present invention retain a
sufficient degree of hardness. In order to achieve a dispersible
tablet having a sufficiently short disintegration time using prior
art formulations, a very low compression force would need to be
used. This would produce a tablet having inadequate hardness and
mechanical properties.
[0068] It is also important to take into account the weight of the
tablet when selecting a compression force. The required level of
hardness is lower for a smaller tablet, and a lower compression
force is typically used. A skilled person could select an
appropriate compression force in order to achieve the desired
disintegration time for a tablet of particular size.
[0069] In one aspect the dispersible tablets of this invention have
a high porosity showing rapid disintegration in an aqueous solution
such as water. The rapid dispersibility may be observed in standard
tests. The disintegration time is preferably measured according the
standard test for dispersible tablets described in European
Pharmacopoeia 4.1, page 2435, (2002) in combination with European
Pharmacopoeia 4, page 191, 2.9.1 (2002). This test examines the
disintegration time of tablets in water at 15 to 25.degree. C.
[0070] The dispersion may be observed visually. Disintegration is
considered to be achieved when no residue remains on the screen, or
if there is residue, it consists of a soft mass having no palpably
firm, unmoistened core, or only fragments of coating (tablets), or
only fragments of shell (capsules) remain on the screen.
[0071] The tablets of the present invention preferably have a
disintegration time of 3 minutes or less, when measured according
to the above test. More preferably the disintegration time is 2
minutes or less, still more preferably the disintegration time is
90 seconds or less and most preferably the disintegration time is
30 to 65 seconds.
[0072] The hardness, or resistance to crushing, of tablets
according to the present invention may be determined by standard
tests. Tablet hardness is preferably determined according to the
standard test specified at European Pharmacopoeia 4, page 201,
2.9.8 (2002). A device such as a Kraemer.RTM. 3S tablet testing
device may be used. This test determines the resistance to crushing
of tablets, measured by the force needed to disrupt them by
crushing.
[0073] The hardness of the tablets of the present invention varies
according to the weight and diameter of the tablets and the
compression force. For a 200 to 300 mg tablet, for example a 250 mg
tablet, having a diameter of approximately 9 mm, the hardness is
preferably 35 to 80 N. In order to achieve such a hardness, a
compression force of 8 to 11 kN is preferably applied. For a 50 to
150 mg tablet, for example a 100 mg tablet, having a diameter of
approximately 7 mm, the hardness is preferably 25 to 60 N, and may
be achieved by applying a compression force of 7 to 9 kN. For other
tablet weights and diameters, the preferred hardness varies.
[0074] Thus the advantageous properties of the present compositions
may be demonstrated by the hardness and disintegration time of
tablets produced from such compositions. Accordingly, in a
preferred embodiment the present invention relates to a
pharmaceutical composition as defined above, wherein 250 mg of the
composition, when compressed using a compression force of 8 to 11
kN with a 9 mm die and standard flat punches, forms a tablet having
a hardness of 35 to 80 N. Preferably the composition is compressed
using a tablet press such as a Fette.RTM. PT 2080 Rotary tablet
press. The hardness is measured by the standard procedure mentioned
above, for example using a Kraemer.RTM. 3S tablet testing device.
The pharmaceutical composition is more preferably such that 250 mg
of the composition, when compressed using a compression force of
9.5 kN with a 9 mm die and standard flat punches, forms a tablet
having a hardness of 40 to 66 N. The disintegration time of a
tablet formed in such a way from the composition is preferably 3
minutes or less, more preferably 90 seconds or less when determined
using the test specified above.
[0075] In an alternative embodiment, the present invention relates
to a pharmaceutical composition as defined above, wherein 100 mg of
the composition, when compressed using a compression force of 7 to
9 kN with a 7 mm die and standard flat punches, forms a tablet
having a hardness of 25 to 60 N. More preferably the pharmaceutical
composition is such that 100 mg of the composition, when compressed
using a compression force of 8.3 kN with a 7 mm die and standard
flat punches, forms a tablet having a hardness of 29 to 53 N. The
disintegration time of a tablet formed in such a way from the
composition is preferably as given in the preceding paragraph.
[0076] The above statements of the invention define the
pharmaceutical composition in terms of the properties of a
particular tablet which may be made from such a composition.
However, it is clear that the invention is in no way thereby
limited to tablets having such a weight, diameter, or hardness, or
only to a production process involving the use of such a
compression force. As discussed above, these values may vary for
different types of tablet. The above definition is rather given in
order to clarify the advantageous intrinsic properties of the
present pharmaceutical compositions, which mean that when they are
formulated into tablets they afford a rapid disintegration time in
combination with a good degree of hardness.
[0077] The tablets obtained by the compression method described
above may vary in shape and be, for example, round, oval, oblong,
cylindrical, flat or curved, or any other suitable shape, and may
also vary in size depending on the concentration of the therapeutic
agents.
[0078] In a preferred embodiment of the invention tablets obtained
by the compression method described above are round and flat. The
edges of the tablets may be bevelled or rounded.
[0079] The compositions of this invention may be administered to a
patient, such as a child, in form of a rapidly disintegrating
composition, e.g. a dispersible tablet, which composition may be
administered together with a liquid, e.g. an aqueous medium such as
water. Upon addition of the liquid to the formulation, e.g. a unit
dosage form or dosage such as a tablet, e.g. on a spoon, the
composition, disintegrates rapidly to form a dispersion, e.g. in
less than 3 minutes, preferably less than 90 seconds, more
preferably between 30 and 65 seconds, thus allowing convenient
administration. For administration to children, a sweetener or
other additives may be added to the aqueous medium in which the
tablet is dispersed, in order to mask any unpleasant taste and to
make the dispersion more palatable.
[0080] When required, the compositions of the invention in form of
a rapidly disintegrating composition are preferably compounded in
unit dosage form, e.g. as a dispersible tablet, capsule, granules
or powder, preferably as a dispersible tablet. Where the
composition is in unit dosage form, each unit dosage form
comprising rapamycin or a derivative thereof will suitably contain
between 0.05 mg and 10 mg of the drug substance, more preferably
between 0.1 and 5 mg; for example 0.1 or 0.25 mg. Such tablets are
suitable for administration 1 to 5 times daily depending upon the
particular purpose of therapy, the phase of therapy and the
like.
[0081] Where the composition of this invention is in unit dosage
form, e.g. a dispersible tablet, comprising an ascomycin, each unit
dosage form will suitably contain between 1 mg and 50 mg of the
drug substance, more preferably between 10 and 25 mg; for example
10, 15, 20 or 25 mg. Such tablets are suitable for administration 1
to 5 times daily depending upon the particular purpose of therapy,
the phase of therapy and the like.
[0082] The compositions of the invention may show good stability
characteristics as indicated by standard stability trials, for
example having a shelf life stability of up to one, two or three
years, and even longer.
[0083] The particles or granules obtained by any of the processes A
to E as described above may be coated, for example using an enteric
coating. Suitable coatings may comprise cellulose acetate
phthalate, hydroxyproyplmethylcellulose phthalate; a
polymethacrylic acid polymer, e.g. Eudragit.RTM. L, S; or
hydroxypropylmethyl cellulose succinate.
[0084] The tablets obtained by the compression method described
above may furthermore be coloured, and the tablets marked so as to
impart an individual appearance and to make them instantly
recognizable. The use of dyes can serve to enhance the appearance
as well as to identify the compositions. Dyes suitable for use in
pharmacy typically include carotinoids, iron oxides, and
chlorophyll. Preferably, the tablets of the invention are marked
using a code.
[0085] Procedures which may be used are known in the art, e.g.
those described in L. Lachman et al. The Theory and Practice of
Industrial Pharmacy, 3rd Ed, 1986, H. Sucker et al, Pharmazeutische
Technologie, Thieme, 1991, Hagers Handbuch der pharmazeutischen
Praxis, 4th Ed. (Springer Verlag, 1971) and Remington's
Pharmaceutical Sciences, 13th Ed., (Mack Publ., Co., 1970) or later
editions.
[0086] The pharmaceutical compositions of the invention are useful
for the same indications as the macrolide, e.g. rapamycin or
ascomycin. The pharmaceutical compositions of the invention
comprising rapamycin or a rapamycin derivative are particularly
useful for:
[0087] a) treatment or prevention of cell, tissue or organ allo- or
xeno-transplant rejection, for example for heart, lung, combined
heart-lung, liver, kidney, bowel, pancreatic, insulin producing
cells, skin or corneal transplants. The pharmaceutical compositions
are also indicated for the prevention of graft-versus-host disease,
such as sometimes occurs following bone marrow transplantation;
[0088] b) treatment or prevention of autoimmune disease and of
inflammatory conditions, in particular inflammatory conditions with
an etiology including an autoimmune component such as arthritis
(for example, rheumatoid arthritis, arthritis chronic progrediente
and arthritis deformans) and rheumatic diseases. Specific
autoimmune diseases for which the compounds of the invention may be
employed include, autoimmune hematological disorders (including
e.g. hemolytic anaemia, aplastic anaemia, pure red cell anaemia and
idiopathic thrombocytopenia), systemic lupus erythematosus,
polychondritis, sclerodoma, Wegener granulomatosis,
dermatomyositis, chronic active hepatitis, myasthenia gravis,
psoriasis, Steven-Johnson syndrome, idiopathic sprue, autoimmune
inflammatory bowel disease (including, e.g., ulcerative colitis and
Crohn's disease) endocrine ophthalmology, Graves disease,
sarcoidosis, multiple sclerosis, primary billiary cirrhosis,
juvenile diabetes (diabetes mellitus type I), uveitis (anterior and
posterior), keratoconjunctivitis sicca and vernal
keratoconjunctivitis, interstitial lung fibrosis, psoriatic
arthritis, glomerulonephritis (with and without nephrotic syndrome,
e.g. including idiopathic nephritic syndrome or minimal change
nephropathy) and juvenile dermatomyositis;
[0089] c) treatment or prevention of asthma d) treatment or
prevention of chronic graft rejection or restenosis;
[0090] e) treatment of cancer, hyperproliferative skin disorder,
and the like;
[0091] f) treatment of infections, e.g. fungal infections;
[0092] g) treatment or prevention of inflammation, especially in
potentiating the action of steroids;
[0093] The pharmaceutical compositions of the invention comprising
ascomycin or an ascomycin derivative are particularly useful, for
example, in the treatment of inflammatory and hyperproliferative
skin diseases and of cutaneous manifestations of
immunologically-mediated diseases. More specifically, the
compositions of this invention are useful as antiinflammatory and
as immunosuppressant and antiproliferative agents for use in the
prevention and treatment of inflammatory conditions and of
conditions requiring immunosuppression, such as
[0094] a) the prevention or treatment of
[0095] rejection of organ or tissue transplantation, e.g. of heart,
kidney, liver, bone marrow and skin,
[0096] graft-versus-host disease, such as following bone marrow
grafts,
[0097] autoimmune diseases such as rheumatoid arthritis, systemic
lupus erythematosus, Hashimoto's thyroidis, multiple sclerosis,
Myasthenia gravis, diabetes type I, and uveitis,
[0098] cutaneous manifestations of immunologically-mediated
illnesses;
[0099] b) the treatment of inflammatory and hyperproliferative skin
diseases, such as psoriasis, atopical dermatitis, contact
dermatitis and further eczematous dermatitises, seborrhoeic
dermatitis, Lichen planus, Pemphigus, bullous Pemphigoid,
Epidermolysis bullosa, urticaria, angioedemas, vasculitides,
erythemas, cutaneous eosinophilias, Lupus erythematosus, and acne;
and
[0100] c) Alopecia greata.
[0101] In a further aspect, the present invention provides use of a
composition as defined above, for the manufacture of a medicament
for use as an immunosuppressant, e.g. in the treatment or
prevention of one of the above mentioned diseases or disorders.
[0102] Thus in another aspect the present invention provides a
method of treatment of a subject suffering from a disorder
treatable with a macrolide, comprising administering a
therapeutically effective amount of a pharmaceutical composition of
the invention to a subject in need of such treatment.
[0103] In another aspect the present invention provides a method of
administering a pharmaceutical composition of the invention to a
subject in need of such therapy which comprises (i) contacting the
composition with water and (ii) ingesting the resultant
dispersion.
[0104] The dispersible tablets of this invention may be dispersed
before ingestion in e.g. 20 to 50 ml water with stirring.
[0105] The exact amount of the compositions to be administered
depends on several factors, for example the desired duration of
treatment and the rate of release of the macrolide.
[0106] The compositions of the invention exhibit especially
advantageous properties when administered orally; for example in
terms of consistency and level of bioavailability obtained in
standard bioavailability trials. These trials are performed in
animals, e.g. rats or dogs, or healthy volunteers.
[0107] Pharmacokinetic parameters, for example absorption and blood
levels, also become surprisingly more predictable and problems in
administration with erratic absorption may be eliminated or
reduced. Additionally the compositions are effective with tenside
materials, for example bile salts, being present in the
gastrointestinal tract.
[0108] The utility of the pharmaceutical compositions can be
observed in standard clinical tests in, for example, known
indications of active agent dosages giving equivalent blood levels
of active agent; for example using dosages in the range of 0.01 mg
to 5 mg/kg body weight per day, e.g. 0.5 to 5 mg/kg body weight per
day of rapamycin or a derivative thereof in mammals, e.g. children
(e.g. below 12 years and e.g. at least 3 years) or elderly, and in
standard animal models; or for example using dosages in the range
of 1 mg to 1000 mg, e.g. 2.5 to 1000 mg, preferably 10 to 250 mg,
per day of an ascomycin for a 75 adult and in standard animal
models. The increased bioavailability of the drug substance
provided by the compositions can be observed in standard animal
tests and in clinical trials.
[0109] Following is a description, by way of example only, of
pharmaceutical composition of the invention.
EXAMPLE 1
[0110] Preparation of a Solid Dispersion
[0111] A 2% solid dispersion (SD) composition is prepared
containing the following ingredients:
1 wt. (g) wt. % 40-O-(2-hydroxyethyl)-rapamycin 0.04 2.0 Butylated
hydroxytoluene 0.04 0.2 HPMC 3 cps 1.6 80.0 Lactose, monohydrate
(200 mesh) 0.356 17.8 Total 2.0 100
[0112] The composition is prepared by (i) mixing the
40-O-(2-hydroxyethyl)-rapamycin and butylated hydroxytoluene (ii)
dissolving the mixture obtained in (i) in an ethanol/acetone
mixture, (iii) adding the HPMC and the lactose, (iv) homogenously
dispersing the mixture obtained in step (iii), and (v) removing the
solvents by evaporation. The resulting residue is dried, sieved and
milled.
[0113] Preparation of a Pharmaceutical Composition
[0114] A pharmaceutical composition (containing the solid
dispersion described above) is prepared containing the following
ingredients (in parts by weight):
2 40-O-(2-hydroxyethyl)-rapamycin SD 2% 5 Crospovidone .RTM. 20
Aerosil .RTM. 3 Magnesium stearate 0.5 Lactose, anhydrous 71.5
Total 100
[0115] The composition is prepared by (i) blending the solid
dispersion (SD), lactose, Crospovidone.RTM. and Aerosil.RTM., (ii)
sieving (0.8 mm), and blending, (iii) adding sieved (0.8 mm)
magnesium stearate and blending.
[0116] Preparation of a Dispersible Tablet
[0117] A dispersible tablet is obtained by tabletting the mixture
obtained in step (iii). 250 mg of the pharmaceutical composition is
compressed with a Fette.RTM. PT 2080 Rotary tablet press using a
compression force of 10.5 kN with a 9 mm die and standard flat
punches. The hardness of the resulting tablet is then assessed by
measuring the force required to crush the tablet using a Kraemer 3S
tablet testing device. The hardness of tablets manufactured under
these conditions was between 35 and 79 N. The disintegration time
of such tablets was 0.4 to 1.4 minutes (24 to 84 seconds).
EXAMPLE 2
[0118] A pharmaceutical composition was prepared as described
above. A dispersible tablet was prepared by compressing 100 mg of
the pharmaceutical formulation with a Fette.RTM. PT 2080 Rotary
tablet press using a compression force of 7.5 kN with a 7 mm die
and standard flat punches. The hardness of tablets manufactured
under these conditions was from 25 to 79 N. The disintegration time
of such tablets was 1.1 to 1.7 minutes (66 to 102 seconds).
[0119] The examples above illustrate compositions and tablets
useful for example in the prevention of transplant rejection or for
the treatment of autoimmune disease, on administration of from 1 to
5 unit dosages/day at a dose of between 0.01 to 5 mg/kg body weight
per day.
[0120] The examples are described with particular reference to
40-O-(2-hydroxyethyl)-rapamycin. However, in further examples the
method described in examples 1 and 2 is repeated except that
40-O-(2-hydroxyethyl)-rapamycin is replaced by an alternative
macrolide. The alternative macrolide may be any rapamycin
derivative or ascomycin derivative mentioned above, for instance
FK-506 or 33-epi-chloro-33-desoxy-ascomycin. Tablets comprising
such alternative macrolides have a hardness and disintegration time
which is similar to that given above for
40-O-(2-hydroxyethyl)-rapamycin containing tablets, and are also
useful as immunosuppressants.
* * * * *