U.S. patent application number 11/997325 was filed with the patent office on 2009-01-29 for dosage forms with improved bioavailability.
This patent application is currently assigned to Abbott GmbH & Co. KG. Invention is credited to Gunther Berndl, Matthias Degenhardt, Markus Maegerlein.
Application Number | 20090028938 11/997325 |
Document ID | / |
Family ID | 37122088 |
Filed Date | 2009-01-29 |
United States Patent
Application |
20090028938 |
Kind Code |
A1 |
Berndl; Gunther ; et
al. |
January 29, 2009 |
DOSAGE FORMS WITH IMPROVED BIOAVAILABILITY
Abstract
A solid dispersion product comprising an effective amount of one
or more active ingredients and an effective amount of one or more
hydroxypropyl methylcellulose(s), which satisfies the Formula
0.35>.DELTA.H.sub.tr (1) (wherein .DELTA.H.sub.tr represents the
endotherm (J/g) accompanying a transition at about 240.degree. C.).
The solid dispersion product is used for the manufacture of a
dosage form having improved bioavailability of said one or more
active ingredients by oral administration to a patient in need
thereof.
Inventors: |
Berndl; Gunther; (Herxheim
Am Berg, DE) ; Degenhardt; Matthias; (Limburgerhof,
DE) ; Maegerlein; Markus; (Mannheim, DE) |
Correspondence
Address: |
EDWARDS ANGELL PALMER & DODGE LLP
P.O. BOX 55874
BOSTON
MA
02205
US
|
Assignee: |
Abbott GmbH & Co. KG
Wiesbaden
DE
|
Family ID: |
37122088 |
Appl. No.: |
11/997325 |
Filed: |
August 8, 2006 |
PCT Filed: |
August 8, 2006 |
PCT NO: |
PCT/EP06/07840 |
371 Date: |
September 18, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60595818 |
Aug 8, 2005 |
|
|
|
Current U.S.
Class: |
424/464 ;
514/781 |
Current CPC
Class: |
A61K 9/1617 20130101;
A61K 9/146 20130101; A61K 9/145 20130101; A61K 9/1652 20130101 |
Class at
Publication: |
424/464 ;
514/781 |
International
Class: |
A61K 9/20 20060101
A61K009/20; A61K 47/38 20060101 A61K047/38 |
Claims
1. A solid dispersion product comprising (i) an effective amount of
one active ingredient or a mixture of two or more active
ingredients and (ii) an effective amount of a hydroxypropyl
methylcellulose or a mixture of two or more hydroxypropyl
methylcelluloses, wherein said solid dispersion product satisfies
the formula 0.35>.DELTA.H.sub.tr wherein .DELTA.H.sub.tr
represents the endotherm (J/g) accompanying a transition at an
endothermic peak temperature in the range of from about 230.degree.
C. to about 260.degree. C.
2. The solid dispersion product of claim 1, which satisfies the
formula 0.20>.DELTA.H.sub.tr wherein .DELTA.H.sub.tr represents
the endotherm (J/g) accompanying a transition at an endothermic
peak temperature in the range of from about 230.degree. C. to about
260.degree. C.
3. The solid dispersion product of claim 1, which satisfies the
formula 0.15>.DELTA.H.sub.tr wherein .DELTA.H.sub.tr represents
the endotherm (J/g) accompanying a transition at an endothermic
peak temperature in the range of from about 230.degree. C. to about
260.degree. C.
4. The solid dispersion product of claim 1, wherein the endothermic
peak temperature is in the range of from about 240.degree. C. to
about 250.degree. C.
5. The solid dispersion product of claim 1, having a weight-average
particle size of less than 600 m.
6. The solid dispersion product of claim 1, wherein the total
content of methoxy and hydroxypropyl groups in the hydroxypropyl
methylcellulose is in the range of 23 to 42% by weight.
7. The solid dispersion product of claim 6, wherein the methoxy
group content is in the range of 19 to 30 wt % and the
hydroxypropyl group content is in the range of 4 to 12% by
weight.
8. The solid dispersion product of claim 7, wherein the
hydroxypropyl methylcellulose has an apparent viscosity of from
about 3 to about 15 mPas, as determined as an 2 wt. % aqueous
solution at 20.degree. C.
9. The solid dispersion product of claim 1, wherein the weight
ratio of active ingredient hydroxypropyl methylcellulose is in the
range of 1:1 to 1:17.
10. A pharmaceutical dosage form comprising particles of the solid
dispersion product of claim 1 and at least one additive selected
from the group consisting of a diluent and a disintegrant.
11. A method for preparing a solid dispersion product, which
comprises: a) blending (i) an effective amount of one active
ingredient or a mixture of two or more active ingredients and (ii)
an effective amount of a hydroxypropyl methylcellulose or a mixture
of two or more hydroxypropyl methylcelluloses; b) heating the
blend, under preset conditions of temperature, shear and throughput
rate, to obtain a homogeneous melt; c) forcing the thus obtained
melt through one or more nozzles; d) allowing the melt to solidify
to obtain a solid dispersion product; e) subjecting a
representative sample of the obtained solid dispersion product to
differential scanning calorimetry measurement; and, if necessary,
e) adjusting the conditions of temperature, shear and throughput
rate used in step b) such that the solid dispersion product
satisfies the formula 0.35>.DELTA.H.sub.tr, preferably
0.20>.DELTA.H.sub.tr, more preferably 0.15>.DELTA.H.sub.tr,
wherein .DELTA.H.sub.tr represents the endotherm (J/g) accompanying
a transition at an endothermic peak temperature in the range of
from about 230.degree. C. to about 260.degree. C.
12. The method of claim 11, wherein step b) is carried out in an
extruder and the blend is subjected to a kneading action in a
kneading section of the extruder.
13. The method of claim 11, wherein step b) is carried out in an
extruder, the extruder operating temperature and the nozzle
temperature being in the range of from about 195.degree. C. to
about 300.degree. C.
14. The method of claim 11, wherein the total content of methoxy
and hydroxypropyl groups in the hydroxypropyl methylcellulose is in
the range of 23 to 42% by weight.
15. The method of claim 14, wherein the methoxy group content is in
the range of 19 to 30 wt % and the hydroxypropyl group content is
in the range of 4 to 12% by weight.
16. The method of claim 15, wherein the hydroxypropyl
methylcellulose has an apparent viscosity of from about 3 to about
15 mPas, as determined as an 2 wt. % aqueous solution at 20.degree.
C.
17. The method of claim 11, wherein the weight ratio of active
ingredient:hydroxypropyl methylcellulose is in the range of 1:1 to
1:17.
18. The method of claim 11, additionally comprising grinding the
solid dispersion product.
19. The method of claim 18, additionally comprising sieving the
ground solid dispersion product.
20. The method of claim 18, additionally comprising compressing the
ground solid dispersion product into a tablet.
21. The use of a solid dispersion product comprising (i) an
effective amount of one active ingredient or a mixture of two or
more active ingredients and (ii) an effective amount of a
hydroxypropyl methylcellulose or a mixture of two or more
hydroxypropyl methylcelluloses, for the manufacture of a dosage
form having improved bioavailability of said one or more active
ingredients by oral administration to a patient in need thereof,
wherein said solid dispersion product satisfies the formula
0.35>.DELTA.H.sub.tr wherein .DELTA.H.sub.tr represents the
endotherm (J/g) accompanying a transition at an endothermic peak
temperature in the range of from about 230.degree. C. to about
260.degree. C.
22. The use of claim 21, wherein said solid dispersion product
satisfies the formula 0.20>.DELTA.H.sub.tr wherein
.DELTA.H.sub.tr represents the endotherm (J/g) accompanying a
transition at an endothermic peak temperature in the range of from
about 230.degree. C. to about 260.degree. C.
23. The use of claim 21, wherein said solid dispersion product
satisfies the formula 0.15>.DELTA.H.sub.tr wherein
.DELTA.H.sub.tr represents the endotherm (J/g) accompanying a
transition at an endothermic peak temperature in the range of from
about 230.degree. C. to about 260.degree. C.
24. The use claim 21, wherein the endothermic peak temperature is
in the range of from about 240.degree. C. to about 250.degree.
C.
25. The use claim 21, wherein the solid dispersion product is
comprised of particles having a weight-average particle size of
less than 600 .mu.m.
26. The use claim 21, wherein the total content of methoxy and
hydroxypropyl groups in the hydroxypropyl methylcellulose is in the
range of 23 to 42% by weight.
27. The use of claim 26, wherein the methoxy group content is in
the range of 19 to 30 wt % and the hydroxypropyl group content is
in the range of 4 to 12% by weight.
28. The use of claim 27, wherein the hydroxypropyl methylcellulose
has apparent viscosity of from about 3 to about 15 mPas, as
determined as an 2 wt. % aqueous solution at 20.degree. C.
29. The use claim 21, wherein the weight ratio of active
ingredient: hydroxypropyl methylcellulose is in the range of 1:1 to
1:17.
Description
[0001] The present invention relates to novel dosage forms with
improved bioavailability as well as to processes for their
preparation.
[0002] A measure of the potential usefulness of an oral dosage form
of a pharmaceutical agent is the bioavailability observed following
oral administration of said dosage form. Various factors can affect
the bioavailability of a drug when administered orally. These
factors include aqueous solubility, drug absorption throughout the
gastrointestinal tract, dosage strength and first pass effect.
Aqueous solubility is one of the most important of these factors.
Unfortunately, many active ingredients are typically characterized
by poor aqueous solubility.
[0003] For a variety of reasons, such as patient compliance and
taste-masking, a solid dosage form is usually preferred over a
liquid dosage form. In most instances, however, solid oral dosage
forms of a drug provide a lower bioavailability than oral solutions
of the drug.
[0004] There have been attempts to improve the bioavailability
provided by solid dosage forms by forming solid dispersions or
solid solutions of the drug. Solid solutions are preferred physical
systems because the components therein readily form liquid
solutions when brought into contact with a liquid medium such as
gastric juice. This increased propensity for dissolution may be
attributed at least in part to the fact that the energy required
for dissolving the components from a solid solution is less than
that required for dissolving the components from a crystalline or
microcrystalline solid phase.
[0005] A continuous process for producing solid pharmaceutical
forms, including solid solution products, has been known for some
time; it entails converting a melt of polymeric binder that
contains active ingredients and that is free from solvents into the
required drug form by injection molding or extrusion and subsequent
shaping (see, for example, EP-A-240 904, EP-A-240 906 and EP-A-337
256). Hydroxypropyl methylcellulose is an example of a particularly
preferred polymeric binder.
[0006] EP-A-1 323 416 exemplifies the preparation of solid
dispersions from an active ingredient and hydroxypropyl
methylcellulose. The reference reports that fibrous materials
occurred when the solid dispersion was pulverized. Presumably, the
occurrence of fibrous material is indicative of a less than optimal
homogeneity of the solid dispersion product.
[0007] It is desirable to provide hydroxypropyl
methylcellulose-based dosage forms with still greater
bioavailability.
[0008] This objective is met by a solid dispersion product
comprising [0009] (i) an effective amount of one active ingredient
or a mixture of two or more active ingredients and [0010] (ii) an
effective amount of a hydroxypropyl methylcellulose or a mixture of
two or more hydroxypropyl methylcelluloses which solid dispersion
product satisfies the formula
[0010] 0.35>.DELTA.H.sub.tr
(wherein .DELTA.H.sub.tr represents the endotherm (J/g)
accompanying a transition at an endothermic peak temperature in the
range of from about 230.degree. C. to about 260.degree. C.).
[0011] Preferably, the solid dispersion product satisfies the
formula
0.20>.DELTA.H.sub.tr
[0012] More preferably, the solid dispersion product satisfies the
formula
0.15>.DELTA.H.sub.tr
[0013] The .DELTA.H.sub.tr is determined by differential scanning
calorimetry (DSC) measurement. More specifically, a melting
endotherm curve is first prepared by the following method using a
differential scanning calorimeter. A finely ground sample of the
dispersion product is placed in an open aluminium pan of a
differential scanning calorimeter. The endotherm between
-20.degree. C. and 300.degree. C. is obtained by heating the sample
at a temperature rise rate of 10.degree. C./minute. A maximum peak
is observed in the thus prepared melting endotherm curve in the
range of from about 230.degree. C. to about 260.degree. C.
preferably 240.degree. C. to about 250.degree. C. (in the following
also referred to as "endotherm at about 240.degree. C."), and the
change rate of enthalpy observed thereupon, in terms of Joules per
one gram of solid dispersion product, is determined to be the
endotherm .DELTA.H.sub.tr. The change rate of enthalpy corresponds
to the area enclosed between the peak and the interpolated base
line.
[0014] The term "solid dispersion" defines a system in a solid
state (as opposed to a liquid or gaseous state) comprising at least
two components, wherein one component is dispersed more or less
evenly throughout the other component or components. When said
dispersion of the components is such that the system is chemically
and physically uniform or homogeneous throughout or consists of one
phase (as defined in thermodynamics), such a dispersion is called a
"solid solution". Solid solutions are preferred physical systems
because the components therein readily form liquid solutions when
brought into contact with a liquid medium such as gastric juice.
This increased propensity for dissolution may be attributed at
least in part to the fact that the energy required for dissolving
the components from a solid solution is less than that required for
dissolving the components from a crystalline or microcrystalline
solid phase.
[0015] The term "solid dispersion product" also comprises
dispersions which are less homogeneous throughout than solid
solutions. Such dispersions are not chemically and physically
uniform throughout or comprise more than one phase. These encompass
systems having small particles, typically of less than 1 .mu.m in
diameter, of active ingredient dispersed in a matrix of
hydroxypropyl methylcellulose, as well as systems having small
particles of active ingredient dispersed in a matrix of a solid
solution of active ingredient in hydroxypropyl methylcellulose.
Preferred systems are those wherein the active ingredient is in an
essentially non-crystalline phase, as these have an intrinsically
faster dissolution rate than those wherein part or all of the
active ingredient is in a microcrystalline or crystalline form. The
absence of microcrystalline or crystalline active ingredient forms
may be ascertained by thermal analysis (DSC) or X-ray diffraction
analysis (WAXS).
[0016] Without wishing to be bound to theory, we believe that
polymer "melting" from a crystalline state to nematic "liquid"
state generally uses a route which includes a passage via a
mesomorphic (liquid crystalline) phase. If the starting
hydroxypropyl methylcellulose is incompletely "molten" some
mesomorphic domains remain in the polymeric matrix. We believe that
the mesomorphic domains have thermodynamic properties, which would
place them between melt and crystals and, hence, the endotherm
observed at about 240.degree. C. is attributable to the latent heat
of transition, i.e., the melting of the mesomorphic domains. The
lower the change rate of enthalpy, the lower the proportion of
mesomorphic domains in the formulation and the more homogeneous the
polymeric matrix. High bioavailability appears to be linked to a
highly homogeneous matrix.
[0017] Active ingredients used to carry out the present invention
are biologically active agents and include those which exert a
local physiological effect, as well as those which exert a systemic
effect, after oral administration. The invention is particularly
useful for water-insoluble or poorly water-soluble (or
"lipophilic") compounds. Compounds are considered water-insoluble
or poorly water-soluble when their solubility in water at
25.degree. C. is less than 1 g/100 ml. The active ingredient should
exhibit a sufficient degree of thermal stability and should not
undergo excessive decomposition during preparation of the solid
dispersion product, i.e. when heated to a temperature in the range
of, for example, about 195.degree. C. to about 300.degree. C.
[0018] Examples of suitable active substances include, but are not
limited to:
analgesic and anti-inflammatory drugs such as NSAIDs, fentanyl,
indomethacin, ibuprofen, ketoprofen, nabumetone, paracetamol,
piroxicam, meloxicam, tramadol, and COX-2 inhibitors such as
celecoxib and rofecoxib; anti-arrhythmic drugs such as
procainamide, quinidine and verapamil; antibacterial and
antiprotozoal agents such as amoxicillin, ampicillin, benzathine
penicillin, benzylpenicillin, cefaclor, cefadroxil, cefprozil,
cefuroxime axetil, cephalexin, chloramphenicol, chloroquine,
ciprofloxacin, clarithromycin, clavulanic acid, clindamycin,
doxyxycline, erythromycin, flucloxacillin sodium, halofantrine,
isoniazid, kanamycin sulphate, lincomycin, mefloquine, minocycline,
nafcillin sodium, nalidixic acid, neomycin, nortloxacin, ofloxacin,
oxacillin, phenoxymethyl-penicillin potassium,
pyrimethamine-sulfadoxime and streptomycin; anti-coagulants such as
warfarin; antidepressants such as amitriptyline, amoxapine,
butriptyline, clomipramine, desipramine, dothiepin, doxepin,
fluoxetine, reboxetine, amineptine, selegiline, gepirone,
imipramine, lithium carbonate, mianserin, milnacipran,
nortriptyline, paroxetine, sertraline and
3-[2-[3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl]ethyl]-2-methyl-4H-pyri-
do[1,2-a]pyrimidin-4-one; anti-diabetic drugs such as glibenclamide
and metformin; anti-epileptic drugs such as carbamazepine,
clonazepam, ethosuximide, gabapentin, lamotrigine, levetiracetam,
phenobarbitone, phenyloin, primidone, tiagabine, topiramate,
valpromide and vigabatrin; antifungal agents such as amphotericin,
clotrimazole, econazole, fluconazole, flucytosine, griseofulvin,
ketoconazole, miconazole nitrate, nystatin, terbinafine and
voriconazole; antihistamines such as astemizole, cinnarizine,
cyproheptadine, decarboethoxyloratadine, fexofenadine, flunarizine,
levocabastine, loratadine, norastemizole, oxatomide, promethazine
and terfenadine; anti-hypertensive drugs such as captopril,
enalapril, ketanserin, lisinopril, minoxidil, prazosin, ramipril,
reserpine, terazosin and telmisartan; anti-muscarinic agents such
as atropine sulphate and hyoscine; antineoplastic agents and
antimetabolites such as platinum compounds, such as cisplatin and
carboplatin; taxanes such as paclitaxel and docetaxel; tecans such
as camptothecin, irinotecan and topotecan; vinca alkaloids such as
vinblastine, vindecine, vincristine and vinorelbine; nucleoside
derivatives and folic acid antagonists such as 5-fluorouracil,
capecitabine, gemcitabine, mercaptopurine, thioguanine, cladribine
and methotrexate; alkylating agents such as the nitrogen mustards,
e.g. cyclophosphamide, chlorambucil, chlormethine, iphosphamide,
melphalan, or the nitrosoureas, e.g. carmustine, lomustine, or
other alkylating agents, e.g. busulphan, dacarbazine, procarbazine,
thiotepa; antibiotics such as daunorubicin, doxorubicin,
idarubicin, epirubicin, bleomycin, dactinomycin and mitomycin; HER
2 antibody such as trastuzumab; podophyllotoxin derivatives such as
etoposide and teniposide; farnesyl transferase inhibitors;
anthrachinon derivatives such as mitoxantron; tyrosine kinase
inhibitors such as imatinib; anti-migraine drugs such as alniditan,
naratriptan and sumatriptan; anti-Parkinsonian drugs such as
bromocryptine mesylate, levodopa and selegiline; antipsychotic,
hypnotic and sedating agents such as alprazolam, buspirone,
chlordiazepoxide, chlorpromazine, clozapine, diazepam,
flupenthixol, fluphenazine, flurazepam, 9-hydroxyrisperidone,
lorazepam, mazapertine, olanzapine, oxazepam, pimozide,
pipamperone, piracetam, promazine, risperidone, selfotel, seroquel,
sertindole, sulpiride, temazepam, thiothixene, triazolam,
trifluperidol, ziprasidone and zolpidem; anti-stroke agents such as
lubeluzole, lubeluzole oxide, riluzole, aptiganel, eliprodil and
remacemide; antitussives such as dextromethorphan and
laevodropropizine; antivirals such as acyclovir, ganciclovir,
loviride, tivirapine, zidovudine, lamivudine,
zidovudine/lamivudine, didanosine, zalcitabine, stavudine,
abacavir, lopinavir, amprenavir, nevirapine, efavirenz,
delavirdine, indinavir, nelfinavir, ritonavir, saquinavir, adefovir
and hydroxyurea; beta-adrenoceptor blocking agents such as
atenolol, carvedilol, metoprolol, nebivolol and propanolol; cardiac
inotropic agents such as aminone, digitoxin, digoxin and milrinone;
corticosteroids such as beclomethasone dipropionate, betamethasone,
budesonide, dexamethasone, hydrocortisone, methylprednisolone,
prednisolone, prednisone and triamcinolone; disinfectants such as
chlorhexidine; diuretics such as acetazolamide, furosemide,
hydrochlorothiazide and isosorbide; enzymes; essential oils such as
anethole, anise oil, caraway, cardamom, cassia oil, cineole,
cinnamon oil, clove oil, coriander oil, dementholised mint oil,
dill oil, eucalyptus oil, eugenol, ginger, lemon oil, mustard oil,
neroli oil, nutmeg oil, orange oil, peppermint, sage, spearmint,
terpineol and thyme; gastro-intestinal agents such as cimetidine,
cisapride, clebopride, diphenoxylate, domperidone, famotidine,
lansoprazole, loperamide, loperamide oxide, mesalazine,
metoclopramide, mosapride, nizatidine, norcisapride, olsalazine,
omeprazole, pantoprazole, perprazole, prucalopride, rabeprazole,
ranitidine, ridogrel and sulphasalazine; haemostatics such as
aminocaproic acid; lipid regulating agents such as atorvastatin,
fenofibrate, fenofibric acid, lovastatin, pravastatin, probucol and
simvastatin; local anaesthetics such as benzocaine and lignocaine;
opioid analgesics such as buprenorphine, codeine, dextromoramide,
dihydrocodeine, hydrocodone, oxycodone and morphine;
parasympathomimetics and anti-dementia drugs such as AIT-082,
eptastigmine, galanthamine, metrifonate, milameline, neostigmine,
physostigmine, tacrine, donepezil, rivastigmine, sabcomeline,
talsaclidine, xanomeline, memantine and lazabemide; peptides and
proteins such as antibodies, becaplermin, cyclosporine, tacrolimus,
erythropoietin, immunoglobulins and insuline; sex hormones such as
oestrogens: conjugated oestrogens, ethinyloestradiol, mestranol,
oestradiol, oestriol, oestrone; progestogens; chlormadinone
acetate, cyproterone acetate, 17-deacetyl norgestimate,
desogestrel, dienogest, dydrogesterone, ethynodiol diacetate,
gestodene, 3-keto desogestrel, levonorgestrel, lynestrenol,
medroxy-progesterone acetate, megestrol, norethindrone,
norethindrone acetate, norethisterone, norethisterone acetate,
norethynodrel, norgestimate, norgestrel, norgestrienone,
progesterone and quingestanol acetate; stimulating agents such as
sildenafil; vasodilators such as amlodipine, buflomedil, amyl
nitrite, diltiazem, dipyridamole, glyceryl trinitrate, isosorbide
dinitrate, lidoflazine, molsidomine, nicardipine, nifedipine,
oxpentifylline and pentaerythritol tetranitrate; their N-oxides,
their pharmaceutically acceptable acid or base addition salts and
their stereochemically isomeric forms.
[0019] Pharmaceutically acceptable acid addition salts comprise the
acid addition salt forms which can be obtained conveniently by
treating the base form of the active ingredient with appropriate
organic and anorganic acids.
[0020] Active ingredients containing an acidic proton may be
converted into their non-toxic metal or amine addition salt forms
by treatment with appropriate organic and inorganic bases.
[0021] The term addition salt also comprises the hydrates and
solvent addition forms which the active ingredients are able to
form. Examples of such forms are, for example, hydrates,
alcoholates and the like.
[0022] The N-oxide forms of the active ingredients comprise those
active ingredients in which one or several nitrogen atoms are
oxidized to the so-called N-oxide.
[0023] The term "stereochemically isomeric forms" defines all
possible stereoisomeric forms which the active ingredients may
possess. In particular, stereogenic centers may have the R- or
S-configuration and active ingredients containing one or more
double bonds may have the E- or Z-configuration.
[0024] The hydroxpropyl methylcellulose (HPMC) (or combination of
HPMCs) used in carrying out the invention contains a sufficient
number of hydroxypropyl and methoxy groups to render it
water-soluble.
[0025] The total content of methoxy and hydroxypropyl groups (or,
if a combination of different HPMCs is used, the average total
content of methoxy and hydroxypropyl groups) is preferably in the
range of 23 to 42% by weight. More preferably, the total content of
methoxy and hydroxypropyl groups is in the range of 30 to 42% by
weight. Preferably, the methoxy group content is in the range of 19
to 30 wt % (in particular 28 to 30 wt %) and the hydroxypropyl
group content is in the range of 4 to 12 wt % (in particular 7 to
12 wt %).
[0026] Hydroxypropyl methylcellulose is also known as hypromellose
(see Martindale, The Extra Pharmacopoeia, 29.sup.th edition
(Pharmaceutical Press, 1989) page 1435). For HPMC, three types are
commercially available: HPMC 2208, HPMC 2906, and HPMC 2910,
depending on the contents of methoxy and hydroxypropyl groups. In
the four digit number associated with HPMC as described by
Martindale, the first two digits represent the approximate
percentage of methoxy groups and the third and fourth digits the
approximate percentage composition of hydroxypropyl groups. It is
specified that hydroxypropyl methyl cellulose 2208 contains 19 to
24 wt % of methoxy groups and 4 to 12 wt % of hydroxypropyl groups
in a total of 23 to 36 wt %; hydroxypropyl methyl cellulose 2906
contains 27 to 30 wt % of methoxy groups and 4 to 7.5 wt % of
hydroxypropyl groups in a total of 31 to 37.5 wt %, and
hydroxypropyl methyl cellulose 2910 contains 28 to 30 wt % of
methoxy groups and 7 to 12 wt % of hydroxypropyl groups in a total
of 35 to 42 wt %. Any of these celluloses may be used in the
practice of the invention, with HPMC 2910 being especially
preferred.
[0027] The molecular weight of the HPMC normally affects both the
release profile of the milled extrudate as well as its physical
properties. A desired release profile can thus be designed by
choosing an HPMC of an appropriate molecular weight. For immediate
release of the active ingredient from the particles, a low
molecular weight polymer is preferred. A high molecular weight HPMC
is more likely to yield a sustained release pharmaceutical dosage
form. The molecular weight of a water-soluble cellulose ether, such
as HPMC, is generally expressed in terms of the apparent viscosity
of an aqueous solution containing two percent by weight of said
cellulose ether at 20.degree. C. Suitable HPMCs include those
having a viscosity from about 1 to about 100 mPas, more preferably
from about 3 to about 15 mPas, and most preferably at about 5 mPas.
The most preferred type of HPMC having a viscosity of 5 mPas is the
commercially available HPMC 2910 5 mPas.
[0028] Although it is believed that the particle size distribution
of the HPMC starting material is of secondary influence to the
properties of solid dispersion product, the HPMC starting material
preferably has a size distribution (as determined using laser light
diffraction; Malvern Mastersizer) with d.sub.0.5 of not more than
125 .mu.m, more preferably of not more than 100. Preferably,
d.sub.0.9 is not more than 300 .mu.m, more preferably not more than
245 .mu.m.
[0029] Preferably, the weight ratio of active
ingredient:hydroxypropyl methylcellulose is in the range of 1:1 to
1:17, more preferably 1:1 to 1:5. In the case of (active
ingredient): (HPMC 2910 5 mPas), this ratio may range from about
1:1 to about 1:2 and is optimally about 1:1.5 (or 2:3). The lower
limit is determined by practical considerations. Indeed, given that
the therapeutically effective amount of active ingredient is from
about 50 mg to about 400 mg per day, preferably 200 mg per day, the
lower limit ratio is determined by the maximum amount of mixture
that can be processed into one dosage form of a practical size.
When the relative amount of water-soluble polymer exceeds the upper
acceptable range, the absolute amount of mixture needed to achieve
a therapeutic level will be too great to be processed into one
capsule or tablet. Tablets, for example, can have a maximum weight
of about 1 gram, of which a maximum of 90% (w/w) can be the
extrudate. In this case, the lower limit of the amount of active
ingredient compared to hydroxypropyl methylcellulose will be about
1:17 (i.e., 50 mg active ingredient and 50 mg polymer).
[0030] As the ratio of active ingredient:hydroxypropyl
methylcellulose increases (i.e. the amount of active ingredient
increases relative to the amount of polymer), then there is the
risk that the active ingredient will not dissolve sufficiently in
the polymer and thus that the required bioavailability will not be
obtained. The degree to which a compound has dissolved in a
water-soluble polymer can often be checked visually. If the
extrudate is clear, then it is likely that the compound has
dissolved completely in the water-soluble polymer. The 1:1 active
ingredient:hydroxypropyl methylcellulose upper limit is determined
by the fact that it has been observed that, at this ratio, the
extrudate resulting from extruding active ingredient with HPMC 2910
5 mPas was not "clear", presumably due to the fact that not all of
the active ingredient had dissolved in the HPMC. It will be
appreciated that the upper limit of 1:1 may be an underestimate for
other types of HPMC.
[0031] The solid dispersion product of the invention is prepared by
a melt-extrusion process.
[0032] The melt-extrusion process typically comprises the following
steps: [0033] a) blending the active ingredient and hydroxypropyl
methylcellulose; [0034] b) heating the blend to obtain a
homogeneous melt, [0035] c) forcing the thus obtained melt through
one or more nozzles; and [0036] d) allowing the melt to solidify to
obtain a solid dispersion product.
[0037] Specifically, the method comprises the following steps:
[0038] a) blending (i) an effective amount of one active ingredient
or a mixture of two or more active ingredients and (ii) an
effective amount of a hydroxypropyl methylcellulose or a mixture of
two or more hydroxypropyl methylcelluloses; [0039] b) heating the
blend, under preset conditions of temperature, shear and throughput
rate, to obtain a homogeneous melt; [0040] c) forcing the thus
obtained melt through one or more nozzles; [0041] d) allowing the
melt to solidify to obtain a solid dispersion product; [0042] e)
subjecting a representative sample of the obtained solid dispersion
product to differential scanning calorimetry measurement; and, if
necessary, [0043] f) adjusting the conditions of temperature, shear
and throughput rate used in step b) such that the solid dispersion
product satisfies the formula
[0043] 0.35>.DELTA.H.sub.tr,
[0044] preferably 0.20>.DELTA.H.sub.tr,
[0045] more preferably 0.15>.DELTA.H.sub.tr,
(wherein .DELTA.H.sub.tr represents the endotherm (J/g)
accompanying a transition at an endothermic peak temperature in the
range of from about 230.degree. C. to about 260.degree. C.,
preferably in the range of from about 240.degree. C. to about
250.degree. C.).
[0046] The terms "melt" and "melting" should be interpreted
broadly. For our purposes, these terms not only mean the alteration
from a solid state to a liquid state, but can also refer to a
transition to a glassy state or a rubbery state, and in which it is
possible for one component of the mixture to get embedded more or
less homogeneously into the other. In particular cases, one
component will melt and the other component(s) will dissolve in the
melt, thus forming a solution, which, upon cooling, may form a
solid solution having advantageous dissolution properties.
[0047] The melting and/or mixing takes place in an apparatus
customarily used for this purpose. Particularly suitable are
extruders or kneaders. Suitable extruders include single screw
extruders, intermeshing screw extruders or else multiscrew
extruders, preferably twin screw extruders, which can be corotating
or counterrotating and are optionally equipped with kneading disks.
The heart of any twin-screw compounding extruder is its screws.
Typically, the screws comprise forward-flighted elements to convey
the materials; further, they may comprise reverse-flighted elements
to create pressure fields, and kneaders and shear elements to exert
a kneading action to the melt. Screws can be made shear intensive
or less aggressive based on the number and type of shearing
elements integrated into the screw program.
[0048] In the method of the invention it is preferred that the melt
is subjected to a kneading action in a kneading section of the
extruder. The kneading section may be equipped with kneading disks
or rotor blades.
[0049] The melt ranges from pasty to viscous. Before allowing the
melt to solidify, the melt may be moulded into virtually any
desired shape. The shaping of the extrudate is conveniently carried
out by a calendar with two counter-rotating rollers with mutually
matching depressions on their surface. A broad range of tablet
forms can be attained by using rollers with different forms of
depressions. Alternatively, the extrudate is cut into pieces,
either before (hot-cut) or after solidification (cold-cut).
[0050] In one embodiment the melt is extruded through a slot die to
obtain a film. The film thus obtained is optionally stretched,
axially or biaxially. The film can be cut into the desired
size.
[0051] It has been found that the energy input during
melt-extrusion production is important for good bioavailability.
Based upon the results of the examples that follow, it is
postulated that the higher the energy input in the extrusion
process, the better the dispersion of the active ingredient in the
matrix. A lower endotherm at about 240.degree. C. is indicative of
better dispersion.
[0052] One of the most important parameters governing energy input
during the melt-extrusion process is the temperature at which the
melt-extruder is operating and the temperature at which the nozzle
or die, through which the melt is forced, is kept. The temperature
may vary along the length of the extruder barrel. For the purposes
herein, the "operating temperature" is the highest temperature the
mixture encounters during its passage through the extruder. It was
found that the operating temperature and the nozzle temperature
should range between about 195.degree. C. and about 300.degree. C.
At temperatures lower than 195.degree. C. the extrudate will not
have the required bioavailability. In addition, the process is
difficult because of the high viscosity of the mixture. At
temperatures of more than 300.degree. C. the hydroxypropyl
methylcellulose may decompose to an unacceptable level. The working
temperatures will also be determined by the kind of extruder or the
kind of configuration within the extruder that is used.
[0053] The throughput rate is also of importance. The longer the
mixture remains in contact with the heating element, the higher the
energy input.
[0054] Although most of the energy needed to melt, mix and dissolve
the components in the extruder is usually provided by the heating
elements, the friction of the material within the extruder may also
provide a substantial amount of energy to the mixture and aid in
the formation of a homogeneous melt of the components. Thus,
variation of the screw speed of the extruder has an impact on the
energy input. We have found that typically a screw speed of more
than 80 revolutions per minute, preferably of more than 100
revolutions per minute up to 350 revolutions per minute, is
required to bring about sufficient mixing and shearing.
[0055] It will be appreciated that, based on the explanation above
and the examples that follow, the person skilled in the art will be
able to select appropriate parameters for the melt extrusion
process to produce extrudates that satisfy the above formula
pertaining to .DELTA.H.sub.tr.
[0056] The solid dispersion product may further comprise one or
more pharmaceutically acceptable excipients such as, for example,
plasticizers, surfactants, flavors, colorants, preservatives and
the like. Said excipients should not be heat-sensitive, in other
words, they should not show any appreciable degradation or
decomposition at the working temperature of the melt-extruder.
[0057] The amount of plasticizer is preferably small, in the order
of 0% to 15% (w/w), preferably less than 5% (w/w). In particular,
no plasticizer is present in the solid dispersion product.
Plasticizers as mentioned hereinbelow lower the temperature at
which a melt of active ingredient, hydroxypropyl methylcellulose
and plasticizer is formed; this lowering of the melting point is
sometimes advantageous. Suitable plasticizers are pharmaceutically
acceptable and include low molecular weight polyalcohols such as
ethylene glycol, propylene glycol, 1,2-butylene glycol,
2,3-butylene glycol, styrene glycol; polyethylene glycols such as
diethylene glycol, triethylene glycol, tetraethylene glycol; other
polyethylene glycols having a molecular weight lower than 1,000
g/mol; polypropylene glycols having a molecular weight lower than
200 g/mol; glycol ethers such as monopropylene glycol monoisopropyl
ether; propylene glycol monoethyl ether; diethylene glycol
monoethyl ether; ester type plasticizers such as sorbitol lactate,
ethyl lactate, butyl lactate, ethyl glycolate, allyl glycolate; and
amines such as monoethanolamine, diethanolamine, triethanolamine,
monoisopropanolamine; triethylenetetramine,
2-amino-2-methyl-1,3-propanediol and the like. Among these, the low
molecular weight polyethylene glycols, ethylene glycol, low
molecular weight polypropylene glycols and especially propylene
glycol are preferred.
[0058] The term "pharmaceutically acceptable surfactant" refers to
a pharmaceutically acceptable non-ionic surfactant. The surfactant
may effect an instantaneous emulsification of the active ingredient
released from the dosage form and prevent precipitation of the
active ingredient in the aqueous fluids of the gastrointestinal
tract. Preferred surfactants are selected from: polyoxyethylene
alkyl ethers, e.g. polyoxyethylene (3) lauryl ether,
polyoxyethylene (5) cetyl ether, polyoxyethylene (2) stearyl ether,
polyoxyethylene (5) stearyl ether; polyoxyethylene alkylaryl
ethers, e.g. polyoxyethylene (2) nonylphenyl ether, polyoxyethylene
(3) nonylphenyl ether, polyoxyethylene (4) nonylphenyl ether or
polyoxyethylene (3) octylphenyl ether; polyethylene glycol fatty
acid esters, e.g. PEG-200 monolaurate, PEG-200 dilaurate, PEG-300
dilaurate, PEG-400 dilaurate, PEG-300 distearate or PEG-300
dioleate; alkylene glycol fatty acid mono esters, e.g. propylene
glycol monolaurate (Lauroglycol.RTM.); sucrose fatty acid esters,
e.g. sucrose monostearate, sucrose distearate, sucrose monolaurate
or sucrose dilaurate; sorbitan fatty acid mono esters such as
sorbitan mono laurate (Span.RTM. 20), sorbitan monooleate, sorbitan
monopalmitate (Span.RTM. 40), or sorbitan stearate, polyoxyethylene
castor oil derivates, e.g. polyoxyethyleneglycerol triricinoleate
or polyoxyl 35 castor oil (Cremophor.RTM. EL; BASF Corp.) or
polyoxyethyleneglycerol oxystearate such as polyethylenglycol 40
hydrogenated castor oil (Cremophor.RTM. RH 40) or polyethylenglycol
60 hydrogenated castor oil (Cremophor.RTM. RH 60); or block
copolymers of ethylene oxide and propylene oxide, also known as
polyoxyethylene polyoxypropylene block copolymers or
polyoxyethylene polypropyleneglycol such as Poloxamer.RTM. 124,
Poloxamer.RTM. 188, Poloxamer.RTM. 237, Poloxamer.RTM. 388, or
Poloxamer.RTM. 407 (BASF Wyandotte Corp.); or mono fatty acid
esters of polyoxyethylene (20) sorbitan, e.g. polyoxyethylene (20)
sorbitan monooleate (Tween.RTM. 80), polyoxyethylene (20) sorbitan
monostearate (Tween.RTM. 60), polyoxyethylene (20) sorbitan
monopalmitate (Tween.RTM. 40), polyoxyethylene (20) sorbitan
monolaurate (Tween.RTM. 20), or mixtures of one or more
thereof.
[0059] The solid dispersion product is preferably milled or ground
to particles having a particle size of less than 600 .mu.m,
preferably less than 400 .mu.m and most preferably less than 125
.mu.m. The particle size proves to be an important factor in
determining the speed at which tablets having sufficient hardness
can be manufactured on a large scale; the smaller the particles,
the higher the tabletting speed can be without detrimental effects
on their quality. The particle size distribution is such that more
than 70% of the particles (measured by weight) have a diameter
ranging from about 50 .mu.m to about 500 .mu.m, in particular from
about 50 .mu.m to about 200 .mu.m and especially from about 50
.mu.m to about 125 .mu.m. Particles with the dimensions mentioned
herein can be obtained by sieving them through nominal standard
test sieves as described in the CRC Handbook, 64.sup.th ed., page
F-114. Nominal standard sieves are characterized by the mesh/hole
width (.mu.m), DIN 4188 (mm), ASTM E 11-70 (No), Tyler.RTM. (mesh)
or BS 410 (mesh) values. Throughout this description, particle
sizes are designated by reference to the mesh/hole width in .mu.m
and to the corresponding Sieve No. in the ASTM E11-70 standard.
[0060] Once the extrudate is obtained, it is milled and sieved and
used as a "normal" ingredient to make pharmaceutical dosage
forms.
[0061] The particles of the solid dispersion product can be
formulated into pharmaceutical dosage forms comprising a
therapeutically effective amount of particles. Although mainly
pharmaceutical dosage forms for oral administration such as tablets
and capsules are envisaged, the particles of the present invention
can also be used to prepare pharmaceutical dosage forms e.g. for
rectal administration. Preferred dosage forms are those adapted for
oral administration shaped as a tablet. They can be produced by
conventional tabletting techniques with conventional ingredients or
excipients and with conventional tabletting machines. In addition,
they can be produced at substantially lower cost than the coated
cores. Preferably, the (milled) solid dispersion product accounts
for not less than 40 wt. % of the weight of the final dosage form,
in particular from 45 to 90 wt. %.
[0062] In order to facilitate the swallowing of such a dosage form
by a mammal, it is advantageous to give the dosage form, in
particular tablets, an appropriate shape. Tablets that can be
swallowed comfortably are therefore preferably elongated rather
than round in shape. Especially preferred are biconvex oblate
tablets. As discussed below in more detail, a film coat on the
tablet further contributes to the ease with which it can be
swallowed.
[0063] Tablets that give an immediate release of the active
ingredient upon oral ingestion and that have good bioavailability
are designed in such a manner that the tablets disintegrate rapidly
in the stomach (immediate release) while keeping the particles
liberated in the process away from one another so that they do not
coalesce, create local high concentrations of the active ingredient
and increase the chances that the drug precipitates
(bioavailability). The desired effect can be obtained by
distributing said particles homogeneously throughout a mixture of a
disintegrant and diluent.
[0064] Suitable disintegrants are those that have a large
coefficient of expansion. Examples thereof are hydrophilic,
insoluble or poorly water-soluble crosslinked polymers such as
crospovidone (crosslinked polyvinylpyrrolidone) and croscarmellose
(crosslinked sodium carboxymethylcellulose). The amount of
disintegrant in immediate release tablets according to the present
invention may conveniently range from about 3 to about 15% (w/w)
and is preferably about 7 to 9%, in particular about 8.5% (w/w).
This amount tends to be greater in tablets in order to ensure that
the particles are spread throughout a large volume of the stomach
contents upon ingestion. Because disintegrants by nature yield
sustained release formulations when employed in bulk, it is
advantageous to dilute them with an inert substance called a
diluent or filler.
[0065] A variety of materials may be used as diluents or fillers.
Examples are spray-dried or anhydrous lactose, sucrose, dextrose,
mannitol, sorbitol, starch, cellulose (e.g. microcrystalline
cellulose Avicel.RTM.), dihydrated or anhydrous dibasic calcium
phosphate, and others known in the art, and mixtures thereof. A
commercial spray-dried mixture of lactose monohydrate (75%) with
microcrystalline cellulose (25%), which is commercially available
as Microcelac.RTM., is preferred. The amount of diluent or filler
in the tablets may conveniently range from about 20% to about 40%
(w/w) and preferably ranges from about 25% to about 32% (w/w).
[0066] The tablet may include a variety of one or more other
conventional excipients such as binders, buffering agents,
lubricants, glidants, thickening agents, sweetening agents,
flavors, and colors. Some excipients can serve multiple
purposes.
[0067] Lubricants and glidants can be employed in the manufacture
of certain dosage forms, and will usually be employed when
producing tablets. Examples of lubricants and glidants are
hydrogenated vegetable oils, e.g hydrogenated Cottonseed oil,
magnesium stearate, stearic acid, sodium lauryl sulfate, magnesium
lauryl sulfate, colloidal silica, talc, mixtures thereof, and
others known in the art. Interesting lubricants and glidants are
magnesium stearate, and mixtures of magnesium stearate with
colloidal silica. A preferred lubricant is hydrogenated vegetable
oil type I, most preferably hydrogenated, deodorized Cottonseed oil
(commercially available from Karlshamns as Akofine NF.RTM.
(formerly called Sterotex.RTM.). Lubricants and glidants generally
comprise 0.2 to 7.0% of the total tablet weight.
[0068] Other excipients such as coloring agents and pigments may
also be added to the tablets of the present invention. Coloring
agents and pigments include titanium dioxide and dyes suitable for
food. A coloring agent is an optional ingredient in the tablet of
the present invention, but, when used, the coloring agent can be
present in an amount of up to 3.5% based on the total tablet
weight.
[0069] Flavors are optional in the composition and may be chosen
from synthetic flavor oils and flavoring aromatics or natural oils,
extracts from plants leaves, flowers, fruits and so forth and
combinations thereof. These may include cinnamon oil, oil of
wintergreen, peppermint oils, bay oil, anise oil, eucalyptus, thyme
oil. Also useful as flavors are vanilla, citrus oil, including
lemon, orange, grape, lime and grapefruit, and fruit essences,
including apple, banana, pear, peach, strawberry, raspberry,
cherry, plum, pineapple, apricot and so forth, The amount of flavor
may depend on a number of factors including the organoleptic effect
desired. Generally the flavor will be present in an amount of from
about 0% to about 3% (w/w).
[0070] As known in the art, tablet blends may be dry-granulated or
wet-granulated before tabletting. The tabletting process itself is
otherwise standard and readily practised by moulding a tablet from
a desired blend or mixture of ingredients into the appropriate
shape using a conventional tablet press.
[0071] Tablets of the present invention may further be film-coated
to improve taste or provide ease of swallowing and an elegant
appearance. Many suitable polymeric film-coating materials are
known in the art. A preferred film-coating material is
hydroxypropyl methylcellulose HPMC, especially HPMC 2910 5 mPas.
Other suitable film-forming polymers also may be used herein,
including hydroxypropylcellulose and acrylate-methacrylate
copolymers. Besides a film-forming polymer, the film coat may
further comprise a plasticizer (e.g. propylene glycol) and,
optionally, a pigment (e.g. titanium dioxide). The film-coating
suspension also may contain talc as an anti-adhesive. In immediate
release tablets according to the invention, the film coat is small
and in terms of weight accounts for less than about 3% (w/w) of the
total tablet weight.
[0072] Preferred dosage forms are those wherein the weight of the
particles is at least 40% of the total weight of the total dosage
form, the weight of the diluent ranges from 20 to 40%, and the
weight of the disintegrant ranges from 3 to 10%, the remainder
being accounted for by one or more of the excipients described
above.
* * * * *