Pharmaceutical composition for treating pain comprising pamecoxib and pregabalin
阅读说明：本技术 包含帕马考昔及普瑞巴林的用于治疗疼痛的药剂学组合物 (Pharmaceutical composition for treating pain comprising pamecoxib and pregabalin ) 是由 曹在平 曹重明 于 2019-03-20 设计创作，主要内容包括：本发明涉及包含帕马考昔及普瑞巴林的复合制剂。本发明涉及帕马考昔及普瑞巴林两种活性成分的药学组合物及药剂或镇痛剂,更具体而言,涉及作为用于治疗因炎症性及多种因素引起的中度急性、慢性或神经病性疼痛的药剂或镇痛剂的效果及用途。(The invention relates to a compound preparation containing pamecoxib and pregabalin. The present invention relates to a pharmaceutical composition of two active ingredients, namely, pamecoxib and pregabalin, and a pharmaceutical agent or analgesic, and more particularly, to the effect and use of the pharmaceutical composition or the analgesic as a pharmaceutical agent or an analgesic for treating moderate acute, chronic or neuropathic pain caused by inflammation and various factors.)
1. A pharmaceutical composition for treating pain, wherein,
comprises palmicoxib and pregabalin.
2. The pharmaceutical composition of claim 1, wherein,
the composition is used for treating acute or chronic pain induced by inflammation or nervous disorders.
3. The pharmaceutical composition of claim 1, wherein,
the composition is indicated for neurogenic pain including diabetic neuropathy, pain due to generalized anxiety disorder, fibromyalgia, hyperalgesia, abnormal pain sensation, cancer pain, osteoarthritis, rheumatoid arthritis, spondylitis, frozen shoulder, lumbago or sciatica.
4. The pharmaceutical composition of claim 1, wherein,
the ratio of pamacyclovir to pregabalin is from 1 to 300:1 to 600 by weight.
5. The pharmaceutical composition of claim 1, wherein,
the ratio of the pamacyclovir to the pregabalin is 1:1 to 1:300 by weight.
6. The pharmaceutical composition of claim 1, wherein,
the ratio of pamacyclovir to pregabalin is from 2:1 to 2:300 by weight.
7. The pharmaceutical composition of claim 1, wherein,
Relative to the total weight of the composition, the composition comprises 0.1 to 10 weight percent of palmicoxib and 10 to 50 weight percent of pregabalin.
8. The pharmaceutical composition of claim 1, wherein,
further comprises pharmaceutically acceptable excipient.
9. The pharmaceutical composition of claim 8,
the excipient comprises more than one selected from the group consisting of ethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, polyethylene oxide, carbomer, sodium alginate, mannitol, croscarmellose sodium, sodium bicarbonate and magnesium stearate.
10. The pharmaceutical composition of claim 1, wherein,
in the form of tablets, capsules or suspensions.
11. The pharmaceutical composition of claim 11, wherein,
in the form of a tablet, capsule or suspension mixed with the pamecoxib and the pregabalin, wherein the tablet comprises a double-layer tablet, a multi-layer tablet or a single tablet.
12. The pharmaceutical composition of claim 1, wherein,
a bilayer sheet having a bilayer structure or a multilayer sheet having a multilayer structure, which is divided into different layers by a region of pamecoxib, pregabalin or a mixture thereof.
13. The pharmaceutical composition of claim 1, wherein,
is divided into a slow release layer and a quick release layer.
14. The pharmaceutical composition of claim 13, wherein,
the sustained-release layer comprises pregabalin and the quick-release layer comprises pamacoside.
15. The pharmaceutical composition of claim 1, wherein,
also comprises a pharmaceutically acceptable coating base.
16. The pharmaceutical composition of claim 1, wherein,
further comprises a pharmaceutically acceptable carrier.
Technical Field
The present invention relates to a composition comprising pamaxib (polacoxib) and pregabalin (pregabalin), and more particularly, to a pharmaceutical composition for treating pain comprising pamaxib and pregabalin, wherein the pamaxib can be usefully used as a non-steroidal anti-inflammatory agent having excellent stability and exhibiting excellent effects at a low content, and the pregabalin is a broad-spectrum anticonvulsant agent for neuropathological pain treatment.
Background
Pain is defined as an unpleasant sensory or emotional experience associated with or described as actual or potential tissue damage. It also refers to pain and sensory disorders caused by stimulating the areas of the cerebral cortex and the limbic system by the nerve pathways composed of pain receptors and nerve fibers. As a defense means for protecting the body, it can be said that an abnormal warning reaction is transmitted inside or outside the body. Pain itself is not a disease and, even if eliminated, is not a cure-causing disease.
The causes are roughly classified into sensory pain caused by injury or inflammation of body tissues or visceral tissues and neuropathic pain occurring after nerve injury. The sensory pain may be, for example, skin pain, visceral pain, somatic pain, perceptual neuralgia, pain related to nerve root, pain related to body, etc., and the neuropathic pain is pain caused by dysfunction of peripheral nerve or central nerve. In the case of prolonged pain or excessive stimulation, it can interfere with daily living and even lead to anxiety and fear. Thus, people suffering from chronic pain often suffer from depression, and this property is also considered in the treatment.
The compound of pregabalin is named as (S) - (+) -3- (aminomethyl) -5-methyl-hexanoic acid ((S) - (+) -3- (aminomethyl) -5-methyl-hexanoic acid) and has the structure of the following chemical formula 1.
[ chemical formula 1]
It is known that pregabalin binds to alpha-2-delta (α 2) subunit (subbunit) of calcium channel, and thus calcium ion influx at the end of nerve cells is reduced, and secretion of various excitatory neurotransmitters including glutamate (glutamate) and norepinephrine (noradrenalin) is reduced, thereby restoring the function of nerve cells to a normal level. Pregabalin, an endogenous neurotransmitter associated with the regulation of brain neuronal activity, is an analog of gamma-aminobutyric acid (G ABA) associated with neural processing.
Pregabalin has been demonstrated to activate L-glutamate decarboxylase (GA D), has a dose-dependent protective effect on seizures, and is a Central Nervous System (CNS) active compound. In addition, pregabalin may be usefully used in anticonvulsant therapy due to activation of GAD because it causes inhibitory postsynaptic potential as an amino acid neurotransmitter that primarily inhibits gamma-aminobutyric acid (G ABA), one of neurotransmitters, by being released to the brain synapse (synapse) of 30% of the brain.
The pregabalin drug can be used for treating epilepsy, neuropathological pain (neuropathological gialpain), generalized anxiety disorder (generalized anxiety disorders), fibromyalgia, etc.
Among them, as causes that may induce neuropathological pain, diabetic polyneuropathy, postherpetic neuralgia, tumors, chemotherapy, trigeminal neuralgia, alcoholism, vitamin B deficiency, phantom pain, borrelia infection, complex site pain syndrome, carpal tunnel syndrome, lumbago, acquired immunodeficiency syndrome, and the like.
The pregabalin drug is white or light yellow crystalline powder and has the characteristic of being easily dissolved in water. The medicine has high absorption rate in vivo, maximum blood concentration in about 1.3 hr, and bioavailability of about 90%. In addition, most are excreted from the urethra through the kidneys with a half-life of about 5 to 6.5 hours. Pregabalin is absorbed by means of an L-amino acid transport system, and thus is not uniformly absorbed in the gastrointestinal tract, and is most absorbed in the upper part of the small intestine where L-amino acid transport carriers (L-amino acid transporters) are dense, and thus the average absorption period is 6 hours or less. For this reason, many pharmaceutical companies are now free from capsule type with low productivity, and tablet dosage forms such as pregabalin sustained release tablets, gastric retention tablets and the like are being developed.
Pamarelix is a drug currently sold under the name Acelex and has a structure shown in the following chemical formula 2.
[ chemical formula 2]
The compound of the active ingredient, which is the pamadecoxib, used in the pharmaceutical composition is named 5- (4- (aminosulfonyl) phenyl) -2, 2-dimethyl-4- (3-fluorophenyl) -3(2H) -furanone. As selective inhibitors of COX-2, gastrointestinal toxicity is lower than that of general NSAIDs, and they are known to be effective against inflammatory diseases, inflammation-related diseases, pain, solid cancers, angiogenesis-related diseases, alzheimer's disease, seizures and convulsions, stroke, epilepsy, and the like (korean patent No. 10-0495389).
COX-2 (cyclooxygenase) is responsible for the production of prostaglandins. Both isomers of C OX-1 and COX-2 (isoform) have been identified, and it has been shown that COX-2 is induced by pro-inflammatory stimuli and is an isomer of an enzyme believed to play a major role in the synthesis of prostaglandin (prostanoid) modulators associated with pain, inflammation and fever.
Attempts were made to treat pain by combining pamecoxib as a COX-2 inhibitor that exerts this effect with pregabalin.
The application focuses on the verification of a pharmaceutical composition that is a combination of pamicoxib and pregabalin that can achieve an additive effect on severe to moderate pain, in particular pain with inflammatory components.
Disclosure of Invention
Problems to be solved by the invention
The present inventors hoped that in order to further enhance the synergistic effect of the combination of pamacoxib (polacoxib) and pregabalin (pregabalin) on pain and the convenience of administration of the drug compared to the original product, two active ingredients different from each other were made into a single dosage form.
Means for solving the problems
The present invention provides a pharmaceutical composition for treating pain comprising pamecoxib and pregabalin.
According to one embodiment, the composition may be used for the treatment of acute or chronic pain induced by inflammatory or neurological conditions. In particular, neurogenic pain (neuropathic pain), pain due to generalized anxiety disorder (generalized anxiety disorder), fibromyalgia (fibromyalgia), hyperalgesia (hyperalgesia), allodynia (allodynia), cancer pain (cancer), osteoarthritis (osteoarthritis), rheumatoid arthritis (rhamatoid arthritis), spondylitis (sponditis), frozen shoulder (frozen shoulder), lumbago (lumbodynia), or sciatica (sciatic) including diabetic neuropathy may be used as an indication.
According to one embodiment, the ratio of pamacyclovir to pregabalin may be from 1:1 to 1:600 by weight.
In addition, the ratio of pamacyclovir to pregabalin may be from 1:1 to 300:1 by weight, and may have a ratio of from 2:1 to 2:300 by weight.
According to one embodiment, pamacoside may be included in an amount of 0.1 to 10% by weight and pregabalin in an amount of 10 to 50% by weight, relative to the total weight of the composition.
According to one embodiment, pharmaceutically acceptable excipients may be additionally included. Specifically, the excipient may include one or more selected from the group consisting of ethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, polyethylene oxide, carbomer, sodium alginate, mannitol, croscarmellose sodium, sodium bicarbonate, and magnesium stearate.
According to one embodiment, the composition may be provided in the form of a tablet, capsule or suspension. Specifically, the compound preparation can be in the form of a tablet, a capsule or a suspension mixed by the palomacoxib and the pregabalin, and the tablet can be in a form of a double-layer tablet, a multi-layer tablet or a single tablet.
In addition, it may be formed as a two-layer sheet of a two-layer structure or a multi-layer sheet of a multi-layer structure in which the pamecoxib, pregabalin, or a mixture thereof is divided into different layers.
According to one embodiment, a bilayer may be formed that is divided into a delayed release layer and an immediate release layer. Specifically, the sustained release layer may comprise pregabalin and the immediate release layer may comprise pamarelix.
According to one embodiment, a pharmaceutically acceptable coating base may be further included.
In addition, the composition can further comprise a pharmaceutically acceptable carrier.
Other details of embodiments of the invention are included in the detailed description below.
Effects of the invention
The pharmaceutical composition for treating pain according to the present invention comprising pamicoxib and pregabalin has respective drug release profiles similar to those of commercially available oral dosage forms of lereca capsule and Acelex tablet containing pregabalin. Specifically, by formulating pamicoxib and pregabalin as a single dosage form, the interaction of the individual drugs within the dosage form can be minimized, and 1 or 2 administrations per day can be complementary to each other to exert the respective drug effects sustainably.
The composition of the present invention has stability against external physical factors, is excellent in particle fluidity, can improve uniformity, and thus can be easily handled, and can improve productivity.
Drawings
FIG. 1 is a graph showing comparative dissolution profiles for palmicoxib of Experimental example 1.
Fig. 2 is a graph showing a comparative dissolution profile of pregabalin of experimental example 1.
FIG. 3 is a graph showing comparative dissolution profiles for palmicoxib of Experimental example 2.
Fig. 4 is a graph showing a comparative dissolution profile of pregabalin of experimental example 2.
FIG. 5 is a graph showing comparative dissolution profiles for pamicoxib of Experimental example 3.
FIG. 6 is a graph showing comparative dissolution profiles for pamicoxib of Experimental example 4.
FIGS. 7 and 8 are graphs showing comparative dissolution curves of Experimental example 5.
FIGS. 9 and 10 are graphs showing comparative dissolution profiles of Experimental example 6.
FIG. 11 is a graph showing a comparative dissolution profile of Experimental example 7.
FIG. 12 is a graph showing a comparative dissolution profile of Experimental example 8.
FIG. 13 is a graph showing a comparative dissolution profile of Experimental example 9.
FIG. 14 is a graph showing a comparative dissolution profile of Experimental example 10.
FIG. 15 is a graph showing a comparative dissolution profile of Experimental example 11.
Fig. 16 is a graph showing comparative dissolution curves of pregabalin of experimental example 11 and experimental example 12.
FIG. 17 is a graph showing comparative dissolution profiles for pamicoxib for Experimental example 12.
Detailed Description
While the invention is susceptible to various modifications and alternative forms, specific embodiments thereof are shown by way of example in the drawings and will herein be described in detail. However, the present invention is not limited to the specific embodiments, and all modifications, equivalents, and alternatives included in the spirit and technical scope of the present invention are understood to be included. In explaining the present invention, when it is judged that the detailed description of the related known art may obscure the gist of the present invention, the detailed description is omitted.
Pharmaceutical compositions of embodiments of the present invention are described in more detail below.
The term "pharmaceutical composition" as used herein may be used in combination with "pharmaceutical composition" and "pharmaceutically acceptable composition", and as a composition which can exert a relatively nontoxic and harmless effective action on a subject, it may mean any organic or inorganic compound dosage form which does not cause a decrease in the efficacy of a drug due to side effects caused by the composition, does not induce severe irritation to the subject to which the compound is administered, and does not impair the biological activity and physical properties of the compound.
The term "subject" used in the present invention may be used in combination with "subject" and "organism to be administered" and may mean all animals including human beings, which have induced or are likely to induce acute or chronic pain.
The present invention provides a pharmaceutical composition for treating pain comprising pamecoxib and pregabalin. The compound preparation of the pamicoxib and the pregabalin can show the effects of reducing the deformation of active ingredients and increasing the stability to time change when being mixed with other pharmaceutically acceptable additives.
According to one embodiment, the composition may be in liquid or solid form, and may be provided in any convenient form such as coated tablets, pills, granules, capsules, suspensions, emulsions or powder forms suitable for formulation with water or other suitable liquid medium. For example, the composition may be formed in the form of tablets, capsules, suspensions, and the like. For example, the dosage form may be prepared as a coated tablet, capsule or suspension of a blend of pamecoxib and pregabalin, which may include single, double or multiple layer coated tablets, which may include double layer tablets, multiple layer tablets or single tablet. In addition, for example, the composition can be formed into a capsule dosage form filled in the form of microparticles, granules, or pills.
Specifically, for example, pregabalin can be prepared in the form of a capsule dosage form that is less affected by external physical factors during the preparation process due to the characteristics of the raw materials. In addition, it can be prepared in a tablet form that minimizes the production of related substances, at a compression pressure capable of improving instability. In addition, because of the in vivo absorption mechanism of the pregabalin component, it remains in the stomach for a long time, which exerts an effective effect on drug absorption, and thus can be prepared into a dosage form of a gastric-retentive tablet.
In addition, according to one embodiment, a two-layer sheet of a two-layer structure or a multi-layer sheet of a multi-layer structure may be formed in which pamecoxib, pregabalin, or a mixture thereof is distinguished into different layer states. For example, the sustained-release agent may be formed as a bilayer or multilayer structure composed of a sustained-release layer and an immediate-release layer, the sustained-release layer may contain pregabalin, and the immediate-release layer may contain pamarelix. According to a specific embodiment, the sustained release tablet can be prepared by layering the immediate release layer with particles of a mixture of pamicoxib and pregabalin and compacting the layered particles, and layering the sustained release layer with particles of pregabalin. For example, a layer containing pamecoxib may be formed in the immediate-release layer and a layer of pregabalin may be formed in the sustained-release layer, and the layers may be prepared by a tableting machine.
The bilayer preparation method may be, but not limited to, a method in which pregabalin and a mixture thereof are granulated to form a lower layer, the lower layer is compacted, and then palomacoxib and a mixture thereof are granulated to form an upper layer, and a tabletting machine is used to prepare the bilayer.
According to one embodiment, the dosage form may be formed in a nucleated dosage form in which the pregabalin layer of the inner core comprises an outer core, or in which the pregabalin layer of the inner core comprises an outer core. In addition, it may be formed in a dual release micro-coated dosage form (DRM) containing a pamacrobyl coating on the inner pregabalin layer or a pregabalin layer on the inner pamacrob layer.
According to one embodiment, the ratio of pamacyclovir to pregabalin may be, for example, from 1 to 300:1 to 600, for example from 1:1 to 1:300, for example from 2:1 to 2: 300.
In addition, pamadecoxib 0.1 to 10 wt% and
According to one embodiment, a pharmaceutically acceptable excipient (exipien t) may be further included. For example, the excipient may include one or more selected from the group consisting of ethyl cellulose (ethylcellulose), hydroxypropyl cellulose (hydroxypropylcellulose), hydroxypropylmethylcellulose (hydroxypropylcellulose), sodium carboxymethylcellulose (sodium carboxymethylcellulose), polyethylene oxide (polyethylene oxide), carbomer (carbomer), sodium alginate (sodium alginate), mannitol (mannitol), croscarmellose sodium (sodium bicarbonate), sodium bicarbonate (sodium hydrogen carbonate), and magnesium stearate (magnesium stearate). Among them, for example, one or more selected from the group consisting of hydroxypropylmethylcellulose, D-mannitol, hydroxypropylcellulose, croscarmellose sodium, sodium bicarbonate, and magnesium stearate may be included.
Specifically, for example, in order to improve the mixing uniformity and tabletting property of the pamicoxib active ingredient in the composition in the form of a mixture, mannitol 200SD, which is an insoluble polymer having uniform particles, may be used, but the present invention is not limited thereto.
Specifically, for example, when the composition is a bilayer dosage form comprising a sustained-release layer and an immediate-release layer, the sustained-release matrix excipient may include one or more selected from the group consisting of hydroxypropylmethylcellulose, polyethylene oxide (PEO), carbomer, sodium alginate, ethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, and the like, and may include, for example, hydroxypropylmethylcellulose. In addition, for example, in order to allow the drug to float in the stomach for a predetermined time and stay in the stomach for a long time, generation of gas on the tablet surface can be induced to increase the floating property, and in this case, an excipient including sodium bicarbonate can be used.
According to one embodiment, the sustained-release base added together with the excipient may be contained in an amount of 10 to 70%, for example 30 to 50%, relative to the entire weight of the sustained-release layer, in consideration of factors affecting gastrointestinal motility and other sustained-release type drug release. In addition, sodium bicarbonate for improving the floatability of the tablet may be contained in an amount of 1 to 15%, for example, 8 to 12% based on the total weight of the composition, since the addition of an appropriate amount of sodium bicarbonate increases the disintegration of the tablet and hinders the release of the drug.
According to one embodiment, the composition may include a coating base in order to ensure long-term stability of the pamecoxib having light-sensitive characteristics and pregabalin whose stability is affected by external factors such as moisture, temperature, etc. As the coating base material, for example, a water-soluble coating base material can be used, and a commonly used coating base material can be used. Specifically, for example, a coating base material containing a polyvinyl alcohol derivative, a methacrylic acid derivative and a polyacrylic acid derivative, for example, a coating base material selected from the group consisting of Opadry
According to one embodiment, a pharmaceutically acceptable carrier may be additionally included. As the carrier, a carrier generally used in the preparation may be used, and examples thereof include, but are not limited to, lactose (lactose), dextrose (d extract), sucrose (sucrose), sorbitol (sorbitol), mannitol (mannitol), starch (starch), gum arabic, calcium phosphate (calcium phosphate), alginate (alginate), gelatin (gelatin), calcium silicate (calcium silicate), microcrystalline cellulose, polyvinylpyrrolidone (polyvinylpyrrolidone), cellulose (cellulose), water, syrup (syrup), methyl cellulose (methyl cellulose), methyl benzoate (methyl benzoate), propyl benzoate (propyl benzoate), talc (talc), magnesium stearate (magnesium stearate), and mineral oil (mineral oil).
According to one embodiment, in addition to the ingredients, a filler, a bulking agent, a binder, a disintegrant, a solubilizer, a preservative, a buffer, a glidant, a moisture absorbent, a coating, a colorant, a water-soluble additive, a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like, which are generally used, pharmaceutically acceptable substances may be included as additional additives. Such additives may be included in the range of content having minimal effect on the active ingredients of the composition of the present invention, for example, may be included in an amount of 5 to 90% by weight, for example, 40 to 90% by weight, relative to the total weight of the composition.
According to one embodiment, the composition may act on pain induced by inflammation or neurological disorders, such as acute pain, chronic pain. Specifically, the present invention can exhibit an effective effect as an analgesic agent for treating neuropathic pain (neuropathic pain) including diabetic neuropathy, pain due to generalized anxiety disorder (generalized anxiety disorder), fibromyalgia (fibromyalgia), hyperalgesia (hyperalgesia), abnormal pain (allodynia), cancer pain (cancer pain), osteoarthritis (osteoarthritis), rheumatoid arthritis (rhematoid arthritis), ankylosing spondylitis (alkylosinitis), frozen shoulder (frozenshoulder), low back pain (umbodynia), or sciatica (sciatic a). In addition, it can be used for therapeutic use for severe pain to moderate pain such as rheumatoid arthritis, ankylosing spondylitis, sciatica, and inflammatory factors of the shoulder fifty, for example.
The pharmaceutical agents or compositions of the present invention may be prepared in any form suitable for use in humans and adult animals, including infants, children, according to standard procedures known to those skilled in the art.
The embodiments of the present invention are described in detail below so that those skilled in the art to which the present invention pertains can easily carry out the embodiments. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.