U.S. patent application number 14/282720 was filed with the patent office on 2014-10-16 for flurbiprofen and muscle relaxant combinations.
This patent application is currently assigned to Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi. The applicant listed for this patent is Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi. Invention is credited to Umit Cifter, Ali Turkyilmaz, Hasan Ali Turp.
Application Number | 20140308348 14/282720 |
Document ID | / |
Family ID | 39032103 |
Filed Date | 2014-10-16 |
United States Patent
Application |
20140308348 |
Kind Code |
A1 |
Cifter; Umit ; et
al. |
October 16, 2014 |
FLURBIPROFEN AND MUSCLE RELAXANT COMBINATIONS
Abstract
This invention is a novel pharmaceutical composition comprising
flurbiprofen or a pharmaceutically acceptable salt thereof in
combination with an .alpha.-2 adrenergic receptor agonist or a
gamma-aminobutiric acid receptor agonist with anti-inflammatory,
analgesic and myorelaxant activity.
Inventors: |
Cifter; Umit; (Istanbul,
TR) ; Turkyilmaz; Ali; (Istanbul, TR) ; Turp;
Hasan Ali; (Istanbul, TR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi |
Istanbul |
|
TR |
|
|
Assignee: |
Sanovel Ilac Sanayi Ve Ticaret
Anonim Sirketi
Istanbul
TR
|
Family ID: |
39032103 |
Appl. No.: |
14/282720 |
Filed: |
May 20, 2014 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
12117378 |
May 8, 2008 |
8778391 |
|
|
14282720 |
|
|
|
|
Current U.S.
Class: |
424/464 ; 514/33;
514/361 |
Current CPC
Class: |
A61K 45/06 20130101;
A61K 31/192 20130101; A61P 21/02 20180101; A61K 31/704 20130101;
A61K 31/192 20130101; A61K 2300/00 20130101; A61K 31/433 20130101;
A61K 9/2018 20130101; A61K 9/209 20130101 |
Class at
Publication: |
424/464 ;
514/361; 514/33 |
International
Class: |
A61K 31/192 20060101
A61K031/192; A61K 31/704 20060101 A61K031/704; A61K 9/24 20060101
A61K009/24; A61K 31/433 20060101 A61K031/433 |
Foreign Application Data
Date |
Code |
Application Number |
May 8, 2007 |
TR |
2007/03092 |
Claims
1. A pharmaceutical composition comprising flurbiprofen or a
pharmaceutically acceptable salt thereof in combination with an
.alpha.-2 adrenergic receptor agonist selected from tizanidine,
clonidine, brimonidine, apraclonidine, guanfacine, guanabenz,
mivazerol, dexmedetomidine and a pharmaceutically acceptable salt
thereof, or a GABA receptor agonist selected from thiocolchicoside,
musimol, and a pharmaceutically acceptable salt thereof
2. The pharmaceutical composition of claim 1, wherein the
flurbiprofen or pharmaceutically acceptable salt thereof is present
in an amount of between 100 and 500 mg.
3. The pharmaceutical composition of claim 1, wherein the .alpha.-2
adrenergic receptor agonist is present in an amount of between 2
and 36 mg.
4. The pharmaceutical composition of claim 1, wherein the GABA
receptor agonist is present in an amount of between 2 and 20
mg.
5. The pharmaceutical composition according to claim 1, wherein the
flurbiprofen or pharmaceutically acceptable salt thereof and the
.alpha.-2 adrenergic receptor agonist or GABA receptor agonist are
combined together with at least one pharmaceutically acceptable
carrier or excipient.
6. The pharmaceutical composition according to claim 5, wherein the
at least one pharmaceutically acceptable carrier or excipient is
selected from water, salt solutions, alcohols, gum arable,
vegetable oils, benzyl alcohols, polyethylene glycols, gelatin,
carbohydrates, lactose, amylose, starch, magnesium stearate, talc,
silicic acid, paraffin, perfume oil, fatty acid esters,
hydroxymethylcellulose, polyvinyl pyrrolidone, lubricants,
preservatives, disintegrants, stabilizers, wetting agents,
emulsifiers, salts, buffers, coloring agents, flavoring agents,
aromatic substances and sweetener.
7. The pharmaceutical composition according to claim 5, wherein the
at least one pharmaceutically acceptable excipient is selected from
gelatin, carbohydrates, lactose, amylose, starch, magnesium
stearate, talc, silicic acid, paraffin, perfume oil, fatty acid
esters, hydroxymethylcellulose, polyvinyl pyrrolidone, lubricants,
preservatives, disintegrants, stabilizers, wetting agents,
emulsifiers, salts, buffers, coloring agents, flavoring agents,
aromatic substances and sweetener.
8. The pharmaceutical composition according to claim 1, wherein
said pharmaceutical composition is administered orally,
parenterally, intramuscularly or topically.
9. The pharmaceutical composition according to claim 1, wherein
said pharmaceutical composition is in the form of a tablet,
capsule, sachet, injectable preparation, suspension, syrup, gel,
cream or ointment.
10. A method of treating painful muscle spasms associated with
static and functional disorders of vertebra or occurred in
post-operations of osteoarthritis, pain and inflammatory symptoms
associated with tissue trauma, degenerative vertebra diseases as
torticollis, dorsalgy, lombalgy, disk hernia, or neurologic and
traumatic disorders associated with spasticity, composing the step
of administering a therapeutically-effective amount of the
pharmaceutical composition of claim 1 to the patient in need
thereof.
11. The pharmaceutical composition of claim 1, wherein the
pharmaceutical composition is a solid dosage form provided in the
form of a bilayer tablet.
12. The solid dosage form according to claim 11, wherein the solid
dosage form takes the form of a bilayer tablet having flurbiprofen
or pharmaceutically acceptable salt thereof in one layer and the
.alpha.-2 adrenergic receptor agonist or GABA receptor agonist in
another layer.
13. The solid dosage form according to claim 12, having
flurbiprofen or pharmaceutically acceptable salt thereof in one
layer and the .alpha.-2 adrenergic receptor agonist in another
layer.
14. The solid dosage form according to claim 12, having
flurbiprofen or pharmaceutically acceptable salt thereof in one
layer and the GABA receptor agonist in another layer.
15. The method according to claim 10, wherein said pharmaceutical
composition is administered orally, parenterally, intramuscularly
or topically.
16. The method according to claim 10, wherein said pharmaceutical
composition is in the form of a tablet, capsule, sachet, injectable
preparation, suspension, syrup, gel, cream or ointment.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation of U.S. patent application Ser. No.
12/117,378, filed on May 8, 2008, which claims priority to Turkish
Patent Application No. TR 2007/03092 filed May 8, 2007, the
disclosures of the application, Ser. No. 12/117,378, are
incorporated herein by reference.
TECHNICAL ASPECT
[0002] This invention is a novel pharmaceutical composition
comprising flurbiprofen or a pharmaceutically acceptable salt
thereof in combination with an .alpha.-2 adrenergic receptor
agonist or a gamma-aminobutyric acid receptor agonist with
anti-inflammatory, analgesic and myorelaxant activity.
[0003] More specifically, this invention relates to pharmaceutical
composition comprising flurbiprofen or a pharmaceutically
acceptable salt thereof in combination with tizanidine or
thiocolchicoside with anti-inflammatory, analgesic and myorelaxant
activity administrated oral, parenteral, intramuscular and topical
in tablet, capsule, injectable preparation, suspension, syrup,
sachet, ointment, cream or gel form.
BACKGROUND OF THE INVENTION
[0004] Flurbiprofen is a propionic acid derivative and is a known
NSAID (non-steroidal anti-inflammatory drug) with analgesic and
anti-inflammatory activity. Its chemical structure is shown in the
Formula 1.
##STR00001##
[0005] The chemical name of flurbiprofen is
2-Fluoro-.alpha.-methyl-[1,1'-biphenyl]-4-acetic acid. It is used
in musculoskeletal and joint disorders such as ankylosing
spondylitis, osteoarthritis and rheumatoid arthritis, in
soft-tissue disorders such as sprains and strains, for
postoperative pain and mild to moderate pain including dysmenorrhea
and migraine.
[0006] Flurbiprofen is also used as lozenges in the symptomatic
relief of sore throat. Flurbiprofen sodium is used in eye drops to
inhibit intra-operative miosis and to control postoperative
inflammation of the anterior segment of the eye. Flurbiprofen
axetil has been given in some countries by intravenous injection
for severe pain.
[0007] For pain and inflammation, flurbiprofen is given in usual
doses of 150 mg to 200 mg daily by mouth in divided doses,
increased to 300 mg daily in acute or severe conditions if
necessary (Sean C Sweetman, Martindale The Complete Drug Reference,
thirty-fifth edition 2007, Vol. 1, pages 52 to 53).
[0008] Muscle relaxants are used in the management of
musculoskeletal and neuromuscular disorders. There are two main
types; centrally acting relaxants and directly acting
relaxants.
[0009] Centrally acting relaxants generally have a selective action
on the central nervous system (CNS) and are principally used for
relieving painful muscle spasms or spasticity occurring in
musculoskeletal and neuromuscular disorders. Their mechanism of
action may be due to their CNS-depressant activity.
[0010] Tizanidine is an example for this group of muscle relaxants.
Its chemical structure is shown in Formula 2.
##STR00002##
[0011] Tizanidine is a .alpha..sub.2-adrenergic agonist and acts
mainly at spinal and supraspinal levels to inhibit excitatory
interneurones. It is used for the symptomatic relief of spasticity
associated with multiple sclerosis or with spinal cord injury or
disease. It is also used in the symptomatic treatment of painful
muscle spasm associated with musculoskeletal conditions (Sean C
Sweetman, Martindale The Complete Drug Reference, thirty-fifth
edition 2007, Vol. 1, page 1727).
[0012] Muscle relaxants also reduce muscle tone and are used in
therapy for the treatment of muscle spasm and contractures.
[0013] Muscle spasm is one of the main factors responsible for
chronic pain; it characterises several pathologies of the locomotor
apparatus as well as inflammatory-rheumatic and degenerative
orthopaedic pathologies; when it affects joints, they cause not
only pain, but also rigidity, which reduces joint mobility and
flexibility in the affected part. Muscle contractures also
characterize several pathologies of the locomotor apparatus and are
one of the main factors responsible for the persistence of the pain
associated to these pathologies.
[0014] For these reasons the study of molecules endowed with muscle
relaxant and antispasmodic properties still raises remarkable
interest from the clinical point of view.
[0015] As it is known, colchicine is a pseudoalkaloid that has been
widely used for a long time in therapy for the treatment of gout.
The use of 3-demethyl-thiocolchicine glucoside, known as
thiocolchicoside, is also widespread in therapy for treating
contractures and inflammatory conditions that affect the muscular
system (Ortopedia e traumatologia Oggi XII, n. 4, 1992).
[0016] Thiocolchicoside, has been claimed to possess GABA-mimetic
and glycinergic actions, in other way we can say that
thiocolchicoside is a gamma-aminobutiric acid receptor agonist. Its
chemical structure is shown in Formula 3.
##STR00003##
[0017] It has recently been shown that thiocolchicoside's activity
can be ascribed to its ability of interacting with the
strychnine-sensitive glycine receptors and therefore that compounds
endowed with glycin-mimetic activity can be used in the
rheumatologic-orthopedic field for their muscle relaxant
properties.
[0018] The usual initial dose is 16 mg daily by mouth. It has also
been given intramuscularly, in doses up to 8 mg daily, or applied
as cream or ointment (Sean C Sweetman, Martindale The Complete Drug
Reference, thirty-fifth edition 2007, Vol. 1, page 1738).
[0019] Muscle relaxants have been evaluated alone or in combination
with conventional analgesics for the treatment of pain. Mixed and
unpredictable results have been obtained in a pharmaceutical
composition. But flurbiprofen has not previously been combined with
an .alpha.-2 adrenergic receptor agonist or a gamma-aminobutiric
acid receptor agonist in a pharmaceutical composition for the
treatment of inflammatory, pain and musculoskeletal diseases.
[0020] Tizanidine and/or Thiocolchicoside is a known muscle
relaxant agents and sequentially they belong to the groups of
.alpha.-2 adrenergic receptor agonists and a gamma-aminobutiric
acid receptor agonists used in the treatment of painful muscle
spasms or spasticity occurring in musculoskeletal and neuromuscular
disorders and for treating contractures and inflammatory conditions
that affect the muscular system.
[0021] PCT application WO 86/03681 A1 (26 Dec. 1984), relates
generally to novel pharmaceutical compositions of matter comprising
one or more non-steroidal anti-inflammatory drugs other than
aspirin, acetaminophen and phenacetin, in combination with at least
one skeletal muscle relaxant, and optionally xanthine or a xanthine
derivative, such as caffeine, and to methods of using said
compositions in the treatment of a variety of skeletal muscle
disorders including skeletal muscle spasm, certain orthopedic
conditions, disk syndromes, low back pain and the like.
[0022] United Kingdom patent application GB 2 197 198 A1 (Sandoz
Ltd.) 3 Nov. 1986, describes to novel pharmaceutical preparations
comprising ibuprofen and tizanidine with analgesic and myotonolytic
activity as well as to methods of inducing analgesia and of
treating conditions associated with increased muscle tone. The
composition is preferably formulated as a tablet and desirably the
weight ratio of tizanidine to ibuprofen is from 1:50 to 1:200,
especially 1:100.
[0023] French patent FR 2 725 134 B1 (LABORATOIRES LEDERLE) 4 Oct.
1994, relates to a new pharmaceutical composition comprising
ibuprofen or a pharmaceutically acceptable salt thereof and
thiocolchicoside or a pharmaceutically acceptable salt thereof in a
ratio generally ranging between approximately 1:50 and
approximately 1:200. According to this invention, the
pharmaceutical composition is used in the treatment of the painful
muscle syndromes and more particularly in the treatment of the
acute lumbagos.
[0024] European patent EP 0 837 684 B1 (Sanofi-Synthelabo) 13 Jun.
1995, relates to pharmaceutical compositions containing, in solid
form, a diclofenac salt and thiocolchicoside combined with at least
one pharmaceutically acceptable carrier are provided for use in
therapy.
[0025] PCT application WO 98/52545 A1 (THE BOOTS COMPANY PLC) 22
May 1997, relates to pharmaceutical compositions comprising a
combination of flurbiprofen with a therapeutically effective amount
of one or more active ingredients selected from an antihistamine, a
cough suppressant, a decongestant, an expectorant, a muscle
relaxant, a centrally acting analgesic, a local anaesthetic, an
antibacterial compound, an antiviral compound, an antibiotic
compound, an antifungal compound, minerals and vitamins and/or a
burn-masking amount of an agent which has a warming effect on the
mucosa of the throat.
[0026] Also in this application, the treatment comprises the
administration to a patient in need thereof of a pharmaceutical
composition in the form of a masticable or suckable solid dosage
form or a liquid or spray which releases the flurbiprofen and
active ingredient(s) and/or burn-masking agent in the oral cavity
so as to deliver the active components to the surface of the sore
throat.
[0027] It is well known that drugs used in the same therapeutic
area or even for treating the same indication cannot always be
combined a priori with the expectation of at least additive
therapeutic effects. The scientific literature is full of examples
wherein compounds of different classes, which are used to treat the
same indications, cannot be combined into safe and efficacious
dosage forms thereby resulting in incompatible drug combinations.
The reasons for this unexpected lack of compatibility are varied;
however, it is often found that the incompatible drug combinations
result in increased side effects, unwanted drug interactions or new
side effects. More specifically, in the area of analgesia there are
drug combinations that are contraindicated for some or all of these
very same reasons.
[0028] Conventional analgesic and myorelaxant therapy generally
involves administration of a pharmaceutical composition containing
one or more different analgesic and muscle relaxant drugs. However,
not all combinations of analgesic drugs and muscle relaxant drugs
are more suitable, in terms of safety or efficacy, than the
administration of a single product.
[0029] To date no pharmaceutical compositions or dosage forms
comprising a combination of a flurbiprofen and a .alpha.-2
adrenergic receptor agonist or a gamma-aminobutiric acid receptor
agonist in particular tizanidine or thiocoichicoside, have been
made.
DEFINITION OF THE INVENTION
[0030] This invention is a pharmaceutical composition comprising
flurbiprofen or a pharmaceutically acceptable salt thereof in
combination with .alpha.-2 adrenergic receptor agonist or a
gamma-aminobutyric acid receptor agonist with anti-inflammatory,
analgesic and myorelaxant activity administrated oral, parenteral,
intramuscular and topical in tablet, capsule, injectable
preparation, suspension, syrup, sachet, ointment, cream or gel
form.
[0031] Novel pharmaceutical composition in the form of a tablet or
a capsule administrated orally may provide a significant advance in
the available treatments. Such combination therapy may also provide
for therapeutic improvements owing to the potential synergistic
effect provided by the combination.
[0032] Therefore, further aspects of the present invention concern
the use of pharmaceutical composition comprising flurbiprofen in
combination with .alpha.-2 adrenergic receptor agonist or a
gamma-aminobutyric acid receptor agonist in particular tizanidine
or thiocolchicoside for the manufacture of a medicament for the
treatment of painful muscle spasms associated with static and
functional disorders of vertebra or occurred in post-operations of
osteoarthritis, pain and inflammatory symptoms associated with
tissue trauma, degenerative vertebra diseases as torticollis,
dorsalgy, lombalgy, disk hernia, neurologic and traumatic disorders
associated with spasticity.
[0033] The main challenges when combining two or more molecules in
the same pharmaceutical form are (a) to guarantee the
chemico-physical compatibility between the different active
ingredients and/or between the active ingredients and the
excipients used; and (b) to insure the therapeutical compatibility
between the two active ingredients regarding their pharmacokinetic
and/or pharmaceutical properties in order that the posology of the
combined composition allows to obtain safe and efficient plasma
levels of both pharmacological agents.
[0034] According to main challenges mentioned above, the
pharmaceutical composition comprising flurbiprofen in combination
with an .alpha.-2 adrenergic receptor agonist or a
gamma-aminobutyric acid receptor agonist in particular tizanidine
or thiocolchicoside have an additive analgesic effect in relief of
postoperative pain and provide greater analgesia with the results
in a lower incidence of side effects according to priori. These
pharmaceutical combinations are administrated oral, parenteral,
intramuscular and topical.
[0035] The pharmaceutical compositions of the invention include
tablets, capsules, injectables, suspensions, syrups, sachets,
ointments, creams and gels can be made in accordance with methods
that are standard in the art (see, e.g. Remington's Pharmaceutical
Sciences, 16.sup.th edition, A Oslo editor, Easton, Pa. (1980)).
Drugs and drug combinations will typically be prepared in admixture
with conventional excipients. Suitable carriers include, but are
not limited to: water; salt solutions; alcohols; gum arable;
vegetable oils; benzyl alcohols; polyethylene glycols; gelatin;
carbohydrates such as lactose, amylose or starch; magnesium
stearate; talc; silicic acid; paraffin; perfume oil; fatty acid
esters; hydroxymethylcellulose; polyvinyl pyrrolidone; etc. The
pharmaceutical preparations can be sterilized and, if desired,
mixed with auxiliary agents such as: lubricants, preservatives,
disintegrants; stabilizers; wetting agents; emulsifiers; salts;
buffers; coloring agents; flavoring agents; aromatic substances or
sweeteners.
[0036] A flurbiprofen and tizanidine or thiocolchicoside
composition of the present invention is typically administered in
admixture with suitable pharmaceutical diluents, excipients, or
carriers, suitably selected with respect to a dosage form for oral
administration. Examples of oral dosage forms include tablets
(including compressed, coated or uncoated), capsules, hard or soft
gelatin capsules, pellets, pills, powders, granules, elixirs,
tinctures, colloidal dispersions, dispersions, effervescent
compositions, films, sterile solutions or suspensions, syrups and
emulsions and the like.
[0037] Preferably, the combination of a flurbiprofen with
tizanidine or thiocolchicoside will be in the form of a
conventional tablet. And it may be granulated by methods such as,
dry granulation, low- or high-shear granulation, wet granulation or
fluidized-bed granulation. Low-shear granulation, high-shear
granulation, wet granulation and fluidized-bed granulation
generally produce harder, less friable tablets.
[0038] This invention is a pharmaceutical composition, wherein the
flurbiprofen or a pharmaceutically acceptable salt with an
.alpha.-2 adrenergic receptor agonist or a gamma-aminobutyric acid
receptor agonist are combined together with at least one
pharmaceutically acceptable carrier or excipient
[0039] As mentioned above, this invention comprising in combination
of flurbiprofen with tizanidine or thiocolchicoside or
pharmaceutically acceptable salt thereof comprising an effective
amount of fillers, excipients, binding agents, disintegrants and
lubricants or their mixtures. Said invention describes a
pharmaceutical combination comprising an effective amount of
fillers selected from the group consisting of starch, lactose,
microcrystalline cellulose, carboxy cellulose sodium, sucrose; an
effective amount of binding agents selected from the group
consisting of povidone, hydroxypropyl cellulose, hydroxypropyl
methyl cellulose, starch, gelatin; an effective amount of
lubricants selected from the group consisting of colloidal
anhydrous silica, magnesium stearate, talc, sodium stearyl
fumarate; an effective amount of disintegrants selected from the
group consisting of microcrystalline cellulose, sodium starch
glycollate, croscarmellose sodium, crospovidone, starch and their
mixtures
[0040] An .alpha.-2 adrenergic receptor agonist, suitable for use
in the context of the present invention is selected from the group
comprising tizanidine, clonidine, brimonidine, apraclonidine,
guanfacine, guanabenz, mivazerol, dexmedetomidine or a
pharmaceutically acceptable salt thereof. Preferably, .alpha.-2
adrenergic receptor agonist is a tizanidine or a pharmaceutically
acceptable salt thereof.
[0041] As mentioned above, this invention comprising active
ingredient, flurbiprofen or a pharmaceutically acceptable salt
thereof in combination with tizanidine wherein the flurbiprofen is
present in an amount of between 100 and 500 mg and the tizanidine
is present in an amount of 2 and 36 mg, preferred embodiments an
amount of the flurbiprofen is between 100 and 300 mg and the
tizanidine is between 6 and 24 mg.
[0042] This invention is further defined by reference to the
following examples. Although the examples are not intended to limit
the scope of the present invention, it should be considered in the
light of the description detailed above.
EXAMPLE 1
[0043] Flurbiprofen and tizanidine conventional released granules
are granulated with high shear granulator or they are obtained from
extruder to become pellets by spheronizer and at last they are
sieved and dried by fluid bed U.
TABLE-US-00001 Content % amount (w/w) Flurbiprofen 13.0-39.0
Tizanidine HCl 0.65-1.95 Lactose 28.0-84.0 Microcrystalline
cellulose 5.00-15.0 Croscarmellose sodium 1.25-3.75 Hydroxypropyl
cellulose 1.50-4.50 Colloidal silica 0.10-0.30 Magnesium stearate
0.50-1.50 Colloidal cilica 0.10-0.30 Magnesium stearate
0.50-1.50
[0044] The granules mentioned above compressed by tablet press
machine to obtain conventional tablet forms and these tablets
preferably covered by a coating material including conventional
coating polymers like Opadry.RTM..
[0045] In other preferred embodiments, these granules are filled in
a capsule by capsule filling machine to obtain conventional capsule
forms in appropriate length.
EXAMPLE 2
[0046] Flurbiprofen and tizanidine conventional released granules
are granulated with high shear granulator or they are obtained from
extruder to become pellets by spheronizer and at last they are
sieved and dried by fluid bed dryer.
TABLE-US-00002 Content % amount (w/w) Flurbiprofen 13.0-39.0
Tizanidine HCl 1.15-3.45 Lactose 27.5-82.5 Microcrystalline
cellulose 5.00-15.0 Croscarmellose sodium 1.25-3.75 Hydroxypropyl
cellulose 1.50-4.50 Colloidal silica 0.10-0.30 Magnesium stearate
0.50-1.50
[0047] The granules mentioned above compressed by tablet press
machine to obtain conventional tablet forms and these tablets
preferably covered by a coating material including conventional
coating polymers like Opadry.RTM..
[0048] In other preferred embodiments, these granules are filled in
a capsule by capsule filling machine to obtain conventional capsule
forms in appropriate length.
[0049] Gamma-aminobutyric acid receptor agonists suitable for use
in the context of the present invention are selected from the group
comprising thiocolchicoside and musimol or a pharmaceutically
acceptable salt thereof. Preferably, the gamma-aminobutyric acid
receptor agonist is a thiocolchicoside or a pharmaceutically
acceptable salt thereof.
[0050] As mentioned above, this invention comprising active
ingredient, flurbiprofen or a pharmaceutically acceptable salt
thereof in combination with thiocolchicoside wherein the
flurbiprofen is present in an amount of between 100 and 500 mg and
the thiocolchicoside is present in an amount of 2 and 20 mg,
preferred embodiments an amount of the flurbiprofen is between 100
and 300 mg and the thiocolchicoside is between 4 and 16 mg.
[0051] The invention is further defined by reference to the
following example. Although the example is not intended to limit
the scope of the present invention, it should be considered in the
light of the description detailed above.
EXAMPLE 3
[0052] Flurbiprofen and thiocoichicoside conventional released
granules are granulated with high shear granulator or they are
obtained from extruder to become pellets by spheronizer and at last
they are sieved and dried by fluid bed dryer.
TABLE-US-00003 Content % amount (w/w) Flurbiprofen 15.0-45.0
Thiocolchicoside 0.75-2.25 Lactose 20.0-60.0 Microcrystalline
cellulose 10.0-30.0 Croscarmellose sodium 1.50-4.50 Hydroxypropyl
cellulose 2.00-6.00 Colloidal silica 0.50-1.50 Magnesium stearate
0.25-0.75 Magnesium stearate 0.25-0.75
[0053] The granules mentioned above compressed by tablet press
machine to obtain conventional tablet forms and these tablets
preferably covered by a coating material including conventional
coating polymers like Opadry.RTM..
[0054] In other preferred embodiments, these granules are filled in
a capsule by capsule filling machine to obtain conventional capsule
forms in appropriate length.
[0055] In other preferred embodiments of this invention, the solid
dosage form is a bilayer tablet having the flurbiprofen in one
layer and an .alpha.-2 adrenergic receptor agonist or a
gamma-aminobutyric acid receptor agonist particular tizanidine or
thiocolchicoside in another layer. The amount of flurbiprofen
employed in such bilayer tablets preferably ranges from 100 mg to
500 mg, and more preferably is 100 mg to 300 mg. The amount of
tizanidine employed in such bilayer tablets preferably ranges from
2 mg to 36 mg, and more preferably is 6 mg or 24 mg. The amount of
thiocolchicoside employed in such bilayer tablets preferably ranges
from 2 mg to 20 mg and more preferably is 4 mg or 16 mg.
[0056] This invention is further defined by reference to the
following example. Although the example is not intended to limit
the scope of the present invention, it should be considered in the
light of the description detailed above.
EXAMPLE 4
Flurbiprofen Granules
[0057] Flurbiprofen granules are granulated with high shear
granulator or they are obtained from extruder to become pellets by
spheronizer and at last they are sieved and dried by fluid bed
dryer.
TABLE-US-00004 Content % amount (w/w) Flurbiprofen 17.5-52.5
Lactose 20.0-60.0 Microcrystalline cellulose 9.00-27.0
Croscarmellose sodium 1.25-3.75 Hydroxypropyl cellulose 1.75-5.25
Colloidal silica 0.25-0.75 Magnesium stearate 0.25-0.75
Thiocolchicoside Granules
[0058] Thiocolchicoside granules are granulated with high shear
granulator or they are obtained from extruder to become pellets by
spheronizer and at last they are sieved and dried by fluid bed
dryer.
TABLE-US-00005 Content % amount (w/w) Thiocolchicoside 1.25-3.75
Lactose 37.5-112.5 Starch 7.50-22.5 Gelatin 0.75-2.25 Sucrose
1.50-4.50 Talc 1.00-3.00 Magnesium stearate 0.50-1.50
[0059] The solid dosage form mentioned above is a bilayer tablet
having the flurbiprofen granules in one layer and thiocolchicoside
granules in second layer. These granules are compressed by 2
layered tablet press machine to obtain bilayer tablet forms and
these bilayer tablets preferably covered by a coating material
including conventional coating polymers like Opadry II
(HP).RTM..
* * * * *