U.S. patent application number 10/933674 was filed with the patent office on 2005-03-17 for immediate release pharmaceutical granule compositions and a continuous process for making them.
Invention is credited to Remon, Jean Paul, Vervaet, Chris.
Application Number | 20050058705 10/933674 |
Document ID | / |
Family ID | 9932403 |
Filed Date | 2005-03-17 |
United States Patent
Application |
20050058705 |
Kind Code |
A1 |
Remon, Jean Paul ; et
al. |
March 17, 2005 |
Immediate release pharmaceutical granule compositions and a
continuous process for making them
Abstract
An immediate or fast release pharmaceutical granule composition
comprising at least one drug (i) classifiable as Class II or Class
IV of the Biopharmaceutical Classification System, wherein the said
drug constitutes at least about 0.5% by weight and no more than 50%
by weight of the composition, the said composition further
comprising (ii) a first excipient being a dextrin-containing
compound and a second excipient (iii) being selected from the group
consisting of polyethylene glycols and polypropylene glycols having
weight number molecular weights between about 300 and 10,000,
glycerol, propylene glycol and glycerides.
Inventors: |
Remon, Jean Paul; (Melle,
BE) ; Vervaet, Chris; (Kachtem, BE) |
Correspondence
Address: |
CLARK & ELBING LLP
101 FEDERAL STREET
BOSTON
MA
02110
US
|
Family ID: |
9932403 |
Appl. No.: |
10/933674 |
Filed: |
September 3, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10933674 |
Sep 3, 2004 |
|
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PCT/BE03/00040 |
Mar 5, 2003 |
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Current U.S.
Class: |
424/464 |
Current CPC
Class: |
A61K 9/1694 20130101;
A61K 9/1652 20130101; A61K 9/1641 20130101 |
Class at
Publication: |
424/464 |
International
Class: |
A61K 009/48; A61K
009/20 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 5, 2003 |
WO |
PCT/BE03/00040 |
Mar 6, 2002 |
GB |
0205253.8 |
Claims
What is claimed is:
1. An immediate or fast release pharmaceutical solid composition
comprising at least one drug (i) classifiable as Class II or Class
IV of the Biopharmaceutical Classification System, wherein said
drug (i) constitutes no more than about 50% by weight of said
pharmaceutical solid composition, and one or more pharmaceutically
acceptable excipients, wherein said solid composition is in the
form of granules and wherein said one or more pharmaceutically
acceptable excipients comprise: (ii) a first excipient being a
dextrin-containing compound in an amount from about 40 to about 85%
by weight of said composition, and (iii) a second excipient
comprising a solid fraction and optionally a liquid fraction, said
second excipient (iii) being in an amount from about 10 to about
40% by weight of the composition and being selected from the group
consisting of polyethylene glycols and polypropylene glycols having
weight number molecular weights between about 300 and 10,000,
glycerol, propylene glycol and glycerides.
2. An immediate or fast release pharmaceutical granule composition
according to claim 1, wherein said drug (i) is selected from the
group consisting of chlorothiazide, hydrochlorothiazide,
nimodipine, flufenamic acid, furosemide, mefenamic acid,
bendroflumethiazide, benzthiazide, ethacrinic acid, nitrendipine,
itraconazole, troglitazone, atovaquone, danazol, glibenclamide,
griseofulvin, ketoconazole, carbamazepine, florfenicol,
sulfadiazine, acetohexamide, ajamaline, benzbromarone, benzyl
benzoate, betamethasone, chloramphe-nicol, chlorpropamide,
chlorthalidone, clofibrate, diazepam, dicumarol, digitoxin,
ethotoin, glutethimide, hydrocortisone, hydroflumethiazide,
hydroquinine, indomethacin, ibuprofen, ketoprofen, naproxen,
khellin, nitrazepam, nitrofurantoin, novalgin, oxazepam,
papaverine, phenylbutazone, phenyloin, prednisolone, prednisone,
reserpine, spironolactone, sulfabenzamide, sulfadimethoxine,
sulfamerazine, sulfamethazine, sulfamethoxypyridazine,
succinylsulfathiazole, sulfamethizole, sulfamethoxazole,
sulfaphenazole, sulfathiazole, sulfisoxazole, sulpiride,
testosterone and diaminopyrimidines.
3. An immediate or fast release pharmaceutical granule composition
according to claim 1, wherein said dextrin-containing compound (ii)
is selected from the group consisting of starch cyclic degradation
products containing 6 to 8 glucose residues, and cyclic
oligosaccharides composed of L-glucose molecules linked by .alpha.
or .beta. osidic bonds having a toric form.
4. An immediate or fast release pharmaceutical granule composition
according to claim 1, wherein said dextrin-containing compound (ii)
is selected from the group consisting of maltodextrins,
cyclodextrins and derivatives thereof, including
hydroxypropyl-.beta.-cyclodextrin.
5. An immediate or fast release pharmaceutical granule composition
according to claim 1, wherein said first excipient (ii) is a
maltodextrin, said second excipient (iii) is a polyethylene glycol
and the weight ratio of said first excipient (ii) to said second
excipient (iii) is in a range from about 1:1 to 5:1.
6. An immediate or fast release pharmaceutical granule composition
according to claim 1, being free from microcrystalline
cellulose.
7. An immediate or fast release pharmaceutical granule composition
according to claim 1, wherein said drug (i) has a water-solubility
below about 2.5 mg/ml.
8. An immediate or fast release pharmaceutical granule composition
according to claim 1, wherein said drug (i) has a water-solubility
below about 5 .mu.g/ml.
9. An immediate or fast release pharmaceutical granule composition
according to claim 1, wherein said granules have a diameter ranging
from about 100 and 2,500 .mu.m.
10. A continuous process for manufacturing a pharmaceutical granule
composition comprising at least one drug (i) classifiable as Class
II or Class IV of the Biopharmaceutical Classification System in an
amount of no more than about 50% by weight of said pharmaceutical
composition, a first excipient (ii) being a dextrin-containing
compound in an amount from about 40 to about 85% by weight of said
composition, and a second excipient (iii) comprising a solid
fraction and optionally a liquid fraction, said second excipient
(iii) being in an amount from about 10 to about 40% by weight of
the composition and being selected from the group consisting of
polyethylene glycols and polypropylene glycols having weight number
molecular weights between about 300 and 10,000, glycerol, propylene
glycol and glycerides, said process comprising the steps of: (a)
homogenising a mixture comprising said drug (i), said first
excipient (ii) and the solid fraction of said second excipient
(iii), (b) feeding the mixture obtained in step (a) and optionally
the liquid fraction of said second excipient (iii) into an
extruding means having one or more mixing zones and one or more
transport zones, and (c) extruding the materials fed in step (b)
while operating said extruding means at a temperature not above the
melting temperature of the solid fraction of the second excipient
until a pharmaceutical granule composition is obtained.
11. A process according to claim 10, wherein said extruding means
is a twin screw extruder.
12. A process according to claim 10, wherein said extruding means
is operated at a temperature not above about 60.degree. C.
13. A process according to claim 10, wherein said extruding means
is operated at a rotating speed between about 5 and 450 rpm.
14. A process according to claim 10, wherein said drug (i) is
selected from the group consisting of chlorothiazide,
hydrochlorothiazide, nimodipine, flufenamic acid, furosemide,
mefenamic acid, bendroflumethiazide, benzthiazide, ethacrinic acid,
nitrendipine, itraconazole, troglitazone, atovaquone, danazol,
glibenclamide, griseofulvin, ketoconazole, carbamazepine,
florfenicol, sulfadiazine, acetohexamide, ajamaline, benzbromarone,
benzyl benzoate, betamethasone, chloramphe-nicol, chlorpropamide,
chlorthalidone, clofibrate, diazepam, dicumarol, digitoxin,
ethotoin, glutethimide, hydrocortisone, hydroflumethiazide,
hydro-quinine, indomethacin, ibuprofen, ketoprofen, naproxen,
khellin, nitrazepam, nitrofurantoin, novalgin, oxazepam,
papaverine, phenylbutazone, phenyloin, prednisolone, prednisone,
reserpine, spironolactone, sulfabenzamide, sulfadimethoxine,
sulfamerazine, sulfamethazine, sulfamethoxypyridazine,
succinylsulfathiazole, sulfamethizole, sulfamethoxazole,
sulfaphenazole, sulfathiazole, sulfisoxazole, sulpiride,
testosterone and diaminopyrimidines.
15. A process according to claim 10, wherein said drug (i) has a
water-solubility below about 2.5 mg/ml.
16. A process according to claim 10, wherein said drug (i) has a
water-solubility below about 5 .mu.g/ml.
17. A process according to claim 10, wherein said granules have a
diameter ranging from about 100 and 2,500 .mu.m.
18. An immediate or fast release pharmaceutical granule composition
according to claim 1, being water-soluble.
19. An immediate or fast release pharmaceutical granule composition
according to claim 1, in combination with animal feed or drinking
water for oral administration to an animal.
20. A method of treatment of a warm-blooded animal comprising
administration to said animal of an effective amount of a
pharmaceutical granule composition comprising at least one drug (i)
classifiable as Class II or Class IV of the Biopharmaceutical
Classification System in an amount of no more than about 50% by
weight of said pharmaceutical composition, a first excipient (ii)
being a dextrin-containing compound in an amount from about 40 to
about 85% by weight of said composition, and a second excipient
(iii) comprising a solid fraction and optionally a liquid fraction,
said second excipient (iii) being in an amount from about 10 to
about 40% by weight of the composition and being selected from the
group consisting of polyethylene glycols and polypropylene glycols
having weight number molecular weights between about 300 and
10,000, glycerol, propylene glycol and glycerides.
21. A method of treatment according to claim 20, wherein said drug
is florfenicol.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of International
Application No. PCT/BE03/00040, filed on Mar. 5, 2003, which was
published in English under PCT Article 21(2), and which claims the
benefit of British patent application No. 0205253.8 filed on Mar.
6, 2002, the disclosures of which are incorporated by reference in
their entirety.
FIELD OF THE INVENTION
[0002] The present invention is in the field of drug delivery
systems and immediate release technology. Particularly, the
invention is in the field of immediate or fast release
pharmaceutical solid, preferably granule, compositions. More
specifically, the invention relates to such compositions with low
to moderate and even high drug loading for immediate or fast
release of drugs which have low or very low solubility in water.
The invention also relates to various solid pharmaceutical dosage
forms such as sachets, gelules and tablets including such immediate
or fast release pharmaceutical granule compositions. Still more
specifically, the invention relates to immediate or fast release
water-soluble granule veterinary compositions which can readily be
administered to animals together with drinking water. Finally the
invention relates to a continuous process for manufacturing said
immediate or fast release pharmaceutical or veterinary granule
compositions.
BACKGROUND OF THE INVENTION
[0003] Some general considerations relating to drug formulation are
provided herein in order to understand the constraints applicable
to the formulation of drugs which have low solubility in water and
at the same time the kind of pharmaceutical solid formulations to
which the present invention relates.
[0004] Tablets and capsules are generally unsuitable for
administering high doses of biologically active ingredients since
individual large dosage forms are difficult to swallow or
necessitate the administration of several tablets or capsules at a
time, leading to impaired patient compliance.
[0005] Hard gelatin capsules are known as a conventional
pharmaceutical dosage form. Their sizes have been standard since
the start of industrial manufacture of drug compositions, ranging
from 5 (corresponding to a volume of 0.13 ml) up to 000
(corresponding to a volume of 1.36 ml). Thus, when a large amount
of ingredient is required for each dosage unit, depending on the
bulk density of the formulation, it may be necessary to use large
size capsules which are too large to swallow or, even worse, a size
000 capsule may be too small to receive the said amount. Pellets
and granules have been filled into hard gelatin capsules to be used
as conventional or controlled release dosage forms, however the
latter are rather difficult to manufacture.
[0006] The concept of tabletting coated active ingredient particles
is therefore of major interest. Attempts have been made to produce
tablets comprising microcapsules because of the advantages
resulting from the microencapsulated substance being protected from
external influences and vice-versa, e.g. increased stability,
reduced chances of irritations or undesirable reactions with other
components in a mixture, ability to mask unpleasant tastes and
smells, etc. However, compaction of coated beads or pellets for
making tablets encounters many difficulties and problems. As is
well known in the pharmaceutical industry, beads or pellets are
quite distinguishable from granules. Beads can be defined as small,
free-flowing spherical or sphere-like particulates manufactured by
pelletization, i.e. the agglomeration of fine powders or granules
of drug substances and excipients using appropriate processing
equipment. As opposed to the process of granulation, the production
of beads by pelletization results in a larger average size and a
narrower size-range distribution.
[0007] Another difficult problem is the formulation of drugs having
low or very low water-solubility into solid dosage forms for
immediate release. Few solutions to this problem have been
disclosed in the art. For instance, U.S. Patent Publication No.
2001/0048946 provides solid dosage forms of sparingly water-soluble
pharmaceutical agents, i.e. solid or crystalline drugs having a
water-solubility of 10 to 33 .mu.g/ml at 25.degree. C., such as
glitazones. More particularly, this document discloses a
pharmaceutical composition in the form of a solid particulate
dispersion of such a pharmaceutical agent dispersed throughout a
matrix of a water-soluble polymer such as polyvinylpyrrolidone,
hydroxypropyl cellulose, or hydroxypropyl methylcellulose. In a
preferred embodiment, the particulate pharmaceutical agent is
dispersed in the water-soluble polymer in a weight ratio of about
10% to about 90% active ingredient to about 90% to about 10%
polymer. Other conventional excipients such as glycerin, propylene
glycol, Tween, stearic acid salts and the like can be added.
[0008] U.S. Patent Publication No. 2001/0044409 discloses a process
for the preparation of a poorly water soluble drug in solid
dispersion comprising the steps of (a) blending the drug with a
carrier, (b) dissolving a surfactant and a plasticizer/solubilizer
in water, (c) spraying the surfactant-plasticizer/solubilizer
solu-tion onto the drug/carrier mixture in a fluid bed granulator,
(d) extruding the resulting granulation through a twin screw
extruder with at least one heating zone, and (e) milling the
extrudate to a powdery mass of the solid drug dispersion. Within
the scope of this process, said carrier may be selected from the
group consisting of polyvinylpyrrolidone, high molecular weight
polyethylene glycol, urea, citric acid, vinyl acetate copolymer,
acrylic polymers, succinic acid, sugars and mixtures thereof; the
said plasticizer/solubilizer may be selected from the group
consisting of low molecular weight polyethylene glycol, propylene
glycol, glycerin, triacetin, triethyl citrate, sugar alcohols and
mixtures thereof, and the said surfactant may be selected from the
group consisting of Tween, Span, Pluronics, polyoxyethylene
sorbitol esters, monodiglycerides, polyoxyethylene acid
polyoxyethylene alcohol and mixtures thereof. This process suffers
from the disadvantage of providing a heating zone in the twin screw
extruder and consequently a need for controlling and monitoring the
temperature profile of the extruder for efficient quality
control.
[0009] However, none of the above processes appear to be successful
in formulating solid dosage forms of drugs having very low
water-solubility, i.e. a solubility lower than 10 .mu.g/ml,
preferably lower than 5 .mu.g/ml. This problem is applicable to a
large number of drugs, including those belonging to the family of
diaminopyrimidines, such as stated in U.S. Pat. No. 6,211,185.
[0010] U.S. Pat. No. 3,639,637 discloses oestrogen compositions for
the preparation of stable aqueous suspensions that can be sprayed
onto animal feed, comprising (by weight) 70-95% of
water-dispersible gel-forming microcrystalline cellulose and 5-30%
of finely-divided diethylstilbestrol (a compound which is virtually
insoluble in water) and optionally further up to one third of the
weight of the composition of a hydrocolloid selected from the group
consisting of sodium carboxy-methylcellulose, methylcellulose and
hydroxyethylcellulose. The two latter cellulose compounds are
known, namely from EP-A-403,383, to contribute to an extended
linear drug release rate.
[0011] EP-A-352,190 discloses a solid pharmaceutical unit with a
delayed dissolution of the active ingredient, i.e. allowing
retention of the active ingredient and avoiding its complete and
immediate availability by a simple contact with an aqueous liquid
medium. It further discloses in example 9 paracetamol microgranules
obtained from a mixture of 182 g paracetamol (a drug belonging to
class 1 of the Biopharmaceutical Classification System and having a
water-solubility of 14 mg/ml), 728 g microcrystalline cellulose
(AVICEL PH 101) and 90 g sodium carboxymethylcellulose.
EP-A-352,190 however does not teach using a cyclodextrin compound
as a drug dissolution enhancer.
[0012] U.S. Pat. No. 5,362,860 discloses (see table VI, example C)
a composition with improved storage stability comprising (by
weight) 0.05% of a pyridine based oxime (a drug undergoing
hydrolysis into an aldehyde in an acidic environment), 70%
cyclodextrin, 3% crosscarmellose (a crosslinked polymer) and 20.95%
microcrystalline cellulose.
[0013] WO-A-99/12,524 solves the problem of drug formulations with
both a relatively fast or quick onset of the therapeutic effect and
the maintenance of a therapeutically active plasma concentration
for a relatively long period of time, by providing an oral modified
release multiple-units composition wherein the unit dosage form
comprises at least (i) a first fraction being able to release at
least 50% of the drug within the first 20 minutes of a certain
dissolution method, and (ii) a second fraction for delayed and
extended release of the drug. The multipleunits of the first
fraction may be granulates or, provided that a surfactant is added
to the formulation, coated or uncoated pellets. Formulation of the
first fraction depends on the specific drug but typically includes
wet-granulation, and an antacid-like or other alkaline substance
was found to have a pronounced increasing effect on the release
rate.
[0014] U.S. Pat. No. 5,646,131 discloses (example 4) rapidly
dissolving capsules containing a granulate formulation of a
water-insoluble or sparingly soluble drug, such as terfenadine
(less than 0.01 mg/ml water-solubility), surfactants (Tween 80 and
sodium lauryl sulfate), cyclodextrin, Avicel PH 101
(microcrystalline cellulose) and a disintegrant/swelling agent
(Primojel.RTM., i.e. sodium carboxymethyl starch) in a weight ratio
of 10:72 to Avicel. These capsules provide better drug absorption,
due to the presence of cyclodextrin, as evidenced by the figure
showing a 90% drug release within 45 minutes.
[0015] Elbers et al. in Drug Development and Industrial Pharmacy
(1992) 18(5):501-517 discloses theophylline pellets with a drug
loading from 10 to 50% obtained by extrusion-spheronization with
AVICEL 581 (a blend of microcrystalline cellulose and sodium
carboxymethylcellulose). Theophylline is a drug with a
water-solubility of 8 mg/ml (according to Merck Index, 12.sup.th
edition 1996) and high permeability (according to FDA Guidance to
Industry, 2000), thus belonging to class I of the Biopharmaceutical
Classification System.
[0016] U.S. Pat. No. 4,235,892 discloses a series of
1-aryl-2-acylamido-3-fluoro-1-propanol antibacterial agents
including D-(threo)-1-p-methylsulfonyl
phenyl-2-dichloroacetamido-3-fluoro-I-propan- ol, an antibacterial
agent known as florfenicol and useful for veterinary purposes.
Florfenicol has low solubility in water (about 1.3 mg/ml), as well
as in many pharmaceutically acceptable organic solvents such as
1,2-propanediol, glycerin, and benzyl alcohol. For oral
administration, these 1-aryl-2-acylamido-3-fluoro-1-propanol may be
compounded in the form of tablets, or may even be admixed with
animal feed. U.S. Pat. No. 4,235,892 therefore discloses making
tablets by compressing granules of a composition comprising the
said 1-aryl-2-acylamido-3-fluoro-1-propanol (in a drug loading
range from 8.3% to 41.7% by weight), lactose, microcrystalline
cellulose, starch and magnesium stearate.
[0017] The Biopharmaceutical Classification System (hereinafter
referred as BCS) according to G. Amidon et al. in Pharm. Res.
(1995) 12:413-420 provides for two classes of poorly soluble drugs,
i.e. Class II and Class IV, and a class of highly soluble drugs,
i.e. Class I. According to M. Martinez et al., Applying the
Biopharmaceutical Classification System to Veterinary
Pharmaceutical Products (Part I: Biopharmaceutics and Formulation
Consideration) in Advanced Drug Delivery Reviews (2002) 54:805-824,
a drug substance should be classified as highly soluble when the
highest dose strength is soluble in at most 250 ml of aqueous media
over the pH range 1-7.5. In view of its water solubility (1.3
mg/ml) and of a maximal dose of 20 mg/kg for pigs, it is easy to
calculate that the highest dose strength of florfenicol
administered to pigs is soluble in an amount of water which is well
above the limit value for the definition of a class I BCS highly
soluble drug. Furthermore it is known from J. Voorspoels et al. in
The Veterinary Record (October 1999) that florfenicol has a good
oral bioavailability, so that it can be classified as a Class II
compound as it is not a highly soluble drug and it shows no
absorption problems.
[0018] U.S. Pat. No. 6,368,634 discloses a solid preparation
suitable for a substantially immediate release of an active agent
having a low or very low solubility, for example wherein more than
80% of the active agent is released within 2 hours, preferably
within 1 hour or less from the administration. This solid
preparation is obtained by pelletisation, i.e. an agglomeration
process whereby fine powders or granules are shaped into fine,
free-flowing units (pellets) with a particle size above 250 .mu.m.
The pellets of this solid preparation comprise one or more carriers
(which may be polymers, or inorganic carriers such as talc,
montmorillonite, bentonite, clay or calcium phosphate) and an
active ingredient dissolved in a liquid phase (liquid as such or to
be liquified for example by means of shear or temperature) which
may be an oil or fat, a tensio-active agent or a polar co-solvent
(such as polyethylene glycol, glycerol or propylene glycol). In
U.S. Pat. No. 6,368,634 the active ingredient is dissolved in a
liquid solubilizer (the weight ratio solubilizer/active agent being
greater than 4) which is fixed on solid carrier particles
preferably with a particle size below 500 .mu.m such as
microcrystalline cellulose, the resulting mixture being then
transformed into pellets using a suitable batch technique such as
extrusion/spheronisation, fluid-bed technology, rotary granulation.
As a result the active ingredient is already in solution inside the
dosage form (i.e. pellets) and hence is very quickly released from
the dosage form upon contact with aqueous media. Therefore
according to U.S. Pat. No. 6,368,634 it is essential to have a
liquid phase in which the active ingredient can dissolve to obtain
the reported dissolution profiles.
[0019] FIGS. 6 and 7 of U.S. Pat. No. 6,368,634 clearly illustrate
that the active ingredient is no longer in its crystalline form
inside the dosage form, but has gone into solution in the
solubilizer. No peaks of crystalline hydrochlorothiazide (at
2.theta.=19.degree.) are present in the X-ray diffraction pattern
of pellets containing 3.5% by weight hydrochlorothiazide (HCT) and
32% by weight polyethylene glycol with a molecular weight of 400,
as shown in FIGS. 6B and 6C. The importance of the active agent
being dissolved in the liquid solubilizer is clearly shown in
example 4 in combination with FIGS. 5 and 7 of U.S. Pat. No.
6,368,634. FIG. 5 shows a higher dissolution rate after 6 months
storage of pellets containing 3.5% by weight HCT and 21% by weight
polyethylene glycol hydrogenated castor oil. Immediately after
preparation a crystalline peak of HCT was still visible (FIG. 7A),
whereas it had disappeared after 6 months storage (FIG. 7B), i.e.
all HCT crystals had dissolved, this behaviour being also
indicative of a need for controlling drug formulation stability
during storage. An increased dissolution rate was obtained after
heat treatment of the pellets immediately after preparation, this
again corresponding to the complete drug fraction going into
solution as shown in FIG. 7C.
[0020] A limitation of the technology disclosed in U.S. Pat. No.
6,368,634 is that it only allows to increase the dissolution rate
of formulations containing a low content of active ingredient (i.e.
drug loading) since the amount of liquid phase (solubilizer) that
can be fixed onto the solid carrier particles is limited to a
weight ratio solubilizer/particles from 1:5 to 1:2, and the active
ingredient further needs to dissolve into the solubilizer. This
limitation is well illustrated in U.S. Pat. No. 6,368,634 teaching
drug loadings in a range from about 1% by weight (examples 1 and 9)
to about 6.7% by weight (example 5). This limitation was confirmed
by our experiments performed while preparing a pellet formulation
based on the teachings of U.S. Pat. No. 6,368,634 but containing
20% by weight of a veterinary active ingredient. The release rate
of this ingredient from the pellets was low and this slow drug
release from the pellets was also reflected in low plasma levels of
broiler chickens after administration of this formulation via
drinking water.
[0021] Furthermore, U.S. Pat. No. 6,368,634 describes the dosage
form as pellets which are produced by a suitable batch technique
such as fluid-bed technology, rotary granulation or, preferably,
extrusion-spheronisation. The extrusion-spheronisation process is a
multi-step process capable of making uniformly sized preferably
spherical particles (pellets). The following steps are required:
(a) dry mixing, (b) wet granulation (i.e. formation of a wet mass,
e.g. in U.S. Pat. No. 6,368,634 through the addition of a liquid
phase and water (in order to get sufficient plasticity for
extrusion), (c) extrusion (i.e. forming the wet mass into long
rod-shaped particles), (d) spheronisation (breaking the rod-shaped
particles into smaller pieces and rounding the individual particles
into spheres) and (e) drying (removal of water added during
granulation). Another limitation of the technology disclosed in
U.S. Pat. No. 6,368,634 is thus that the stickiness of the wet mass
formed in step (b) should not exceed a level where its extrusion in
step (c) would become impossible and/or would block the extruder.
This proviso implies significant limitations on the liquid
solubilizer that may be used according to U.S. Pat. No. 6,368,634.
In particular, the latter document does not teach or suggest the
use of maltodextrins, and the skilled person knows that a mixture
of water and a maltodextrin would have a stickiness much higher
than permitted for extrusion. Another limitation of this technology
is the need for an energy-consuming drying step in the final stage
of the extrusion-spheronisation process.
[0022] Therefore, there is still a need in the art for formulating
poorly soluble drugs classifiable as or belonging to Class II or
Class IV of the Biopharma-ceutical Classification System not only
into formulations with low drug contents (such as known from U.S.
Pat. No. 6,368,634) but also into formulations with moderate and
even high drug contents. There is also a need in the art for making
formulations of poorly soluble drugs classifiable as or belonging
to Class II or Class IV of the Biopharma-ceutical Classification
System by means of a continuous production method, not a batch-wise
production method, in order to decrease their production cost.
There is also a need in the art for making formulations of poorly
soluble drugs classifiable as or belonging to Class II or Class IV
of the Biopharma-ceutical Classification System by an energy-saving
production method which does not require a drying step, in order to
decrease their production cost. There is also a need in the art for
formulating poorly soluble drugs classifiable as or belonging to
Class II or Class IV of the Biopharma-ceutical Classification
System as granules, not pellets. There is also a need in the art
for formulating poorly soluble drugs classifiable as or belonging
to Class II or Class IV of the Biopharma-ceutical Classification
System in the absence of a costly pharmaceutical grade material
such as microcrystalline cellulose.
[0023] There is a specific need in the art to provide a solid
formulation of drugs with a water-solubility like florfenicol or
lower. Florfenicol is a drug for administration to warm-blooded
animals, such as cattle with naturally-occurring bovine respiratory
disease, swine, sheep, goats and poultry, which at present is
mainly available in the form of injectable solutions. Until now the
skilled person has failed in the design of such a solid formulation
of florfenicol, which can further be admixed with animal feed if
necessary. There is therefore a need in the art for a florfenicol
formulation in the form of a water-soluble granulate for
administration to animals together with drinking water. Also there
is a need for a solid formulation for many low solubility drugs for
human and veterinary therapies.
SUMMARY OF THE INVENTION
[0024] The present invention is based on the unexpected finding
that drugs classifiable as or belonging to Class 11 (poorly
soluble, highly permeable) or Class IV (poorly soluble, poorly
permeable) of the Biopharmaceutical Classification System,
including drugs having very low water-solubility, can be
successfully formulated into immediate or fast release
pharmaceutical solid dosage forms provided that:
[0025] (1) they are admixed in suitable proportions with a first
pharmaceutically acceptable excipient comprising a
dextrin-containing compound or, in a less preferred embodiment, a
blend of microcrystalline cellulose and a swellable polymer, or a
mixture of the said dextrin-containing compound and the said blend,
and with a second pharmaceutically acceptable excipient being a
non-aqueous wetting compound comprising at least a solid fraction,
and that
[0026] (2) they are formulated into granule compositions, not
pellet compositions.
[0027] Preferably, these granule formulations are advantageously
obtained by a continuous manufacturing process involving a low
temperature extruding step in an extruding means. Based on the
above teachings, the invention also provides various pharmaceutical
dosage forms such as sachets and solid shaped articles such as
tablets and hard gelatin capsules including the said granule
compositions. The invention also provides water-soluble granule
composi-tions of poorly soluble drugs that may be administered to
animals in admixture with drinking water. The invention also
relates to the treatment of bacterial infections in human beings
and in animals, such as poultry, pigs, cattle (e.g. the treatment
of bovine respiratory disease) and fish, by the oral administration
to the human being or animal of an effective amount of the
above-referred immediate or fast release pharmaceutical granule
compositions.
BRIEF DESCRIPTION OF THE DRAWINGS
[0028] FIG. 1 represents the release, as a function of time, of
hydrochloro-thiazide from a granule composition according to one
embodiment of the invention.
[0029] FIG. 2 represents the release, as a function of time, of
florfenicol from a granule composition according to one embodiment
of the invention.
[0030] FIG. 3 shows a twin screw extruder useful for manufacturing
granule compositions according to one embodiment of the present
invention.
[0031] FIG. 4 shows the release, as a function of time, of
florfenicol from a pellet composition according to the prior
art.
[0032] FIG. 5 shows florfenicol plasma concentrations in chickens
after administration of a bolus dose of a florfenicol granule
composition according to one embodiment of the invention, compared
to intravenous administration of the same dose.
[0033] FIG. 6 shows florfenicol plasma concentrations in pigs after
administration of a bolus dose of a florfenicol granule composition
according to one embodiment of the invention, compared to
intravenous administration of the same dose.
[0034] FIG. 7 shows florfenicol plasma concentrations in chickens,
as a function of time, after continuous administration of a
florfenicol granule composition according to one embodiment of the
invention, compared to a florfenicol pellet composition of the
prior art.
[0035] Definitions
[0036] The terms "low drug content" and "low drug loading" as used
herein, unless otherwise stated, are intended to mean a drug
content, with respect to the total solid formulation, in a range
below about 7% by weight.
[0037] The terms "moderate drug content" and "moderate drug
loading" as used herein, unless otherwise stated, are intended to
mean a drug content, with respect to the total solid formulation,
in a range from about 7% by weight to about 20% by weight.
[0038] The terms "high drug content" and "high drug loading" as
used herein, unless otherwise stated, are intended to mean a drug
content, with respect to the total solid formulation, in a range
above about 20% by weight.
[0039] The term "solid shaped article" as used herein means any
article being in a hard solid state at temperatures not exceeding
about 60.degree. C. and having a definite geometrical shape, such
as for instance ordinary tablets, effervescent tablets, pills,
lozenges and other compressed dosage forms.
[0040] The term "immediate release" as used herein means a release
of at least about 50% of a drug within 30 minutes in water,
preferably a release of at least about 70% of said drug within 10
minutes in water, and more preferably a release of at least about
80% of said drug within 10 minutes in water, under physiological
temperature and pH conditions.
[0041] The term "fast release" as used herein means a release from
about 40% to about 50% of a drug within 30 minutes in water, under
physiological temperature and pH conditions.
DETAILED DESCRIPTION OF THE INVENTION
[0042] In a first embodiment, this invention relates to an
immediate or fast release pharmaceutical solid composition
comprising at least one drug (i) classifiable as Class II (poorly
soluble, highly permeable) or Class IV (poorly soluble, poorly
permeable) of the Biopharmaceutical Classification System, e.g. a
drug having very low water-solubility such as defined herein,
wherein said drug is present in said solid composition in a low
drug content, a moderate drug content or a high drug content, i.e.
said drug constitutes at least about 0.5% by weight but no more
than 50% by weight, for instance from 0.5% to about 20% by weight
(low and moderate drug loadings), preferably from 1 to 15% by
weight, or alternatively from 20% to 50% by weight (high drug
loadings) of the solid composition, wherein said solid composition
is in the form of granules comprising one or more pharmaceutically
acceptable excipients, wherein said one or more pharmaceutically
acceptable excipients comprise
[0043] (ii) a first excipient selected from the group consisting
of:
[0044] blends of a microcrystalline cellulose and a swellable
polymer in respec-tive amounts such that the weight ratio of the
said polymer to the microcrystalline cellulose in the blend is
above about 2:100 and up to about 30:100,
[0045] one or more dextrin-containing compounds selected from the
group consisting of maltodextrins, cyclodextrins and derivatives
thereof, and
[0046] mixtures of the said dextrin-containing compounds and the
said blends, and
[0047] (iii) a wetting amount of a second excipient being a
non-aqueous wetting compound or meltable compound and comprising a
solid fraction and optionally a liquid fraction.
[0048] In a second embodiment, this invention relates to a
continuous process for manufacturing the aforesaid immediate or
fast release solid pharmaceutical composition. More particularly,
this invention provides a continuous process for manufacturing a
pharmaceutical granule composition comprising at least one drug (i)
classifiable as Class II or Class IV of the Biopharma-ceutical
Classification System in an amount of no more than about 50% by
weight, for instance from 0.5% to about 20% by weight (low and
moderate drug loadings), preferably from 1 to 15% by weight, or
alternatively from 20% to 50% by weight (high drug loadings), of
said pharmaceutical composition, a first excipient (ii) being a
dextrin-containing compound in an amount from 40 to 85% by weight
of said composition, and a second excipient (iii) comprising a
solid fraction and optionally a liquid fraction, said second
excipient (iii) being in an amount from 15 to 40% by weight of the
composition and being selected from the group consisting of
polyethylene glycols and polypropylene glycols having weight number
molecular weights between about 300 and 10,000 (preferably between
300 and 5,000), glycerol, propylene glycol and glycerides,
comprising the steps of:
[0049] (a) homogenising a mixture comprising the drug (i)
classifiable as Class II or Class IV of the Biopharmaceutical
Classification System, e.g. a drug having low or very low
water-solubility, the first excipient (ii) and the solid fraction
of the second excipient (iii),
[0050] (b) feeding the mixture obtained in step (a) and optionally
the liquid fraction of the second excipient (iii) into an extruding
means having one or more mixing zones and one or more transport
zones, and
[0051] (c) extruding the materials fed in step (b) while operating
the extruding means at a temperature not above the melting
temperature of the solid fraction of the second excipient until an
immediate release pharmaceutical granule composition is
obtained.
[0052] More detailed ways of implementing the invention will now be
described in more details by referring both to the immediate or
fast release pharmaceutical granule composition and the process for
manufacturing the same. In a first but less preferred embodiment of
the invention, the first excipient (ii) may be a blend of a
microcrystalline cellulose and a swellable polymer and the said
swellable polymer may be an uncrosslinked carboxyalkylcellulose
metal salt such as for instance sodium or calcium
carboxymethylcellulose.
[0053] In a preferred embodiment of the invention the first
excipient (ii), whatever its nature (i.e. the aforesaid blend or a
dextrin-containing compound such as a maltodextrin), may be present
in the pharmaceutical granule composition in an amount from about
40% to about 85% by weight of the said composition.
[0054] Microcrystalline cellulose, in particular a pharmaceutical
grade thereof, is well known in the art of pharmaceutical industry
for its high surface porosity and its outstanding capillary
character. It is available from a variety of commercial sources,
e.g. Avicel.RTM. PH 101 (commercially available from FMC
Corporation, Philadelphia, Pa.), Emcocel.RTM. (Mendell),
Vivocel.RTM. (JRS) and the like. Microcrystalline cellulose is a
partially purified depolymerized form of cellulose and is obtained
by treating pulps derived from fibrous plant material with mineral
acid. The acid preferentially attacks the less ordered or amorphous
regions of the cellulose polymer chain, thereby exposing and
freeing the crystalline sites which form cellulose crystallite
aggregates. The reaction mixture is washed to remove the degraded
byproducts, the resulting wet-cake is freed of water and the dried
cellulose crystallite aggregates, or more commonly microcrystalline
cellulose, recovered. Microcrystalline cellulose is a white,
odourless, tasteless, relatively free-flowing powder, insoluble in
water, organic solvents, dilute alkalies and dilute acids.
[0055] A swellable polymer suitable for use in the blend being an
embodiment of the first excipient (ii) of the present invention may
be defined herein preferably as an ionic hydrocolloid polymer which
is easily miscible with microcrystalline cellulose and which, on
its own, is able to form a colloidal suspension in an aqueous
environment, the colloidal particles e.g. forming a
three-dimensional network or grid-like structure throughout the
liquid phase. Suitable examples of such polymer include
pharmaceutical grades of sodium carboxymethylcellulose such as
commercially available under the tradenames Nymcel.RTM.,
Tilose.RTM. and Blanose.RTM. (Aqualon). Preferably, the swellable
polymer is a low molecular weight and/or low viscosity polymer. For
instance when the swellable polymer is an uncrosslinked
carboxyalkylcellulose metal salt, it should preferably have
sufficient unsubstituted hydroxyl groups in order to hydrogen bond
to the microcrystals of the microcrystalline cellulose upon drying
and the substituent groups should have ability to impart
water-solubility. The degree of substitution of the
carboxyalkyl-cellulose should preferably not exceed about 0.9 and
more preferably be within a range of 0.5 to 0.9. Also, the
viscosity of a 2% aqueous solution of the swellable polymer at
20.degree. C. should preferably be below 1,000 mPa.multidot.s, more
preferably within a range from about 20 to 800 mPa.multidot.s.
[0056] The swellable polymer and the microcrystalline cellulose
being part of the first excipient (ii) may be afforded separately
at the time of making the pharmaceutical granule compositions of
the present invention or they may be present in the form of a
co-processed blend. A co-processed blend of the swellable polymer
together with microcrystalline cellulose is readily available, e.g.
as Avicel.RTM. RC 581 and Avicel.RTM. CL 611 (both commercially
available from FMC Corporation), both well known in the art in the
form of pharmaceutically acceptable grades. This cellulosic blend
may alternatively be prepared by bringing the two blend components
into intimate contact under suitable conditions, for instance by
subjecting the washed filter cake containing microcrystalline
solids from the acid degradation of cellulose to intense attritive
forces, thus resulting in a further break up of the cellulose
crystallite aggregates and an increase in sub-micron particles. As
the attrition proceeds, a sufficient amount of the swellable
polymer (e.g. sodium carboxymethyl cellulose) is added to the
aqueous mixture in order to at least partially coat the individual
microcrystals of the microcrystalline cellulose. Upon completion of
the attrition, the blend is dried and recovered. The dried product
is readily redispersible in aqueous media to give gels. Important
for its effectiveness in the present invention is the fact that
this blend is a non-disintegrating water-insoluble
water-dispersible powder before it is granulated in admixture with
the poorly soluble drug and the second excipient. Preferably at
least about 1% by weight and more preferably at least about 30% by
weight of the powder blend particles have an average size not
greater than about 1.0 .mu.m as determined by electron microscopic
examination.
[0057] For optimal efficiency, the weight ratio of the said
swellable polymer to the microcrystalline cellulose in this first
but less preferred embodiment of the first excipient (ii) for the
immediate or fast release pharmaceutical granule composition of the
invention, or respectively in the (co-processed) blend as above
defined, should be above about 2:100 and up to about 30:100,
preferably between about 7:100 and 20:100.
[0058] In a much preferred second embodiment of the invention, the
first excipient (ii) is a dextrin-containing compound such as
described hereinafter.
[0059] Drug dissolution enhancing agents, in particular being
dextrin-containing compounds such as maltodextrins, cyclodextrins
and related substances such as chemically-modified derivatives
thereof, in particular their pharmaceutically acceptable grades,
are well known in the art and are available from a variety of
commercial sources. They may be collectively referred as starch
cyclic linear degradation products containing 6 to 8 glucose
residues, or alternatively as cyclic oligosaccharides composed of
L-glucose molecules linked by .alpha. or .beta. osidic bonds having
a toric form. Among the above group of compounds, special attention
will be paid to cyclodextrins, and still more preferably, to
maltodextrins for inclusion in the first excipient (ii) of the
pharmaceutical granule composition. Cyclodextrins are crystalline
(usually white powder), non-hygroscopic, cyclic oligosaccharides
derived from starch. Among the most commonly useful are .alpha.-,
.beta.-, and .gamma.-cyclodextrins which have respectively 6, 7,
and 8 glucose units. Suitable representative embodiments of
cyclodextrin derivative enhancing agents include
2-hydroxypropyl-.beta.-c- yclodextrin,
dimethyl-.beta.-cyclodextrin, 2-hydroxyethyl-.beta.-cyclodext- rin,
3-hydroxypropyl-.beta.-cyclodextrin, and
trimethyl-.beta.-cyclodextri- n. Maltodextrins occur as non-sweet,
odourless, white powders or granules and are saccharide mixtures of
polymers that consist of D-glucose units with a dextrose equivalent
less than 20.
[0060] Preferably the amount of the first excipient (ii),
particularly in the form of a dextrin-containing compound,
represents from about 40% by weight to about 85% by weight, more
preferably from 50% to 75% by weight of the immediate or fast
release pharmaceutical granule composition of the invention,
depending on the amounts of the other excipients (such as fillers)
that may optionally be present therein.
[0061] According to the invention, the aforesaid immediate release
is a release of at least about 50% of the said drug within 30
minutes in water, preferably a release of at least about 70% of the
said drug within 10 minutes in water, and more preferably a release
of at least about 80% of the said drug within 10 minutes in water,
preferably under physiological temperature and pH conditions. As
shown in the following examples, the present invention is also
successfully applicable to drugs having low, but not very low,
water-solubility but which are relatively highly dosed drugs (i.e.
constitute from about 10% to about 20% by weight of the
composition) for therapeutic efficiency, such as florfenicol.
[0062] The immediate or fast release pharmaceutical granule
compositions of this invention may further comprise one or more
pharmaceutically acceptable fillers. The aforesaid pharmaceutically
acceptable fillers may be selected for instance from hydrocolloids
(such as xanthan gum), binding agents, glidants, lubricants,
surfactants and diluents. The term "pharmaceutically acceptable
filler" as used herein is intended to refer to any material which
is inert in the sense that it does not have any therapeutic and/or
prophylactic effect per se but does not adversely interfere with
the therapeutic or prophylactic property of the drug or
pharmaceutical active ingredient being formulated. The nature and
amount of such fillers are not critical to the present invention.
They include for instance binding agents such as starch, gelatin,
glucose, alginic acid, sodium and calcium alginates, water-soluble
acrylic (co)polymers, polyvinylpyrrolidone, polyamino-acids,
ethylene-vinyl acetate copolymers and the like; natural and
synthetic mineral fillers or glidants such as fumed (colloidal)
silica (e.g. commercially available under the tradename
Aerosil.RTM.), magnesium silicates such as talc, diatomaceous
earth, aluminium silicate such as kaolinite, montmorillonite or
mica, magnesium aluminium silicate such as attapulgite and
vermiculite, carbon such as charcoal, sulphur and highly dispersed
silicic acid polymers; water-soluble diluents such as lactose,
sorbitol and the like. Although the nature of fillers is not
critical, it is however preferred when the first excipient (ii) is
a dextrin-containing compound, that the immediate or fast release
pharmaceutical granule composition of the invention be
substantially free of micro-crystalline cellulose.
[0063] According to this invention, the drug (i) is classifiable as
Class II or Class IV of the BCS and preferably has a
water-solubility below about 2.5 mg/ml, even between 0.1 and 1
mg/ml (i.e. "very slightly soluble" as defined according to the
United States Pharmacopeia), even below 0.1 mg/ml (i.e.
"practically insoluble" as defined according to the United States
Pharmacopeia), even below about 5 .mu.g/ml and may even have a
water-solubility as low as about 0.2 .mu.g/ml, at room temperature
and physiological pH. Non-limiting examples of such drugs include
for instance chlorothiazide, hydrochlorothiazide, nimodipine,
flufenamic acid, furosemide, mefenamic acid, bendroflumethiazide,
benzthiazide, ethacrinic acid, nitrendipine, itraconazole,
saperconazole, troglitazone, prazosin, atovaquone, danazol,
glibenclamide, griseofulvin, ketoconazole, carbamazepine,
sulfadiazine, florfenicol, acetohexamide, ajamaline, benzbromarone,
benzyl benzoate, beta-methasone, chloramphenicol, chlorpropamide,
chlorthalidone, clofibrate, diazepam, dicumarol, digitoxin,
ethotoin, glutethimide, hydrocortisone, hydro-flumethiazide,
hydroquinine, indomethacin, ibuprofen, ketoprofen, naproxen,
khellin, nitrazepam, nitrofurantoin, novalgin, oxazepam,
papaverine, phenylbutazone, phenyloin, prednisolone, prednisone,
reserpine, spironolactone, sulfabenzamide, sulfadimethoxine,
sulfamerazine, sulfamethazine, sulfamethoxy-pyridazine,
succinylsulfathiazole, sulfamethizole, sulfamethoxazole (also in
admixture with trimethoprim), sulfaphenazole, sulfathiazole,
sulfisoxazole, sulpiride, testosterone and diaminopyrimidines.
Suitable examples of diamino-pyrimidines include, without
limitation, 2,4-diamino-5-(3,4,5-trimethoxy-benzyl) pyrimidine
(known as trimethoprim), 2,4-diamino-5-(3,4-dimethoxybenzyl)
pyrimidine (known as diaveridine), 2,4
diamino-5-(3,4,6-trimethoxybenzyl) pyrmidine,
2,4-diamino-5-(2-methyl-4,5-dimethoxybenzyl) pyrimidine (known as
ormetoprim), 2,4-diamino-5-(3,4-dimethoxy-5-bromobenzyl)
pyrimidine, and 2,4-diamino-5-(4-chloro-phenyl)-6-ethylpyrimidine
(known as pyrimethamine). The above-mentioned drugs are known as
belonging to Class II (poorly soluble, highly permeable) or Class
IV (poorly soluble, poorly permeable) of the Biopharmaceutical
Classification System according to G. Amidon et al. in Pharm. Res.
(1995) 12:413-420. As will be appreciated by those skilled in the
art, these drugs belong to various therapeutic classes, including
diuretics, anti-hypertensive agents, anti-viral agents
(particularly anti-HIV), antibacterial agents, antifungals, etc,
and are not limited to human or veterinary use alone.
[0064] According to this invention, the granules of the immediate
or fast release pharmaceutical granule composition preferably have
a diameter ranging from about 100 and 2,500 .mu.m.
[0065] The second excipient (iii) of the immediate or fast release
pharmaceutical granule composition of this invention is preferably
one which will not give rise to difficulties during extrusion and
may suitably be selected from the group consisting of
polyethyleneglycols and polypropyleneglycols having weight number
molecular weights between about 300 and about 10,000, preferably
between 300 and 5,000; glycerol; propylene glycol and glycerides
(such as mono-, di- and triglycerides of polyethyleneglycol fatty
acid esters, including those commercially available under the
tradename Gelucire.RTM.). Suitable examples of the latter include
those having both a portion derived from a glyceride and a portion
derived from a polyethylene glycol ester. For instance, it is
suitable to use polyglycosylated glycerides. The term
"polyglycosylated glycerides" as used herein denotes a mixture of
mono-, di- and triglycerides with polyethylene glycol (PEG) mono-
and diesters of C.sub.8-C.sub.18 fatty acids with a molecular
weight preferably between about 200 and about 600, optionally
further including glycerol and/or free PEG, the
hydrophilic-lipophilic balance (HLB) value of which is controlled
by the chain length of the PEG and the melting point of which is
controlled by the chain length of the fatty acids, of the PEG and
of the degrees of saturation of the fatty chains, and thus of the
starting oil. Similarly the expression "C.sub.8-C.sub.18 fatty
acids" as used herein denotes mixtures in various proportions of
caprylic acid, capric acid, lauric acid, myristic acid, palmitic
acid and stearic acid, when these acids are saturated, and the
corresponding unsaturated acids. As is well known to the skilled
person, the proportions of these fatty acids may vary as a function
of the starting oils. Examples of the latter include, but are not
limited to, saturated polyglycolized C.sub.8-C.sub.10 glycerides,
such as the PEG-8 caprylate/caprate glyceride esters sold by
Gattefosse Corporation under the tradename Labrasol; PEG-6
caprylic/capric glycerides sold by Huls Aktiengesellschaft under
the trade name Softigen 767; PEG-60 corn glycerides sold by Croda
under the trade name Crovol M-70; Ceteareth-20 sold by Henkel
Corporation under the trade name Emulgin B2; diethyleneglycol
monoethylethers sold by Gattefosse Corporation under the trade name
Transcutol; a mixture of C.sub.8-C.sub.18 saturated
polyglycosylated glycerides having a melting point within a range
of about 42-48.degree. C. and a HLB within a range of about 8 to 16
such as sold by Gattefosse Corporation under the trade names
Gelucire 48/09, Gelucire 44/14 and Gelucire 42/12; and mixtures
thereof in various proportions. When a polyethyleneglycol is used
for instance, it may comprise a higher molecular weight solid
fraction and a lower molecular weight liquid fraction, the latter
acting as a plasticizer.
[0066] In a preferred embodiment of the invention the second
excipient (iii), particularly when the first excipient (ii) is a
dextrin-containing compound, may be present in the immediate or
fast release granule composition of this invention in an amount
from about 10% to about 40% by weight, more preferably from 15% to
40% by weight, most preferably from 20% to 30% by weight, of the
said composition. In yet another preferred embodiment of the
invention, the weight ratio between the liquid fraction and the
solid fraction of the second excipient (iii) may be from 0:1 (no
liquid fraction) to about 1:1, more preferably from 0:1 to about
1:2, most preferably not more than 1:3. In yet another more
preferred embodiment of the invention, for instance when a
maltodextrin is used as the first excipient (ii) and a
polyethyleneglycol is used as the second excipient (iii), the
weight ratio of the first excipient (ii) to the second excipient
(iii) is in a range from about 1:1 to about 5:1.
[0067] According to this invention, the immediate or fast release
pharmaceutical granule composition may optionally further comprise
one or more other drugs different from the drug having poor
water-solubility, but preferably belonging to the same therapeutic
class, in particular when combined drug therapy is desired.
[0068] The continuous process for manufacturing a pharmaceutical
granule composition of the present invention is preferably
performed in an apparatus, such as a twin screw extruder,
comprising a barrel having a granulation chamber provided with
inlets for supplying the drug (i), the first excipient (ii) and the
solid fraction of the second excipient (iii), and at least one
continuously operated rotating transporting means. The said
extruder is preferably operated at a temperature not above about
60.degree. C., more preferably not above 45.degree. C., most
preferably at a temperature not above about 35.degree. C., i.e.
there is no need to provide a heating zone on the said extruder,
therefore no need to provide sophisticated means for controlling
and monitoring the temperature of the extruder. The extruder is
preferably operated at a rotating speed between about 5 and 450
rpm, for instance between 5 and 300 rpm, depending upon whether low
shear, medium shear or high shear is desired. The continuously
operated rotating transporting means of the extruder comprises one
or more mixing zones and one or more transport zones. The
configuration and number of these zones may be widely varied,
however at least one mixing zone is most preferred, being very
advantageous to induce interaction between the various components
of the composition to be extruded. The remaining of the screw may
then consist of transportation zones. Single or twin lead discharge
screws can be used. As is standard in this art, the length to
diameter ratio of each rotating transporting means may be within a
range from about 15 to about 60.
[0069] The present invention also provides solid shaped articles
comprising a core consisting of an immediate or fast release
pharmaceutical granule composition as defined herein-above. This
solid shaped article may be in the form of a tablet or a hard
gelatine capsule. Methods for producing tablets, such as
compression, or hard gelatine capsules from pharmaceutical granule
compositions are well known to those skilled in the art. In the
case of a tablet, the solid shaped article may further comprise a
coating, according to standard practice in the art.
[0070] The solid shaped articles of the present invention may
further optionally contain additives typically used in the
formulation of such articles, for instance flavoring agents (such
as anethole, benzaldehyde, vanillin, ethyl vanillin, ethyl acetate,
methyl salicylate and the like), lubricants (such as magnesium
stearate), sweeteners (such as sucrose, mannitol, aspartame,
saccharin and its salts), colorants and/or buffering agents.
[0071] The present invention further provides a sachet comprising
an immediate or fast release pharmaceutical granule composition as
above defined.
[0072] The present invention provides a number of advantages over
the existing formulations of poorly soluble drugs and over the
existing methods of making the latter, such as:
[0073] the same technology is able to formulate such drugs at low,
but also at moderate and even high drug contents, as defined
herein,
[0074] the production cost of such formulations can be decreased by
making use of a continuous, rather than batch-wise, process, and/or
by avoiding an energy-consuming drying step,
[0075] formulations of poorly soluble drugs can be obtained as
granules instead of pellets, and
[0076] formulations of poorly soluble drugs can be obtained in the
absence of a costly pharmaceutical grade material such as
microcrystalline cellulose.
[0077] In particular the present invention provides a solid
formulation of florfenicol for oral administration, optionally
together with animal feed, to warm-blooded animals such as cattle
with naturally-occurring bovine respiratory disease, swine, sheep,
goats and poultry. The present invention also provides a solid
formulation of trimethoprim, optionally in combination with
sulfadiazine (usually in a trimethoprim/sulfadiazine weight ratio
of about 1:5), for oral administration to fish as an antibacterial
agent effective against both gram-positive and gram-negative
bacteria.
[0078] Thus, the present invention also provides a method of
treatment of a warm-blooded animal comprising administration to
said animal of an effective amount of a pharmaceutical granule
composition comprising at least one drug (i) classifiable as Class
II or Class IV of the Biopharma-ceutical Classification System in
an amount of no more than about 50% by weight of said
pharmaceutical composition, a first excipient (ii) being a
dextrin-containing compound in an amount from about 40 to about 85%
by weight of said composition, and a second excipient (iii)
comprising a solid fraction and optionally a liquid fraction, said
second excipient (iii) being in an amount from about 10 to about
40% by weight of the composition and being selected from the group
consisting of polyethylene glycols and polypropylene glycols having
weight number molecular weights between about 300 and 10,000,
glycerol, propylene glycol and glycerides. In particular drug (i)
used in such a method may be florfenicol or trimethoprim.
[0079] The following examples are provided solely for the purpose
of illustrating various embodiments of the invention, and without
any intention of limiting the scope thereof.
EXAMPLE 1
Twin Screw Extruder for Producing a Pharmaceutical Granule
Composition
[0080] The twin screw extruder used for performing the following
pharmaceutical granule preparations is described in FIG. 3. It
consists of seven distinct zones, wherein zones (1), (2), (4) and
(6) are three transport zones, zones (3) and (5) are two mixing
zones and zone (7) is a densification zone (which could
alternatively be omitted, if desired). The extruder is placed
within a granulation chamber provided with inlets for supplying the
drug and the various excipients.
EXAMPLES 2 AND 3
Pharmaceutical Granule Formulations Including a Maltodextrin and
Xanthan Gum
[0081] The following formiulations were prepared using the
extruding equipment of example 1:
1 Low water-soluble drug: 100 g Polyethyleneglycol 400: 52.5 g
Polyethyleneglycol 4000: 187.5 g Maltodextrin 01982 622.5 g Xanthan
gum: 37.5 g
[0082] Maltodextrin 01982 is a neutral taste, medium DE
maltodextrin with good dispersibility which complies with European
and U.S. Pharmacopeia and which is commercially available from
Cerestar (Neuilly-sur-Seine, France). The solid fraction of the
formulation consisting of hydrochlorothiazide (example 2), PEG
4000, maltodextrin and xanthan gum was homogenised in a planetary
mixer. This mixture was fed into the twin screw extruder at a rate
of 29.9 g/min. The liquid phase (PEG400) was continuously pumped
into the twin screw extruder at a rate of 6.9 g/min. The screw
speed during the extrusion was 250 rpm. The temperature of the
different zones of the twin screw extruder was set at 25.degree.
C., yielding experimental extrusion temperatures of 25.degree. C.
in zone (1), 26.degree. C. in zone (2), 26.degree. C. in zone (3)
and 25.degree. C. in zones (4) and (5).
[0083] In the case of florfenicol (example 3) being used as the
drug instead of hydrochlorothiazide, the same parameters were used
and the experimental temperatures measured in zones (1) to (5) were
26.degree. C., 28.degree. C., 28.degree. C., 27.degree. C. and
25.degree. C. respectively.
[0084] The extruded granules were collected, sieved and further
analysed for drug dissolution (data shown in FIGS. 1 and 2,
formulations B and D). FIG. 1 shows that 72% release of
hydrochlorothiazide (example 2) is obtained after 10 minutes, and
90% after 25 minutes. FIG. 2 shows that 80% release of florfenicol
(example 3) is already obtained after 10 minutes, and 100% after 20
minutes.
EXAMPLES 4 AND 5
Pharmaceutical Granule Formulations Including Microcrystalline
Cellulose
[0085] The following formiulations were prepared using the
extruding equipment of example 1:
2 Low water-soluble drug: 100 g Polyethyleneglycol 400: 52.5 g
Polyethyleneglycol 4000: 250 g Avicel PH 101: 298.75 g Avicel
CL611: 298.75 g
[0086] The solid fraction of the formulation consisting of
hydrochlorothiazide (example 4), PEG 4000, Avicel PH 101/Avicel CL
611 (commercially available from FMC Corporation, Philadelphia,
Pa.) was homogenised in a planetary mixer. The homogeneous mixture
was then fed into the twin screw extruder at a rate of 27.6 g/min.
The liquid phase (PEG 400) was continuously pumped into the twin
screw extruder at a rate of 9.2 g/minute. The screw speed during
the extrusion was 250 rpm. The temperature of the different zones
of the twin screw extruder was set at 25.degree. C. yielding
experimental temperatures of 25.degree. C., 28.degree. C.,
27.degree. C., 26.degree. C. and 25.degree. C. in zones 1 to 5,
respectively.
[0087] In the case of florfenicol (example 5) being used as a drug
instead of hydrochlorothiazide, the same parameters were used and
the experimental temperatures measured were 25.degree. C.,
26.degree. C., 27.degree. C., 27.degree. C. and 28.degree. C. for
the zones (1) to (5) respectively.
[0088] The extruded granules were collected, sieved and further
analysed for drug dissolution (data shown in FIGS. 1 and 2,
formulations A and C). FIG. 1 shows that 100% release of
hydrochlorothiazide (example 4) is obtained after 10 minutes. FIG.
2 shows that 78% release of florfenicol (example 5) is already
obtained after 10 minutes, and 100% after 15 minutes.
EXAMPLE 6 (COMPARATIVE)
Pharmaceutical Pellet Formulation
[0089] A pharmaceutical pellet formulation was made according to
the extrusion-spheronisation process as disclosed in the examples
of U.S. Pat. No. 6,368,634, but starting from the following
composition (by weight):
3 Florfenicol: 20% Polyethyleneglycol 400: 21% Avicel PH 101:
59%
[0090] The release rate of florfenicol from these pellets was
determined as in the previous examples and, as shown in FIG. 4, was
found to be quite slow: only 11% and 43% of the drug were dissolved
after 10 minutes and after 60 minutes, respectively.
EXAMPLE 7
Pharmacokinetics of Florfenicol Granule Formulations in Broiler
Chickens
[0091] The effect of a bolus oral administration of a florfenicol
granule formulation according to the invention in fasted and
non-fasted broiler chickens (average weight 2-3 kgs) was compared
to the effect of a bolus intravenous administration of an
injectable florfenicol formulation in the same animals. In both
cases, the dosage used was 30 mg/kg.
[0092] The comparative formulation used for intravenous
administration was Nuflor.RTM., a commercially available injectable
preparation with a drug concentration of 300 mg/ml.
[0093] The granule formulation used for oral administration was
prepared according to the procedure of examples 2 and 3, except
that the florfenicol content was 20% by weight of the formulation
and the maltodextrin content was reduced accordingly.
[0094] Blood samples were taken from broilers at the following
times after administration: 0.25 h, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h,
3 h, 4 h, 6 h, 8 h and 12 hours, respectively. Plasma analysis was
performed by high performance liquid chromatography (HPLC) with UV
detection with chloramphenicol as internal standard.
[0095] Results of mean plasma florfenicol concentrations (expressed
in .mu.g/ml) in chickens as a function of time are shown in FIG.
5.
EXAMPLE 8
Pharmacokinetics of Florfenicol Granule Formulations in Pigs
[0096] The effect of a bolus oral administration of a florfenicol
granule formulation according to the invention in fasted and
non-fasted pigs (average weight 20-35 kgs) was compared to the
effect of a bolus intravenous administration of an injectable
florfenicol formulation in the same animals. In both cases, the
dosage used was 15 mg/kg.
[0097] The comparative formulation used for intravenous
administration was Nuflor.RTM., a commercially available injectable
preparation with a drug concentration of 300 mg/ml.
[0098] The granule formulation used for oral administration was
prepared according to the procedure of examples 2 and 3, except
that the florfenicol content was 20% by weight of the formulation
and the maltodextrin content was reduced accordingly.
[0099] Blood samples were taken from pigs at the following times
after administration: 0.33 h, 0.66 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6
h, 8 h, 12 h, 24 h and 30 hours, respectively. Plasma analysis was
performed by high performance liquid chromatography (HPLC) with UV
detection with chloramphenicol as internal standard.
[0100] Results of mean plasma florfenicol concentrations (expressed
in .mu.g/ml) in pigs as a function of time are shown in FIG. 6.
EXAMPLE 9
Plasma Florfenicol Concentrations in Chickens after Continuous
Administration of Granules, as Compared to Pellets. Together with
Drinking Water
[0101] The effect of a continuous oral administration, together
with drinking water, of florfenicol solid formulations in broiler
chickens (average weight 1.2-1.6 kg) was investigated. Comparison
was made between the granule florfenicol formulation of example 7
(this invention) and the pellet florfenicol formulation of example
6 (i.e. according to U.S. Pat. No. 6,368,634), both having a
florfenicol content of 20% by weight, in the same animals. In both
cases, the dosage used was 30 mg florfenicol per kg of the animal,
or 140 mg/L in drinking water, and administration was continued for
2 days.
[0102] Blood samples were taken from broilers at regular intervals,
4 times daily, after administration of said formulations. Plasma
analysis was performed by high performance liquid chromatography
(HPLC) with UV detection with chloramphenicol as internal
standard.
[0103] Results of mean plasma florfenicol concentrations (expressed
in .mu.g/ml) in broiler chickens as a function of time are
presented in the following table and shown in FIG. 7 (wherein WO
94/23700 corresponds to U.S. Pat. No. 6,368,634, and PCT/BE03/00040
refers to this invention). It is quite surprising that the mean
plasma concentration of florfenicol in chickens was continuously
more then 2.3 times higher with the granule formulation of this
invention than with the pellet formulation of the prior art, over
the whole 48 hours period of the study. It is more particularly
surprising that the mean plasma concentration of florfenicol ion
chickens remained more than 9 times higher with the granule
formulation of this invention than with the pellet formulation of
the prior art over the 12 hours period following the first day
administration, and remained more than 4.4 times higher with the
granule formulation of this invention than with the pellet
formulation of the prior art over the 12 hours period following the
second day administration. These facts are indicative of a
significantly much more efficient treatment, at the same dosage,
with this invention than according to the prior art
formulation.
4TABLE Pellets (U.S. Pat. No. Granules Time (hours) 6,368,634)
(PCT/BE03/00040) 4 0.11 1.18 8 0.09 1.41 12 0.15 1.38 24 0.38 1.36
28 0.19 1.23 32 0.22 0.98 36 0.28 1.23 48 0.52 1.23 50 0.17
1.46
* * * * *