KR101625344B1 - Pharmaceutical compositions comprising celecoxib and duloxetine - Google Patents

Abstract

The present invention relates to a complex formulation comprising celecoxib and duloxetine hydrochloride and a manufacturing method and, more specifically, to a pharmaceutical formulation having an entering coating independence unit of acid-unstable duloxetine hydrochloride and an independence unit for solubilizing celecoxib as a poorly water-soluble drug in a separated environment for two ingredients which are not in contact with each other, and to a manufacturing method. The complex formulation is incomplete with mutual influence of main ingredients of the delayed-release duloxetine hydrochloride and the immediate-release celecoxib with respect to drug release, and is satisfied with the stability of each of the drugs.

Description

[0001] PHARMACEUTICAL COMPOSITIONS COMPRISING CELECOXIB AND DULOXETINE [0002]

The present invention relates to a pharmaceutical composition comprising celecoxib known as selective COX-2 inhibitor as active ingredient and duloxetine as selective serotonin-norepinephrine reuptake inhibitor (SNRI).

Cerexoxib is a selective COX-2 inhibitor, a non-steroidal anti-inflammatory agent (NSAIDs). It is known to be suitable for the relief of the symptoms or signs of osteoarthritis (degenerative arthritis), relieving symptoms or signs of rheumatoid arthritis, alleviating symptoms or signs of ankylosing spondylitis, acute pain relief in adults, or inflammation such as primary dysmenorrhoea.

Here, we will pay attention to osteoarthritis.

Osteoarthritis is caused by degeneration of cartilage function. Cartilage is a soft tissue that covers the bones and bones in the joints. Healthy cartilage helps to prevent bones from coming into direct contact with each other and to absorb the impact of bone movement. However, when such cartilage is degraded and worn out due to aging, the bones eventually directly rub against each other, resulting in chronic inflammation and pain at the site.

Humans have been suffering from pain, which is inevitably caused by degenerative diseases, for a long time as the average life expectancy is prolonged. This pain has become a companion of the journey of life, and overcoming and managing it is the time when quality of life is influenced. In most developed countries, it takes a lot of money to solve pain and related problems. In the United States, for example, about $ 100 billion a year is spent on pain treatment, and the loss of labor due to pain is estimated to reach about $ 65 billion annually. In addition, according to the Korean Pain Research Society, four out of ten chronic pain patients felt suicidal impulse, so the pain is becoming more serious both economically and socially.

In addition, celecoxib and duloxetine have been prescribed for the treatment of osteoarthritis.

Duloxetine is a selective serotonin norepinephrine reuptake inhibitor (SNRI) family developed by Lilly. Duloxetine has been shown to prevent pain from re-absorbing neurotransmitters and to treat pain at the same time as depression. Thus, although duloxetine is prescribed for the treatment of major depressive disorders and for the treatment of generalized anxiety disorder, duloxetine is not appropriate for the treatment of diabetic peripheral neuropathic pain, treatment of fibromyalgia, or nonsteroidal anti-inflammatory drugs (NSAIDs) Osteoarthritis pain, and the like.

Celecoxib and duloxetine have been reported to cause a synergistic effect in the treatment of chronic pain caused by osteoarthritis, according to a recently published paper, and attention is focused on the combination of these two drugs.

Korean Patent Publication No. 10-0356240 Korean Patent Publication No. 10-0501034

The present inventors have focused on the synergistic effect of the combination of celecoxib and duloxetine, and attempted to formulate two different active ingredients in a single formulation in order to enhance the convenience of taking each drug.

The first consideration was the design of release patterns for each drug.

Cerecoxibs are generally constituted with immediate release formulations. However, as disclosed in Korean Patent Publication No. 10-0501034, since the drug is substantially poor in solubility, it is difficult to formulate and dissolve the drug at the top, so that it is difficult to use a general formulation technique. In the case of the above patents, attempts were made to achieve solubility improvement by finely dividing the particle size of cerecoxib. To compensate for the homogeneity of the drug caused by the undifferentiated particle size and to prevent aggregation of the undifferentiated particles, A means for intimately mixing is added separately.

Subsequently, duloxetine needs to be composed of an enteric preparation because its stability is pH sensitive. Therefore, it is required to have a structure in which the enteric coating agent is blended and the formulation is disintegrated in the small intestine as soon as it passes over the top so that the main ingredient can be absorbed. It is generally known that the main ingredient is capable of rapid release in the form of pellets rather than the tablet form. However, in the case of pellet form, duloxetine interacts with an enteric coating agent system and may be adversely affected by emission pattern or stability. However, Korean Patent Registration No. 10-0356240 discloses that hydroxypropylmethylcellulose acetate succinate This problem has been overcome by adopting an enteric polymer.

On the other hand, when preparing two active ingredients which have different release times from each other as a single preparation, the first emerging form is a sustained release formulation. The press-coated tablet is a pellet containing any one active ingredient or a formulation in which the granules containing another active ingredient are re-compressed by using a special tablet machine on the outer layer of the tablet. In this case, the external angle can be made to have a quick effect, and the nucleus can be made into an enteric.

The inventors of the present invention firstly reflected the idea of the prior patent, and duloxetine was blended with an enteric polymer to prepare pellets. Celecoxib was micronized to form wet granules with an excipient, The release pattern of each drug was compared to the single agent of each of celecoxib and duloxetine.

But the result was quite disappointing. Once the dissolution rate of cerecoxib did not show the shape of the inner ear. In addition to this, it may be helpful to increase the solubility of the drug as well as the undifferentiated particles applied to the cerecoxib, but it is not a preferable means in terms of cost in terms of mass production or quality deviation between products. In addition, pellets applied to Duloxetin require special manufacturing facilities, which is costly.

Accordingly, the present inventor has been intensively engaged in the development of a solid oral formulation suitable for combination of celecoxib and duloxetine, and as a result, the present invention has been completed.

The present invention has solved the above-mentioned problems through the following means.

(1) A combination preparation comprising a first compartment containing duloxetine as an active ingredient and a second compartment containing cerecoxib as an active ingredient, wherein the first compartment and the second compartment are in the form of a multi-unit tablet Lt; / RTI >

(2) The combined preparation according to (1) above, wherein the first compartment contains a sugar alcohol as an excipient.

(3) The combination preparation as described in (2) above, wherein the sugar alcohol comprises at least one selected from the group consisting of mannitol, maltitol, lactitol, ribitol, xylitol and maltotritol.

(4) The combined preparation as described in (2) above, wherein the sugar alcohol is contained in an amount of 5-50% by weight based on the total weight of the first compartment.

(5) The combined preparation as described in (1) above, wherein the second compartment contains at least one selected from the group consisting of a water-soluble polymer, a surfactant and a saccharide.

(6) The water-soluble polymer according to (5), wherein the water-soluble polymer is at least one selected from the group consisting of hydroxypropyl cellulose, polyvinyl pyrrolidone, hydroxypropyl methyl cellulose and vinyl pyrrolidone vinyl acetate copolymer Compound preparation.

(7) The method according to (5), wherein the surfactant comprises at least one member selected from the group consisting of sodium lauryl sulfate, glyceryl fatty acid ester, sucrose fatty acid ester, fatty acid macrogol glyceride and polyoxyglyceride .

(8) The combined preparation as described in (5) above, wherein the water-soluble polymer and the surfactant are contained in an amount of 0.1-20% by weight based on the total weight of the second compartment.

(9) The combination preparation as described in (5) above, wherein the saccharide is at least one selected from the group consisting of mannitol, lactose, glucose, maltitol, xylitol, maltotritol and glucose.

(10) The combined preparation according to (5), wherein the saccharide is contained in an amount of 10 to 50% by weight based on the total weight of the second compartment.

(11) The combined preparation according to (1) above, wherein the first compartment includes a separation layer and an enteric coating layer on the drug layer.

(12) The combination preparation according to the above (11), wherein the separation layer is at least one selected from the group consisting of polyvinyl alcohol and hydroxypropyl methylcellulose, and is 3-10% by weight based on the weight of the first compartment .

(13) The combination preparation as described in (12) above, wherein the enteric coating layer is at least one selected from the group consisting of hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate and methacrylic acid copolymer.

(14) A process for producing granules or tablets as described in (13) above, wherein the granules or tablets comprise duloxetine hydrochloride and sugar alcohol;

Step 2 of preparing granules or tablets comprising celecoxib, a surfactant and a saccharide;

And filling the hard capsule with the duloxetine-containing granules or tablets obtained in the step 1 and the granules or tablets containing the cerecoxib obtained in the step 2 separately.

(15) The production method according to (14), wherein the product of step (1) and step (2) is purified.

The present invention, which is a solid oral solid preparation, is characterized in that when the same solid oral single-agent product of cerecoxib and duloxetine oral solid preparation are mixed, the release pattern of each drug is similar, and the stability of each drug So that there is no problem in commercializing the product. Specifically, the present invention is a preparation of a single formulation of an active ingredient called cerecoxib and duloxetine, wherein the insoluble drug, cerecoxib, is composed of a solubilized quick-release drug, and the pH-sensitive duloxetine is an enteric drug And by allowing the interaction of each drug in the formulation to be minimized, the two drugs are complementary to each other, so that a pharmacologically synergistic effect can be sustained in the human body in the treatment of pain .

According to one embodiment of the present invention, the final formulation is a hard capsule, and the two types of active ingredients packed therein are in the form of a multi-unit tablet. Each multi-unit tablet is excellent in hardness and can be packaged, And it is suitable for mass production because of not only difficulties such as capping and laminating. In addition, it is possible to manufacture the above multi-unit tablets through a simple wet process, thereby simplifying the manufacturing process.

Since the combination preparation contains two or more active ingredients, the total volume has to be made larger than that of the single preparation. However, if the volume is too large, the first purpose of introducing a complex drug may not be achieved. One embodiment of the present invention is a multi-unit tablet in which each drug is packaged in a capsule, wherein the multi-unit tablet of each drug is a new formulation not known in the field of celecoxib and duloxetine The volume of the excipient or the like is minimized so that the volume thereof is not large, and a specific shape is taken, so that it does not take up a large volume when filled into capsules.

Figure 1 shows the dissolution profile of the active ingredient duloxetine according to Example 1-1.
Figure 2 shows the elution evaluation of the active ingredient celecoxib according to Example 1-1.
Figure 3 shows the dissolution profile of the active ingredient duloxetine according to Example 4.
Figure 4 shows an elution profile of the active ingredient celecoxib according to Example 5-1.
Figure 5 shows the elution profile of the active ingredient celecoxib according to Example 5-2.
Figure 6 shows elution evaluation of the active ingredient celecoxib according to Examples 5-3.

The present invention relates to an oral solid composition containing a serekoxib compartment formed with quick-release properties and an enterically formed duloxetine compartment. When formulating two or more drugs that need to exhibit different release patterns into one single formulation, it is important to design so that the composition of any compartment does not affect the release of the drug in the other compartment. In particular, when celecoxib is intended to be formulated into a single preparation, the drug itself is considerably weaker, so that it is necessary to add special solubilizing means and is a very sensitive and difficult drug in achieving satisfactory dissolution.

However, when the release pattern was examined by simply contacting the previously known duloxetine-type pellet-type duloxetine compartment and particles with the excipient and the wet-granulated celecoxib compartment, The release pattern of the cerecoxib was unsatisfactory even though the release pattern of the sieve was adversely affected or the solubilization means according to the prior patent documents were incorporated in the cercoxic compartment. In addition, according to the prior patent documents, duloxetine pellets composed of an enteric polymer of hydroxypropylmethylcellulose acetate succinate have no interaction with the active ingredient. According to the experiment of the present inventor, the stability of duloxetine was problematic.

Accordingly, the present invention provides an enteric duloxetine compartment in which the stability of duloxetine can be maintained while at the same time minimizing the influence on the release pattern of celecoxib and allowing the drug to disintegrate immediately upon entry into the small intestine area, Concentrating on the preparation of formulations capable of harmoniously arranging the serectocidal compartments capable of sufficient solubilization and the prescription of each compartment thereof. This will be described.

[Justice]

As used herein, the term " cerecoxib " and " duloxetine " refers to an active ingredient having pharmacological activity, including all forms of main components to which ordinary artisans such as various salts and prodrugs can be grafted. For example, it is possible to derive duloxetine hydrochloride from "duloxetine".

By "solubilizing means" is meant one of the well-known methods for dissolving poorly soluble drugs. Non-limiting examples of solubilizing means known for celecoxib include atomization of particles, mixing with poloxamer, and solid dispersion, etc. have.

The term "water-soluble polymer" refers to a resin or a polymeric material that is soluble in water or can be swollen or dispersed in small particles. Examples of non-limiting examples include hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC) Pyrrolidone (PVP), and the like.

The term " surfactant " refers to a substance that simultaneously has a hydrophilic group and a lipophilic group in a molecule, and is dissolved or dispersed in a solvent to selectively adsorb to the interface to thereby significantly change the properties of the interface. Examples of the material include, but not limited to, sodium lauryl sulfate (SLS) And poloxamer.

&Quot; Saccharide " is generically referred to as sugar or sugar alcohol.

The term " sugar alcohol " refers to a polyhydric alcohol formed by reducing a carbonyl group of a monosaccharide, and includes, but not limited to, erythritol, traitol, xylitol, ribitol, mannitol, and sorbitol.

The specific ingredients of the various excipients or additives referred to herein, including "water-soluble polymers", "surfactants" and "sugar alcohols", unless otherwise specified, may be selected from among pharmaceutically addable substances known to HANDBOOK OF PHARMACEUTICAL EXCIPIENTS Enemy is selectable.

[Second compartment containing cerecoxib]

Known means for solubilizing cerecox in a solid preparation for oral use include particle pulverization, mixing with poloxamer, and solid dispersion. For example, Korean Patent Laid-Open Publication No. 10-2015-0112416 discloses a water-soluble polymeric carrier of polyvinylpyrrolidone, which is obtained by combining a solubilizing agent (surfactant) and an adsorbent of magnesium metasilicate alumina to improve the solubility of cerecoxib Dispersion technology is published. Korean Patent Publication No. 10-1455901 discloses a common mixture wherein cerecoxib and poloxamer are blended in a specific ratio of 3: 7 to 6: 4. However, in the present invention, the solubility problem of a drug is solved only by the combination of a specific water-soluble polymer, a surfactant and a saccharide. The present invention has various advantages in manufacturing because it is relatively simple in comparison with processes and equipment for introducing particle fine powder, solid dispersion or common compound. In the present invention, the second compartment includes at least one selected from a water-soluble polymer, a surfactant and a saccharide. And preferably both.

As the water-soluble polymer, at least one of hydroxypropyl cellulose, polyvinyl pyrrolidone, hydroxypropyl methyl cellulose and vinyl pyrrolidone vinyl acetate copolymer is selected. As the surfactant, at least one of sodium lauryl sulfate, glyceryl fatty acid ester, sucrose fatty acid ester, fatty acid macrogol glyceride and polyoxyglyceride is selected. The saccharides are selected from at least one of mannitol, lactose, glucose, maltitol, xylitol, maltotritol, and glucose. Among these, the most preferable combination is the prescription introduced in the following examples.

The water-soluble polymer and the surfactant each contain 0.1 to 20% by weight of the total weight of the second compartment. Outside the stomach content range, the dissolution rate of cerecoxib may be lowered by about 10% or more. Above all, when the content of the surfactant does not satisfy the lower limit and the upper limit, the surfactant force of about 10% or more may be significantly deteriorated.

The saccharide is preferably contained in the range of 10-50 wt% of the total weight of the second compartment. If the content of the saccharide does not satisfy the above lower limit and upper limit, sufficient solubilization of the cerecoxib may not be achieved, and the problem of increased precision and size of the tablet may arise.

The second compartment may contain, in an appropriate amount, other well-known additives which can be selected as long as they do not interfere with the desired effect of the present invention. However, it is preferable that the total amount of the excipient or additive does not exceed twice the volume of the main ingredient in consideration of the total volume.

[First compartment containing duloxetine]

Enteric coatings are essential for acid labile drugs. Enteric coatings are film coatings intended to be released when the drug passes through the intestinal tract without being released in the stomach. It is used when the drug is intended to prevent digestion or degradation in the stomach or to prevent gastrointestinal disturbance or vomiting by the drug. Various ingredients are known as enteric coating agents. The pH of healthy gastric juice is 1-3 (postprandial 2.5-5), and the intestinal pH is 5-7 in the duodenum and 7-8 in the ileum. In general, the enteric gelatin is stable in the pH of the gastric juice and dissolves in the serous pH, dissolves and dissolves. The degree of disintegration of the tablet due to ionization at a specific pH due to the bound functional groups, It is necessary to select suitable components. Particularly, when designing a combination preparation as in the present invention, consideration should be given to the extent that it affects other active ingredients. In the present invention, at least one selected from the group consisting of hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate and methacrylic acid copolymer is used as an enteric polymer.

The first compartment may introduce a separation layer separating the drug and enteric coating layer prior to enteric coating. In the Korean Patent Publication No. 10-0356240, the introduction of the separation layer is arbitrary, however, according to the results of repeated experiments, the inventors of the present invention have found that the effect And was more preferable for expression. As the separating layer, polyvinyl alcohol and / or hydroxypropyl methylcellulose are preferably employed, and it is preferable that the separating layer contains about 3 to 10% by weight based on the weight of the first compartment.

The first compartment is then blended with a sugar alcohol as an excipient. The sugar alcohol may be selected from at least one of mannitol, maltitol, lactitol, ribitol, xylitol and maltotritol. Among them, the use of mannitol was the most desirable in terms of stability of duloxetine hydrochloride. Especially when the mannitol was selected in the same manner as the excipient of the first compartment and the second compartment, the most desirable synergistic effect was manifested in terms of release pattern and stability effect of each drug, though the exact reason is not clear.

The sugar alcohol is formulated in an amount of 5-50% by weight based on the total weight of the first compartment.

The first compartment may contain, in an appropriate amount, other well-known additives which can be selected as long as they do not impair the desired effect of the present invention. However, it is preferable that the total amount of the excipient or additive does not exceed 2 to 5 times the capacity of the first compartment main component, considering the volume problem. At this time, when mannitol was selected as the excipient for the first compartment, the volume could be minimized. It is undeniable that mannitol is one of the excipients employed in the formulation of formulations (as is the case with all excipients), but in the combination of duloxetine and celecoxib, the drug stability, release pattern, Which is essential and the most desirable ingredient for achieving the minimization of the number of the cells. Obviously, the effect of mannitol on this combination was astonishing.

Korean Patent Publication No. 10-0356240, which is a prior patent document, suggests that duloxetine is preferably formed in the form of pellets. However, pellets are disadvantageous in that they are difficult and costly to manufacture. Clearly, the enteric compartment is not disintegrated in gastric juice, but has a desire that it should disintegrate quickly in the small intestine. Such a homework may be preferred in pellet form rather than in tablet form. However, the inventor of the present invention solved the above homework in tablets form according to the above-mentioned prescription characteristic, and also confirmed that the pellet form, unfortunately, is not as preferable as the present compound. Finally, the benefits of mannitol are once again being reevaluated. No mixing of mannitol was proposed at all in the above prior art document examples.

[Formulation]

One of the deepest distress of the present inventors was the formulation of the combination preparation.

International Publication No. 2013-065936 discloses a combination of an immediate release clopidogrel and an enteric-type aspirin. Here, each drug is applied to the inner core, and then the capsules are filled with a kind of pellet-shaped granules coated thereon. However, according to the experiment of the present inventors, according to the above-described combination preparation, when the pellets-pellets or the pellet-granules were filled in capsules as described above, the stability of duloxetine was negative, and the release pattern of each drug was not satisfactory.

The commercially available biomonitoring is a combination of enteric-coated naproxen and immediate-release S-omeprazole, which is a tablet formulation coated with S-omeprazole in a naproxen core. However, this combination preparation was not stable when the formulation of a similar press-coated tablet was taken.

After repeated troubles and experiments, the formulation selected by the present inventor is a multi-unit tablet. Duloxetine hydrochloride is the most commonly used duloxetine hydrochloride. When it is packed into capsules in the form of a multi-unit tablet, the stability of duloxetine hydrochloride and celecoxib is the most excellent. Also, The drug release pattern could also be close to the release pattern of each single drug. As described above, the present invention is characterized in that the formulation of the multi-unit tablet is selected unlike the conventional formulation of the immediate-enteric combination preparation.

Since the multi-unit tablets need to be prepared by tableting each drug and then filling them into capsules, the volume of the final product is inevitably relatively larger than that of the above-described granules or tablet, and the enteric drug is rapidly disintegrated in the small intestine It was not a commonly introduced formulation because it was anticipated that there could be limitations in making Surprisingly, however, the inventors have found that in the case of duloxetine and cerecoxib, it is possible to develop multi-unit tablets which can contain a high content of drug, thereby minimizing the volume of the final product, .

Particularly, this multi-unit tablet is suitable for combination with the excipients of the first and second compartments described above.

The multi-unit tablets of each compartment may be preferred in that the capsule has a diameter of 4-6 mm and a thickness of 4-6 mm to minimize the final volume.

The present invention can be manufactured as a final product by filling multi-unit tablets of each compartment into hard capsules. At this time, the hard capsule can be selected from 0, 1, 2, 3 or 4.

[Usage capacity]

Cerechoxib is commonly prescribed 200 mg once a day, so if you look at the marketed single product, there are products containing 100 mg of celecoxib and 200 mg of product, while duloxetine is 60 mg once daily It is recommended, but it is prescribed to take 30 mg once a day at the beginning. There is a product containing 60 mg and a product containing 30 mg by duloxetine on the market.

The complex agent according to the present invention can be designed in various doses and can be taken in an appropriate manner, but according to one embodiment of the present invention, cercoxiche is composed of a solubilized rapid-release layer, Duloxetine may be prescribed as 200 mg of celecoxib and 60 mg of duloxetine (67.3 mg of duloxetine hydrochloride) for each drug in order to expect a pain-sustaining effect. A satisfactory pain relief can be expected even if it is taken by taking the medicine.

However, the usage dose is only one preferred embodiment, and the scope of the present invention is not limited thereto.

Hereinafter, the present invention will be described by way of examples. It should be noted, however, that the embodiments do not limit the invention in any way.

[Example 1] Dissolution difference according to formulation

Example 1-1) Confirmation of dissolution pattern according to formulation

Method for producing multi-unit tablets (duloxetetin tablets + cerecoxib tablets capsules)

Preparation of duloxetetin tablets: Tablets were tabletted in the form of wet granules using the excipients described in the prescription of duloxetetin tablets, below, tableting, drying, sizing and mixing. The tableted duloxetine tablets were subjected to separation layer coating using hydroxypropyl methylcellulose as a solvent of ethanol / purified water (80/20 wt / wt%). Separation Layer Coating layer was coated intramuscularly with ethanol / purified water (80/20 weight / weight) solvent by adding hypromellose phthalate, triethyl citrate, titanium oxide and yellow No. 203 to the coating layer.

Preparation of serekoxib tablets: The granules were combined, dried, sized and mixed in the form of wet granules using the excipients described in Table 1 below in the form of celecoxib prescription.

Capsule filling: Celecoxib tablets - Duloxetine tablets - Celecoxib tablets were filled sequentially into hard capsules.

Method for producing a press-coated tablet (duloxetine tablet + cerecoxib granule tabletting)

Preparation of duloxetetin tablets: Tablets were tabletted in the form of wet granules using the excipients described in the prescription of duloxetetin tablets, below, tableting, drying, sizing and mixing. The tableted duloxetine tablets were subjected to separation layer coating using hydroxypropyl methylcellulose as a solvent of ethanol / purified water (80/20 wt / wt%). Separation Layer Coating layer was coated intramuscularly with ethanol / purified water (80/20 weight / weight) solvent by adding hypromellose phthalate, triethyl citrate, titanium oxide and yellow No. 203 to the coating layer.

Preparation of Cerecoxib Granules Granules were prepared by combining, drying, sizing and mixing in the form of wet granules using the excipients described in Table 1 below in the form of Cerecoxib prescription.

The duloxetine coated tablets were placed in a tablet machine, and granules of cerecoxib were placed in the tablets to complete the preparation of the press-coated tablets.

Preparation of Duloxetine Tablets + Celecoxib Granule Capsules

Preparation of duloxetetin tablets: Tablets were tabletted in the form of wet granules using the excipients described in the prescription of duloxetetin tablets, below, tableting, drying, sizing and mixing. The tableted duloxetine tablets were subjected to separation layer coating using hydroxypropyl methylcellulose as a solvent of ethanol / purified water (80/20 wt / wt%). Separation Layer Coating layer was coated intramuscularly with ethanol / purified water (80/20 weight / weight) solvent by adding hypromellose phthalate, triethyl citrate, titanium oxide and yellow No. 203 to the coating layer.

Preparation of Cerecoxib Granules Granules were prepared by combining, drying, sizing and mixing in the form of wet granules using the excipients described in Table 1 below in the form of Cerecoxib prescription.

Duloxetine tablets and cerecoxib granules were filled in hard capsules.

Preparation of Duloxetine Pellet + Celecoxib Granule Capsule

Preparation of Duloxetine Pellets: Pellets were prepared using a fluidized bed machine with the pellet formulation in Table 3 below.

Preparation of Cerecoxib Granules Granules were prepared by combining, drying, sizing and mixing in the form of wet granules using the excipients described in Table 1 below in the form of Cerecoxib prescription.

Duloxetine pellets and celecoxib granules were filled in hard capsules.

Duloxetetin pellet + Celecoxib Tablet Capsule

Preparation of Duloxetine Pellets: Pellets were prepared using a fluidized bed machine with the pellet formulation in Table 3 below.

Preparation of Celecoxib Purification Tablets were combined, dried, sized and mixed in the form of wet granules using the excipient described in the Celecoxib Prescription Table below.

Duloxetine pellets and celecoxib tablets were filled in hard capsules.

Duloxetine Pellet + Celecoxib Granule Tablets

Preparation of Duloxetine Pellets: Pellets were prepared using a fluidized bed machine with the pellet formulation in Table 3 below.

Preparation of Cerecoxib Granules Granules were prepared by combining, drying, sizing and mixing in the form of wet granules using the excipients described in Table 1 below in the form of Cerecoxib prescription.

Duloxetine pellets and celecoxib granules were mixed and tableted in a tablet machine to prepare tablets.

The main ingredient is duloxetine hydrochloride, and so is the table below.

Dissolution test

The dissolution test of duloxetine according to Example 1-1 was carried out by dissolving the duloxetin at 900 rpm and 100 rpm in the dissolution test method, Method 1, pH 6.8 in the Korean Pharmacopoeia. The dissolution results in Example 1 were as shown in Tables 4, 5, 1 and 2. Celecoxib elution was evaluated by dissolution test at pH 6.8 900 mL + 1% Tween 80, 100 rpm in dissolution test method 2 in General Test Methods of the Korean Pharmacopoeia.

Example 1-2 Evaluation of acid resistance of pellet formulation

(Duloxetine pellet + cerecoxib granules) capsule of Example 1-1), (duloxetine pellet + cerecoxib granule) tablets, and multiunit tablets for the confirmation of acid resistance when the pellet formulation was tableted, Dissolution in Method Method 1 Method 1 The elution test was carried out at pH 1.2 (900 mL, 100 rpm) (standard 10% or less). The results are shown in Table 6.

[ Example  2] Depending on formulation Stability difference

Total formulation was evaluated for HDPE bottle without lid under the Open Hardness Test (60 ° C). Within each period, the content of the flexible substance is expressed as a percentage of total flexible substance (based on cerecoxib: 0.2% or less of each individual flexible substance, 1.0% or less of total flexible substances, 0.2% or less of the unknown substance, % Below).

It can be confirmed that the stability of the multi-unit formulation is better than that of capsules (duloxetetin pellet + cerecoxib granules) capsules, (duloxetetin pellets + cerecoxib tablets) capsules. The results of the duloxetine stability test are shown in Table 7, and the results of the serekoxib stability test are shown in Table 8.

[ Example  3] Duloxetin  Prescription stability

Stability test according to prescription of duloxetine tablets using sugar alcohols

The stability test was carried out at 60 ° C (standard: not more than 0.2% of the unknown substance, not more than 0.4% of the total substance) by wet-granulating, drying, sizing, mixing and tableting using the following Table 9 excipient. The results are shown in Table 10.

The stability of duloxetine hydrochloride, the major component of YYC-301-2-106CT, which is the most commonly used excipient, formulated with lactose, was measured. As a result, it was confirmed that the stability was insufficient. In the case of YYC-301-2-124CT, sodium bicarbonate which is a stabilizer was mixed. However, stability was still insufficient. In the meantime, when I tried to use mannitol as an excipient, the stability of the active ingredient was improved remarkably. Because the excipient was known to be merely a function of the volume of the drug, it was unexpected that the stability of the excipient would be improved by such modification of the excipient. Thus, the present invention is characterized by using mannitol as an excipient as shown in Table 2 or YYC-301-123CT.

[ Example  4] Duloxetin  Confirmation of dissolution pattern according to prescription

Dissolution test according to prescription of duloxetine tablets using sugar alcohols

The duloxetine tablets were purified by the prescription of Table 9 and filled in the hard capsules of the cerecoxib tablets purified by the prescription of Table 1. The results are shown in Table 12 and FIG. 3 below.

[ Example  5] Cerecoxib  Confirmation of dissolution pattern according to prescription

Example 5-1) Prescription using polymer, surfactant and saccharide - Determination of dissolution profile according to the type of surfactant using HPMC as a polymer

Using the prescription of Table 13, the wet granules were combined, dried, sized, mixed, and purified to prepare a dissolution test. The results are shown in Table 14 and FIG.

When sucrose fatty acid ester (product name: Sugar ester P-1570) was used as a surfactant, elution of cerecoxib could be most suitably derived. Also, the sodium lauryl sulfate (prescription in Table 2) was also one of the most satisfying results.

Example 5-2 Prescription using Polymer and Surfactant and Saccharide - Using Sugar-ester P-1570 as a surfactant and mannitol as a saccharide, and confirming the dissolution profile according to the type of polymer

Using the prescription of Table 15, the wet granules were coalesced, dried, sized, mixed, and tabletted to conduct a dissolution test. The results are shown in Table 16 and FIG.

YYC-301-1-31tab, which is a combination of Soluplus and polymer, did not satisfy the dissolution rate of cerecoxib. The dissolution rate of celecoxib was implemented to some extent, and especially when hydroxypropylcellulose (product name: HPC-L) was combined (YYC-301-1-38tab) as shown in Table 1.

Example 5-3 Prescription using polymer, surfactant and saccharide -Preparation of HPMC as a polymer and sugar-ester as a surfactant,

Using the prescription of Table 17, they were combined, dried, sized, mixed, and tabletted in wet granular form to conduct a dissolution test. The results are shown in Table 18 and FIG.

YYC-301-1-36tab in which dextrin (product name: HP-β-CD) was blended was not satisfactory in the dissolution rate of cerecoxib and the rest was in a somewhat dissolution rate. Mannitol (product name: mannitol100SD) (YYC-301-1-39tab) was the best when it was mixed.

Claims (15)

A combination preparation comprising a first compartment containing duloxetine as an active ingredient and a second compartment containing cerecoxib as an active ingredient, wherein the first compartment and the second compartment are in the form of a multi-unit tablet, Wherein the second compartment contains at least one selected from the group consisting of a water-soluble polymer, a surfactant, and a saccharide. delete delete 2. The combination preparation according to claim 1, wherein mannitol is contained in an amount of 5-50% by weight based on the total weight of the first compartment. delete The combination preparation according to claim 1, wherein the water-soluble polymer is at least one selected from the group consisting of hydroxypropyl cellulose, polyvinyl pyrrolidone, hydroxypropyl methyl cellulose and vinyl pyrrolidone vinyl acetate copolymer. 2. The combination preparation according to claim 1, wherein the surfactant comprises at least one member selected from the group consisting of sodium lauryl sulfate, glyceryl fatty acid ester, sucrose fatty acid ester, fatty acid macrogol glyceride and dioxyglyceride . 2. The combination preparation according to claim 1, wherein the water-soluble polymer and the surfactant are contained in an amount of 0.1 to 20 wt% based on the total weight of the second compartment. The combination preparation according to claim 1, wherein the saccharide is at least one selected from the group consisting of mannitol, lactose, glucose, maltitol, xylitol, maltotritol, and glucose. 2. The combination preparation according to claim 1, wherein the saccharide is contained in an amount of 10-50 wt% based on the total weight of the second compartment. 2. The combination preparation of claim 1, wherein the first compartment comprises an isolation layer and an enteric coating layer on the drug layer. 12. The combination preparation according to claim 11, wherein the separation layer is at least one selected from the group consisting of polyvinyl alcohol and hydroxypropylmethylcellulose, and comprises 3-10% by weight based on the weight of the first compartment Lt; / RTI > 12. The combination preparation according to claim 11, wherein the enteric coating layer is at least one selected from the group consisting of hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate and methacrylic acid copolymer. Preparing a tablet comprising duloxetine hydrochloride and mannitol;
A step 2 of preparing a tablet comprising at least one selected from the group consisting of cerecoxib, a water-soluble polymer, a surfactant and a saccharide;
And filling the hard capsule with the duloxetine-containing tablet obtained in the step 1 and the serekoxib-containing tablet obtained in the step 2 separately. delete

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