KR20190075718A - Multi-layer solid formulation with enhanced dissolution rate comprising tramadol or pharmaceutically acceptable salt thereof and pregabalin or pharmaceutically acceptable salt thereof - Google Patents

Abstract

The present invention relates to a multi-layer solid formulation comprising: a first drug layer comprising tramadol or a pharmaceutically acceptable salt thereof, cured castor oil, and a lubricant; and a second drug layer comprising pregabalin or a pharmaceutically acceptable salt thereof, and a cellulose-based excipient. According to the present invention, it is possible to effectively and rapidly reduce pain due to excellent rapid release of pregabalin while effectively controlling the initial release of tramadol or the pharmaceutically acceptable salt thereof.

Description

TECHNICAL FIELD [0001] The present invention relates to a multi-layer formulation comprising tramadol or a pharmaceutically acceptable salt thereof having improved dissolution rate and pregabalin or a pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt thereof}

The present invention relates to solid preparations comprising tramadol or a pharmaceutically acceptable salt thereof and pregabalin or a pharmaceutically acceptable salt thereof and more particularly to a solid preparation comprising tramadol or a pharmaceutically acceptable salt thereof and pregabalin or a pharmaceutically acceptable salt thereof, Or a pharmaceutically acceptable salt thereof, characterized in that the initial release of tramadol or a pharmaceutically acceptable salt thereof is effectively controlled.

Chronic pain, such as neuropathic pain, is a pathologic pain caused by nerve damage or abnormal neuronal function, resulting in severe personal pain and poor quality of life, great loss in economic productivity, Which is caused by a large direct or indirect cost. Studies in Europe have shown that the prevalence of neuropathic pain is as low as 7 to 8% and continues to increase with population aging, raising concerns about chronic pain including neuropathic pain .

The characteristic clinical symptoms of neuropathic pain are persistent or sudden spontaneous provoked pain. The pain complains of burning, numbing, stinging, numbing sensation. Sensory deterioration due to nerve damage, abnormal sensations, and unpleasant sensations may also be present. It also feels pain (allodynia) in the touching and touching stimuli, and more severe pain (hyperalgesia) in the same invasive stimulus. Excessive pain other than the injured area may be accompanied by exercise paralysis, muscle spasms, and symptoms of the autonomic nervous system.

Currently, drugs used to treat chronic pain are classified into opioid narcotic analgesics and non-narcotic analgesics. Non-narcotic analgesics include acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), antidepressants and anticonvulsants. Acetaminophen is relatively safe, but at risk for hepatotoxicity. Nonsteroidal anti- (Ulcers, bleeding, perforation) and cardiovascular risk are known. In the case of narcotic analgesics, it is known that the analgesic effect is excellent, but the risk of constipation, gastrointestinal disorders (nausea, vomiting), respiratory insufficiency, withdrawal symptoms side effects and abuse risk are high. Therefore, there is still a need for a therapeutic agent that can treat chronic pain safer and more effectively.

Combination therapy of two or more drugs is widely used because it has the advantage of reducing the side effects of each drug and increasing the analgesic effect. One example is the combination of tramadol hydrochloride and acetaminophen, which are in circulation in the market. In addition, International Patent Publication Nos. WO 01/13904 and WO 12/048294 describe pharmaceutical compositions for the treatment of pain symptoms, including tramadol compounds and anticonvulsant drugs.

Both tramadol hydrochloride and pregabalin are used in the treatment of chronic pain, such as neuropathic pain, and may be prescribed in combination to increase analgesic effects.

Commercially available tramadol hydrochloride exhibits a sustained release which is slowly absorbed and pregabalin exhibits a rapid drug elution pattern which is rapidly absorbed. As described above, since the release patterns of the two drugs are different, development of a multi-layer formulation is indispensable for the development of a complex drug, and it is possible to reduce the side effects that are the problem of controlling the initial dissolution rate of tramadol hydrochloride in existing products, Is required.

Tramadol hydrochloride is highly soluble in water and it is very difficult to control the initial dissolution rate by a general sustained-release technique. Control of the initial dissolution rate is crucial for the sustained release of tramadol hydrochloride, since it can cause adverse effects with transient overdoses of the drug if the initial dissolution rate is not controlled. In the case of the ultraset, which is a combination of tramadol hydrochloride and acetaminophen, which is in circulation in the market, there is still the problem of controlling the initial dissolution rate of tramadol hydrochloride, and the digestive organs such as vomiting, drowsiness, sleeping, headache, Adverse effects such as central nervous system related side effects such as agitation, and respiratory system side effects such as respiratory depression are observed. In particular, M1, a major metabolite of tramadol, has a very high incidence of side effects because it targets the mu-opioid receptor (OPRM1), which is known to be expressed in vomiting central to vomiting, Research to lower the initial elution is urgently needed.

There are the following patents for controlling the dissolution rate of the sustained-release tablet containing tramadol hydrochloride as a main component. Specifically, in Korean Patent Registration No. 10-0840393, a special excipient of high amylose starch is prepared and used. In Korean Patent Registration Nos. 10-1366365 and 10-0474793, a core material is coated on a core by a fluidized bed granulation method Afterwards, the dissolution rate is controlled by coating the release control agent. In Korean Patent Registration No. 10-1631140, an anionic polymer, carrageenan, is used to inhibit the release of tramadol hydrochloride. In Korean Patent Registration No. 10-0893727, tablets are crushed and melted using oils and fatty acids, .

However, the techniques of the above patents require additional equipment which is troublesome to apply to general production, and in the case of fluidized bed coating, there is a disadvantage that main component loss can occur.

Furthermore, Korean Patent Registration No. 10-1710792 discloses a preparation prepared by wet granulation by additionally adding a wax-like substrate while using ethylcellulose as a sustained-release agent in the tramadol hydrochloride layer. In the case of the above patent, the ratio of ethylcellulose and wax-like substrate of the sustained-release-crystal type is used within 60%. If two types of sustained release agents having different crystal form are used, there may occur a problem that mixing unevenness occurs. Mixing non-uniformity of the sustained release agent causes a deviation in the release, which is likely to cause side effects due to temporary overdose of the drug.

In a solid preparation containing tramadol or a pharmaceutically acceptable salt thereof and pregabalin or a pharmaceutically acceptable salt thereof as an active ingredient under the above-mentioned background, the initial release of tramadol or a pharmaceutically acceptable salt thereof is effectively As a result of intensive efforts to provide a controllable solid preparation, it has been found that cured castor oil, especially selected for tramadol or a pharmaceutically acceptable salt thereof, is used in a specified amount as a sustained release formulation to provide tramadol or a pharmaceutically acceptable salt thereof and pregabalin Or a pharmaceutically acceptable salt thereof, a preparation capable of effectively inhibiting the initial release of tramadol and reducing adverse effects due to tramadol, while ensuring effective dissolution of pregabalin Manufactured in a conventional manufacturing process The present invention has been completed.

In order to overcome the above problems, the present invention relates to a pharmaceutical composition comprising tramadol or a pharmaceutically acceptable salt thereof and pregabalin or a pharmaceutically acceptable salt thereof, wherein the initial release of tramadol or a pharmacologically acceptable salt thereof, It is an object to provide a controlled multi-layer type solid preparation.

Further, as yet another object, the present invention relates to a tramadol or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt thereof, wherein said tramadol or pharmaceutically acceptable salt thereof comprises a layer comprising a wet granulation process. It is an object of the present invention to provide a process for producing a solid preparation of a multilayered form comprising gabbullin or a pharmaceutically acceptable salt thereof.

As one aspect to achieve the above object,

(a) a first drug layer comprising cured castor oil as tramadol or a pharmaceutically acceptable salt thereof, a lubricant and a release agent; And

(b) a second drug layer comprising pregabalin or a pharmaceutically acceptable salt thereof and an excipient. Preferably, the multi-layered solid preparation is in a two-layered form.

Hereinafter, the present invention will be described in detail.

Tramadol or a pharmaceutically acceptable salt thereof, which is an active ingredient contained in the first drug layer of the present invention, is currently marketed under the trade names of Zithram, Ultram and the like, and the compound is named (±) -cis - 2- aminomethyl) -1- (3-methoxyphenyl) cyclohexanol ((±) - and the cis -2- (Dimethylaminomethyl) -1- (3 -methoxyphenyl) cyclohexanol), it has the structure of formula I:

[Chemical Formula 1]

The pharmaceutically acceptable salt includes a pharmaceutically acceptable inorganic or organic acid. Examples of suitable acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, Sulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid and the like. Preferably, tramadol hydrochloride is used in the present invention, but the present invention is not limited thereto.

In addition, pregabalin or its pharmaceutically acceptable salt, which is an active ingredient contained in the second drug layer of the present invention, is currently marketed under the trade name of Lilica, and the compound is named (3S) -3- (aminomethyl) -5 Methylhexanoic acid ((3S) -3- (aminomethyl) -5-methylhexanoic acid)

(2)

The pharmaceutically acceptable salt includes a pharmaceutically acceptable inorganic or organic acid. Examples of suitable acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, Sulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid and the like.

Specifically, the solid preparation according to the present invention is characterized in that, in addition to the tramadol or a pharmaceutically acceptable salt thereof, the first drug layer contains hardened castor oil as a sustained release agent. Preferably, the hardened castor oil may be the only water insoluble hardened castor. In one embodiment of the present invention, water insoluble hardened castor oil, Cutina HR, was used. In a preferred embodiment, the hardened castor oil may be a water-insoluble hardened castor uniquely and may be present in an amount ranging from about 1% by weight of the first drug layer active ingredient (i. E., The weight of tramadol or a pharmaceutically acceptable salt thereof: : 3 to 1: 9, the initial release of tramadol or a pharmaceutically acceptable salt thereof can be effectively controlled.

As used herein, the term "lubricant" is a material that imparts improved flow properties to pharmaceutical compositions. As one example, it may be a substance that facilitates the production process by reducing the adsorption power of hardened castor oil having poor fluidity with high adsorption power. Examples of the lubricant include, but are not limited to, at least one selected from the group consisting of stearic acid, magnesium stearate, glyceryl behenate, sodium stearyl fumarate, talc and colloidal silicon dioxide.

Also preferably, the first drug layer of the combined preparation according to the present invention is characterized in that it is produced by a process comprising a wet granulation method. In this connection, when hardened castor oil is produced by direct tableting with a lipophilic substance, the hardness of the tablet is weak and production is impossible. In addition, hardened castor oil is strongly adsorbed on the wall during the mixing process in the high-speed mixer by the wet granulation method due to strong adsorption force, but the mixing process can not be performed. However, the first drug layer of the combined preparation according to the present invention is tramadol or its pharmaceutical Combination of the lubricant with the hardened castor oil as a sustained release of the acceptable salt in a specific ratio, preferably 3.0 to 13.0% by weight relative to the total weight of the first drug layer in the multilayer solid preparation, provides excellent control of the initial release of tramadol But also has the advantage of having a hardness of the appropriate formulation.

In addition, the first drug layer of the solid preparation according to the present invention may further contain pharmaceutically acceptable additives such as excipients, stabilizers and binders in addition to the above components.

As used herein, the term "excipient " refers to a material added to impart a suitable hardness or shape to a drug, or to be of a size that is easy to handle given a constant dose weight when the amount of the active ingredient is low. For example, it is not limited to sugar derivatives such as mannitol or sorbitol, cellulose derivatives such as corn starch, potato starch, lactose, and microcrystalline cellulose, and inorganic excipients such as carbonates such as calcium carbonate.

As used herein, the term "stabilizer " means a material that ensures chemical stability of a pharmaceutical preparation. For example, there may be mentioned, for example, ascorbic acid, ascorbyl palmitate, butylhydroxyanisole, butylhydroxytoluene, citric acid hydrate, erysorbic acid, fumaric acid, hypophosphoric acid, lactobionic acid, malic acid, methionine, propionic acid, But are not limited to, sodium lauryl sulfate, sodium lauryl sulfate, sodium lauryl sulfate, sodium lauryl sulfate, sodium lauryl sulfate, sodium lauryl sulfate, sodium lauryl sulfate, sodium lauryl sulfate,

As used herein, the term "binder " means a material capable of imparting elasticity and tackiness to increase the strength of the formed formulation, especially the strength of the formed tablet. In addition, the binder may impart elasticity and tackiness to the formulation, thereby delaying release of the active agent from the formulation. Examples of the binder include a plasticizer such as ethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, polyethylene oxide , Polyvinyl alcohol, polyacrylic acid, polymethacrylic acid, and the like. Preferred examples of the binder include ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl methyl cellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, and polyethylene Oxide, but is not limited thereto.

In the solid preparation according to the present invention, the hardened castor oil may be coated with a binder. The solid preparation according to the present invention comprising the hardened castor oil and the binder is characterized in that the fat solubility of the hardened castor oil is reduced due to the coating of the binder, whereby the hardness of the solid preparation appears to be at a level suitable for purification.

In addition, the solid preparation according to the present invention is characterized in that, in addition to the pregabalin or pharmaceutically acceptable salt thereof, the second drug layer contains a cellulose-based excipient. The dose of pregabalin or a pharmaceutically acceptable salt thereof contained in the second drug layer may be from 50 to 200 mg, preferably from 75 to 150 mg. Pregabalin or a pharmaceutically acceptable salt thereof has a very large content as a main component, and is in a crystalline form and has good flowability but poor stability. Therefore, the tablets have a disadvantage that they are fragile because they have a low hardness. For this reason, pregabalin or its pharmaceutically acceptable salt has been difficult to develop into tablets, and the reference drug has been circulating in capsules (Rilica® capsules).

However, the present invention is preferably used as an excipient for such a solid preparation, preferably a cellulose compound, for example, at least one selected from the group consisting of crystalline cellulose, powdered cellulose, silicified crystalline cellulose and low-substituted hydroxypropyl cellulose , In particular in a weight ratio of 1: 0.7 to 1: 2, relative to the weight of the active ingredient of the second drug layer (pregabalin or a pharmaceutically acceptable salt thereof), an excellent pregabalin or pharmaceutically acceptable salt thereof It is possible to provide a preparation containing an acceptable salt, and in particular, it is possible to secure an appropriate hardness in the case of tablets.

In addition, preferably, the second drug layer according to the present invention may further comprise a pharmaceutically acceptable additive such as a disintegrant and a binder to improve the release of pregabalin or a pharmaceutically acceptable salt thereof. The binder may be as previously mentioned in the first drug layer, and the disintegrant may consist of sodium starch glycolate, carboxymethylcellulose sodium, croscarmellose sodium, low substituted hydroxypropylcellulose, pregelatinized starch and crospovidone And the like.

In addition, the second drug layer of the solid preparation according to the present invention may further include pharmaceutically acceptable additives such as a lubricant and a stabilizer in addition to the above components. The lubricant and the stabilizer contained in the second drug layer can be applied equally to those mentioned in the first drug layer.

In a preferred embodiment, the second drug layer according to the present invention, unlike the first drug layer, can be applied by any of a variety of methods for making conventional formulations, such as direct tabletting, dry granulation or wet granulation, It may be manufactured.

The multi-layered solid preparation according to the present invention may further comprise a film coating layer on the preparation surface.

As a specific example, the tramadol or its pharmaceutically acceptable salt of the multi-layered solid preparation of the present invention is characterized by exhibiting a dissolution rate of 0 to 60% for 4 hours from the start of elution in an aqueous solution. It is possible to provide a multi-layered solid preparation containing excellent tramadol and pregabalin, wherein the ultraset, which is a commercially available product, satisfies the initial release suppression effect, which is much superior to the sustained release formulation, and which has significantly reduced side effects in vivo. In addition, the pregabalin or pharmaceutically acceptable salt thereof of the multilayered solid preparation of the present invention is characterized by exhibiting a dissolution rate of 60% or more after 5 minutes from the start of elution in an aqueous solution. It satisfies the rapid release effect, which is much superior to that of the existing commercial lirika capsules, and it can provide a multi-layered solid preparation which reduces pain by acting pregabalin in vivo in a short time.

In another aspect of the present invention, the present invention provides a method for preparing a solid preparation of a multilayered tablet form in which the initial release of tramadol or a pharmaceutically acceptable salt thereof is effectively controlled. The solid preparation of the present invention can be produced by a production method known in the art.

Preferably, the method further comprises:

(i) preparing a first drug layer comprising tramadol or a pharmaceutically acceptable salt thereof, a hardened castor oil and a glidant,

(ii) preparing a second drug layer comprising pregabalin or a pharmaceutically acceptable salt thereof and a cellulosic excipient, and

Compressing said first drug layer and said second drug layer to produce a solid formulation in a multilayer form

Multilayer And a method for producing a solid preparation.

Unless otherwise specified, the matters described in the solid preparation according to the present invention are directly applied to the present manufacturing method.

Specifically, step (i) according to the present invention is a step of preparing a first drug layer comprising a hardened castor oil and a glidant as a sustained release agent in tramadol or a pharmaceutically acceptable salt thereof, Castor oil can be the only insoluble hardened castor. In one embodiment of the present invention, water insoluble hardened castor oil, Cutina HR, was used. In a preferred embodiment, the hardened castor oil may be a water-insoluble hardened castor uniquely and may be present in an amount ranging from about 1% by weight of the first drug layer active ingredient (i. E., The weight of tramadol or a pharmaceutically acceptable salt thereof: : 3 to 1: 9, so that the initial release of tramadol or a pharmaceutically acceptable salt thereof can be effectively controlled.

Preferably, the first drug layer is produced by a process comprising wet granulation. In this connection, it has been found that the hardened castor oil is fat-soluble and that the hardness of the tablet when produced by direct compression method (dry method) or dry granulation method is too low to be applied to production (see Comparative Example 4). In addition, the hardened castor oil had a strong adsorption force due to the fat-solubility, and thus it was confirmed that the hardened castor oil was adsorbed on the wall during the mixing process in the high-speed mixer by the wet granulation method. In order to solve the problems of such hardened castor oil, the production method according to the present invention is characterized in that the lubricant referred to in the solid preparation is added in a specific ratio, preferably 3.0 to 13.0 wt% It is possible to easily produce the solid preparation according to the present invention by reducing the adsorption force of the hardened castor oil.

Also preferably, the preparation method of the present invention is characterized in that the first drug layer is prepared by a process comprising a wet granulation method further comprising, besides the ingredients, a pharmaceutically acceptable additive such as excipients, stabilizers and binders .

In a preferred embodiment, the lubricant is preferably granulated by mixing together the components other than the lubricant, such as tramadol or a pharmaceutically acceptable salt thereof, a hardened castor oil, and a lubricant to granulate the lubricant so that the lubricant is coated with the lubricant . Further, a lubricant may be further added to the granules so as to be compression-molded.

Further, the preparation method of the present invention includes a pharmaceutically acceptable additive such as pregabalin or a pharmaceutically acceptable salt thereof, a cellulose-based excipient, and additionally a lubricant and a stabilizer for the preparation of the second drug layer A method that can be used for the production of a conventional solid preparation (tablet) such as a direct compression method, a wet granulation method, or a dry granulation method can be used without limitation. Particularly, as mentioned in the above-mentioned solid preparation according to the present invention, when the excipient is a cellulosic excipient, when excipients other than cellulose are used, the stability is poor and it is difficult to secure the hardness of a suitable solid preparation. In order to secure such hardness, the cellulose-based excipient may be used at a weight ratio of 1: 0.7 to 1: 2, relative to the weight of the active ingredient (pregabalin or a pharmaceutically acceptable salt thereof) of the second drug layer.

In still further embodiments, pharmaceutically acceptable additives such as disintegrants and binders may be further administered to control the release of pregabalin or a pharmaceutically acceptable salt thereof in the manufacture of said second drug layer. The above-mentioned disintegrants and binders can be applied as mentioned above in the solid preparation.

Thus, the first drug layer and the second drug layer thus prepared can be produced by combining both layers using a conventional two-layer molding machine.

In a preferred embodiment, the preparation of the multi-layered, fixed-bed preparation may further comprise coating the formulation.

The dosage form of the multi-layered solid dosage form in which the initial release of tramadol or pharmaceutically acceptable salts thereof of the present invention is effectively inhibited can be in an oral dosage form. Formulations for oral administration may be tablets, capsules, and the like, and may be preferably tablets, but are not limited thereto.

When such a solid preparation preparation method of the present invention is used, by using the hardened castor oil, tramadol or a pharmaceutically acceptable salt thereof is superior to the conventional preparation in that the initial release is suppressed, It is possible to economically produce the cured castor oil at a relatively low price and to use the cured castor oil at a high ratio to lower the hardness which may be caused by the problem of adsorption and fat solubility of the cured castor oil, Can be solved by using. Further, it has an advantage that a wet granule type preparation containing hardened castor oil which is difficult to manufacture in the past can be produced.

Furthermore, according to the method for preparing a solid preparation according to the present invention, it is possible to solve the low hardness problem caused by using a high-dose pregabalin or a pharmaceutically acceptable salt thereof, and to obtain an excellent dissolution rate And a solid preparation exhibiting a hardness suitable for the solid preparation can be prepared.

According to the solid preparation of the present invention and its preparation method, the active ingredient tramadol or its pharmaceutically acceptable salt can suppress the initial release of the ultraset, which is a commercially available drug, While the pregabalin layer exhibits an early release that is earlier than the dissolution rate of the licorice capsule in circulation so that the initial pain suppressing effect is enhanced while a strong side effect due to tramadol is suppressed and a solid preparation with appropriate hardness can be prepared .

FIG. 1 is a graph showing the tablets containing tramadol hydrochloride of Examples 1 to 3 and the dissolution rate of tramadol hydrochloride of ultra-long-shelf serum.
FIG. 2 is a graph showing the tablets containing tramadol hydrochloride of Comparative Examples 1 to 6 and the dissolution rate of tramadol hydrochloride of ultra-fast-slow-release tablets.
FIG. 3 is a graph showing the dissolution rate of tramadol hydrochloride of the two-layer tablets and the ultrascelial tablet of Example 7 according to the present invention.
4 is a graph showing the dissolution rate of pregabalin in the bilayer tablets and lilica capsules according to Example 7. Fig.

Hereinafter, the present invention will be described in detail with reference to examples. However, the following examples are illustrative of the present invention, and the present invention is not limited by the following examples.

Example  And Comparative Example

- Tramadol  The hydrochloride layer and 2nd floor definition Example  And Comparative Example

One. Example  1 to 3

The mixture was prepared by a conventional wet granulation process with ingredients and contents shown in Table 1 below, and then tableted into a single layer using a tablet machine.

1) All components except for magnesium stearate (colloidal silicon dioxide added with apple No. 40) added to the post-mix were added to a high-speed mixer and mixed for 5 minutes.

2) The mixture was granulated by adding purified water containing an appropriate amount of ethanol.

3) The granules were dried at 60 ° C.

4) The dried material was set up as a 20-size fuselage.

5) Magnesium stearate (post-mix) was added to the sizing product and mixed.

6) The mixture was tableted into tablets using a tablet machine.

division Example 1 Example 2 Example 3 Raw material name mg / tablet % mg / tablet % mg / tablet % Tramadol hydrochloride 75.00 21.4 75.00 18.8 75.00 16.7 Hardened castor oil (Cutina HR) 237.80 67.9 287.80 72.0 337.80 75.1 Hydroxypropylcellulose 10.50 3.0 10.50 2.6 10.50 2.3 Colloidal silicon dioxide (pre-mixed) 3.20 0.9 3.20 0.8 3.20 0.7 Talc (pre-mix) 16.00 4.6 16.00 4.0 16.00 3.6 Magnesium stearate (post-mix) 7.50 2.1 7.50 1.9 7.50 1.7 sub Total 350.00 100.0 400.00 100.0 450.00 100.0

2. Example  4 to 6

A single-layer tablet was prepared in the same manner as the preparation methods of Examples 1 to 3 with the components and contents shown in Table 2 below.

division Example 4 Example 5 Example 6 Raw material name mg / tablet % mg / tablet % mg / tablet % Tramadol hydrochloride 75.00 22.4 75.00 21.4 75.00 21.4 Hardened castor oil (Cutina HR) 237.80 71.0 237.80 67.9 237.80 67.9 Hydroxypropylcellulose 10.50 3.1 10.50 3.0 10.50 3.0 Sodium stearyl fumarate (pre-mixed) - - - - 19.2 5.5 Talc (pre-mix) 4.2 1.3 - - - - Magnesium stearate (pre-mixed) - - 19.2 5.5 - - Magnesium stearate (post-mix) 7.50 2.2 7.50 2.1 7.50 2.1 sub Total 335.00 100.0 350.00 100.0 350.00 100.0

3. Example  7

The tramadol hydrochloride layer was wet granulated and the pregabalin layer was prepared by a direct tableting process using the components and contents shown in Table 3 below. The mixture was compressed into two layers using a multi-layer tableting machine.

≪ Tramadol hydrochloride layer production method >

1) All components except for magnesium stearate (colloidal silicon dioxide added by apodization with a 40-piece sieve) were added to a high-speed mixer and mixed for 5 minutes.

2) The mixture was granulated by adding purified water containing an appropriate amount of ethanol.

3) The granules were dried at 60 ° C.

4) The dried material was set up as a 20-size fuselage.

5) Magnesium stearate (post-mix) was added to the sizing product and mixed.

≪ Preparation method of pregabalin layer >

1) The main component was mixed with talc and magnesium stearate, and then apically prepared with a 20-piece sieve.

2) The remaining components were added and mixed for 5 minutes.

The mixture of the tramadol hydrochloride layer mixture and the pregabalin layer prepared according to the above preparation method was compressed into a two-layer tablet using a multi-layer tablet machine.

Configuration division Example 7 Raw material name mg / tablet % Tramadol hydrochloride layer Tramadol hydrochloride 75.00 21.4 Hardened castor oil (Cutina HR) 237.80 67.9 Hydroxypropylcellulose 10.50 3.0 Colloidal silicon dioxide (pre-mixed) 3.20 0.9 Talc (pre-mix) 16.00 4.6 Magnesium stearate (post-mix) 7.50 2.1 Total tramadol hydrochloride layer 350.00 100.0 Pregabalin layer Pregabalin 150.00 42.9 Microcrystalline cellulose
(Prosolv SMCC 50) 87.00 24.9 Microcrystalline cellulose
(Prosolv HD 90) 88.00 25.1 Hydroxypropylcellulose 9.00 2.6 Starch glycolate sodium 9.00 2.6 Talc 5.25 1.5 Magnesium stearate 1.75 0.5 Pregabalin Floor Subtotal 350.00 100.0 Two-layered quasi- 700.00 100.0

4. Example  8 and 9

Single-layer tablets were prepared in the same manner as in Examples 1 to 3 with the ingredients and contents shown in Table 4 below.

division Example 8 Example 9 Raw material name mg / tablet % mg / tablet % Tramadol hydrochloride 37.50 16.7 37.50 9.4 Hardened castor oil (Cutina HR) 168.90 75.1 303.30 75.8 Hydroxypropylcellulose 5.25 2.3 10.50 2.6 Colloidal silicon dioxide (pre-mixed) 1.60 0.7 3.20 0.8 Talc (pre-mix) 8.00 3.6 38.00 9.5 Magnesium stearate (post-mix) 3.75 1.7 7.50 1.9 sub Total 225.00 100.0 400.00 100.0

5. Comparative Example  1 to 3

The ingredients were mixed with the ingredients shown in Table 5 below in a conventional direct tableting process, and the mixture was compressed into tablets using a tablet machine.

1) All ingredients except magnesium stearate added to post-mix were mixed for 5 minutes.

2) Magnesium stearate was added to the mixture after 40 hours of sieving, and mixed for 5 minutes.

3) The mixture was compressed into tablets using a tablet machine.

division Comparative Example 1 Comparative Example 2 Comparative Example 3 Raw material name mg / tablet % mg / tablet % mg / tablet % Tramadol hydrochloride 75.00 30.0 75.00 30.0 75.00 30.0 Hydroxypropylcellulose 172.50 69.0 - - - - Polyox WSR301 - - 172.50 69.0 - - Ethylcellulose 10 cps - - - - 172.50 69.0 Magnesium stearate (post-mix) 2.50 1.0 2.50 1.0 2.50 1.0 sub Total 250.00 100.0 250.00 100.0 250.00 100.0

6. Comparative Example  4 and 5

A single layer tablet was prepared by the manufacturing method of Comparative Examples 1 to 3 with the components and contents shown in Table 6 below.

division Comparative Example 4 Comparative Example 5 Raw material name mg / tablet % mg / tablet % Tramadol hydrochloride 75.00 30.0 75.00 30.0 Hydroxypropylcellulose - - - - Hardened castor oil 172.50 69.0 - - Hephromolose 2208 200,000 cps - - 172.50 69.0 Magnesium stearate (post-mix) 2.50 1.0 2.50 1.0 sub Total 250.00 100.0 250.00 100.0

7. Comparative Example  6 and 7

The tablets were prepared in the same manner as in Examples 1 to 3 with the ingredients and contents shown in Table 7 below.

division Comparative Example 6 Comparative Example 7 Raw material name mg / tablet % mg / tablet % Tramadol hydrochloride 75.00 30.0 75.00 22.7 Hardened castor oil (Cutina HR) 137.80 55.1 237.00 71.8 Hydroxypropylcellulose 10.50 4.2 10.50 3.2 Colloidal silicon dioxide (pre-mixed) 3.20 1.3 - - Talc (pre-mix) 16.00 6.4 - - Magnesium stearate (post-mix) 7.50 3.0 7.50 2.3 sub Total 250.00 100.0 330.00 100.0

- Pregabalin Example  And Comparative Example

8. Example  10 to 13

The ingredients were mixed and prepared in a conventional direct tableting process with the ingredients shown in Table 8 below and then tableted using a tablet machine.

1) The main component was mixed with talc and magnesium stearate, and then apically prepared with a 20-piece sieve.

2) The remaining components were added and mixed for 5 minutes.

3) The mixture was compressed into tablets using a tablet machine.

division Example 10 Example 11 Example 12 Example 13 Raw material name mg / tablet % mg / tablet % mg / tablet % mg / tablet % Pregabalin 150.00 42.9 150.00 42.9 150.00 50.0 150.00 37.5 Microcrystalline cellulose
(Prosolv SMCC 50) 96.00 27.4 87.00 24.9 63.00 21.0 109.75 27.4 Microcrystalline cellulose
(Prosolv HD 90) 97.00 27.7 88.00 25.1 63.00 21.0 113.00 28.3 Hydroxypropylcellulose - - 9.00 2.6 9.00 3.0 9.00 2.3 Starch glycolate sodium - - 9.00 2.6 9.00 3.0 9.00 2.3 Talc 5.25 1.5 5.25 1.5 6.00 2.0 5.25 1.3 Magnesium stearate 1.75 0.5 1.75 0.5 - - 4.00 1.0 sub Total 350.00 100.0 350.00 100.0 300.00 100.0 400.00 100.0

9. Example  14 to 17

The components were mixed with the ingredients shown in Table 9 below in a conventional direct tableting process, and then tableted using a tableting machine.

1) The main component and talc, magnesium stearate, and colloidal silicon dioxide were mixed and then apically excised with a 20-piece sieve.

2) The remaining components were added and mixed for 5 minutes.

3) The mixture was compressed into a single layer using a tablet machine

division Example 14 Example 15 Example 16 Example 17 Raw material name mg / tablet % mg / tablet % mg / tablet % mg / tablet % Pregabalin 150.00 42.9 150.00 42.9 150.00 50.0 150.00 37.5 Microcrystalline cellulose 101 96.00 27.4 92.50 26.4 - - - - Microcrystalline cellulose
(Vivapur12) 97.00 27.7 97.00 27.7 - - 189.50 54.1 Low-substituted hydroxypropylcellulose - - - - 189.50 54.1 - - Talc 5.25 1.5 5.25 1.5 5.25 1.5 5.25 1.5 Magnesium stearate 1.75 0.5 1.75 0.5 1.75 0.5 1.75 0.5 Colloidal silicon dioxide - - 3.50 1.0 3.50 1.0 3.50 1.0 sub Total 350.00 100.0 350.00 100.0 350.00 100.0 350.00 100.0

10. Comparative Example  8 to 11

A single layer tablet was prepared by the manufacturing methods of Examples 14 to 17 with the components and contents shown in Table 10 below.

division Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11 Raw material name mg / tablet % mg / tablet % mg / tablet % mg / tablet % Pregabalin 150.00 50.0 150.00 50.0 150.00 50.0 150.00 42.9 Mannitol 126.00 42.0 - - - - - - Lactose baggage - - 126.00 42.0 - - - - Calcium hydrogen phosphate - - - - 126.00 42.0 - - Pregelatinized starch - - - - - - 189.50 54.1 Hydroxypropylcellulose 9.00 3.0 9.00 3.0 9.00 3.0 - - Starch glycolate sodium 9.00 3.0 9.00 3.0 9.00 3.0 - - Talc - - - - - - 5.25 1.5 Magnesium stearate 3.00 1.0 3.00 1.0 3.00 1.0 1.75 0.5 Colloidal silicon dioxide 3.00 1.0 3.00 1.0 3.00 1.0 3.50 1.0 sub Total 300.00 100.0 300.00 100.0 300.00 100.0 350.00 100.0

11. Comparative Example  12 and 13

The components were mixed with the components shown in Table 11 below in a conventional direct tableting process, and the mixture was compressed using a tablet machine.

1) The main component was mixed with magnesium stearate and colloidal silicon dioxide, and then apically excised with a 20-piece sieve.

2) The remaining components were added and mixed for 5 minutes.

3) The mixture was compressed into a single layer using a tablet machine

division Comparative Example 12 Comparative Example 13 Raw material name mg / tablet % mg / tablet % Pregabalin 150.00 75.0 150.00 60.00 Microcrystalline cellulose
(Prosolv SMCC 50) 34.00 17.0 80.20 32.08 Hydroxypropylcellulose 6.00 3.0 7.50 3.00 Starch glycolate sodium 6.00 3.0 7.50 3.00 Talc - - - - Magnesium stearate 2.00 1.0 2.40 0.96 Colloidal silicon dioxide 2.00 1.0 2.40 0.96 sub Total 200.00 100.0 250.00 100.0

Experimental Example

One. Experimental Example  1: Dissolution test - Monolayer

The tablets prepared in the above Examples and Comparative Examples were subjected to a dissolution test. The elution test was carried out with 900 ml of an aqueous solution, the paddle method, and the rotation speed of 50 rpm as the eluent with the purified tablets. Approximately 5 mL of each sample was taken after the start of the elution test, and then filtered with a membrane filter. 3 mL of the sample was discarded and 1 mL of the sample was collected and analyzed by high performance liquid chromatography. For comparative purposes, the UltraSets, which are in circulation on the market, were used as the comparison group. The results are shown in Tables 12 and 13, and Figs. 1 and 2.

2. Experimental Example  2: Dissolution test - Two-storied house

The multilayered tablet prepared in Example 7 was subjected to 900 mL of an aqueous solution, paddle method, at a rotation speed of 50 rpm. Approximately 5 mL of each sample was taken after the start of the elution test, and then filtered with a membrane filter. 3 mL of the sample was discarded and 1 mL of the sample was collected and analyzed by high performance liquid chromatography. For comparative purposes, a commercially available Ultraset was used as a control group. The results are shown in Tables 14 and 15, Figs. 3 and 4.

Pregabalin dissolution rate in multi-layered preparations Sample name 0 5 minutes 10 minutes 15 minutes Example 7 0.0 89.8 94.4 99.4 Lilika Capsule 0.0 44.5 93.5 100.5

3. Experimental Example  3: Hardness measurement

The hardness of the tablets was measured by a hardness meter (model: TBH125) manufactured by ERWEKA. The results are shown in Tables 16 to 18 below.

Comparison of hardness of tablets prepared by wet granulation process and direct tabletting process using hardened castor oil Sample name Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Comparative Example 4 Hardness (kp) 9.9 10.3 9.8 9.4 10.5 9.8 4.1

Comparison of hardness of tablets prepared by direct tableting process of pregabalin layer Sample name Example 10 Example 11 Example 12 Example 13 Example
14 Example 15 Example
16 Example
17 Hardness (kp) 14.7 13.8 10.3 18.2 11.0 14.6 11.9 10.6

Comparison of hardness of tablets prepared by direct tableting process of pregabalin layer Sample name Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11 Comparative Example 12 Comparative Example 13 Hardness (kp) 2.4 2.9 2.4 4.7 2.5 5.5

Claims (21)

(a) a first drug layer comprising tramadol or a pharmaceutically acceptable salt thereof, a hardened castor oil and a glidant; And
(b) a second drug layer comprising pregabalin or a pharmaceutically acceptable salt thereof and a cellulosic excipient. The solid formulation of claim 1, wherein the pharmaceutically acceptable salt of tramadol is tramadol hydrochloride. The method of claim 1, wherein the hardened castor oil is present in a weight ratio of 1: 3 to 1: 9 by weight of the first drug layer active ingredient (i.e., tramadol or pharmaceutically acceptable salt thereof: hardened castor oil free weight) By weight of the solid formulation. The solid formulation of claim 1, wherein the lubricant of the first drug layer is from 3.0 to 13.0 wt% based on the total weight of the first drug layer. The pharmaceutical composition according to claim 1, wherein the lubricant of the first drug layer is at least one selected from the group consisting of stearic acid, magnesium stearate, glyceryl behenate, sodium stearyl fumarate, talc and colloidal silicon dioxide. Multi-layered solid preparation. The solid preparation according to claim 1, wherein the first drug layer further comprises at least one member selected from the group consisting of excipients, stabilizers, and binding agents. The pharmaceutical composition of claim 1, wherein the cellulosic excipient of the second drug layer is included in a weight ratio of 1: 0.7 to 1: 2 by weight of the second drug layer active ingredient (pregabalin or a pharmaceutically acceptable salt thereof) ≪ / RTI > The solid preparation according to claim 1, wherein the cellulose-based excipient is at least one selected from the group consisting of crystalline cellulose, powdered cellulose, silicified crystalline cellulose and low-substituted hydroxypropyl cellulose. The solid preparation according to claim 1, wherein the second drug layer further comprises at least one member selected from the group consisting of a lubricant, a stabilizer, a disintegrant, and a binder. The solid preparation of claim 1, wherein the tramadol or pharmaceutically acceptable salt thereof in the formulation exhibits a dissolution rate of 0 to 60% for 4 hours after the start of elution in the aqueous solution. The solid preparation of claim 1, wherein the pregabalin or pharmaceutically acceptable salt thereof in the formulation exhibits a dissolution rate of 60% or more after 5 minutes from the start of elution in the aqueous solution. 2. The formulation according to claim 1, wherein the formulation is in a two-layered form. (i) preparing a first drug layer comprising tramadol or a pharmaceutically acceptable salt thereof, a hardened castor oil and a glidant,
(ii) preparing a second drug layer comprising pregabalin or a pharmaceutically acceptable salt thereof and a cellulosic excipient, and
(iii) compressing the first drug layer and the second drug layer to produce a solid formulation in a multilayered form. 14. The method of claim 13, wherein the hardened castor oil of step (i) is used in a weight ratio of 1: 3 to 1: 9 by weight of the first drug layer active ingredient. 14. The method of claim 13, wherein the first drug layer of step (i) is produced by a process comprising wet granulation. 14. The method of claim 13, wherein the amount of glidant used in the first drug layer of step (i) is from 3.0 to 13.0% by weight based on the total weight of the first drug layer. 14. The method of claim 13, wherein the lubricant used in the first drug layer of step (i) is selected from the group consisting of stearic acid, magnesium stearate, glyceryl behenate, sodium stearyl fumarate, talc and colloidal silicon dioxide Wherein said at least one species is selected from the group consisting of: 14. The method of claim 13, wherein the first drug layer of step (i) further comprises at least one selected from the group consisting of excipients, stabilizers, and binding agents. The method according to claim 13, wherein the cellulose-based excipient in step (ii) is used in a weight ratio of 1: 0.7 to 1: 2 by weight of the second drug layer active ingredient. 14. The method according to claim 13, wherein the cellulose-based excipient in step (ii) is at least one selected from the group consisting of crystalline cellulose, powdered cellulose, silicified crystalline cellulose and low-substituted hydroxypropyl cellulose. 14. The method of claim 13, wherein the second drug layer of step (ii) further comprises at least one selected from the group consisting of a lubricant, a stabilizer, a disintegrant, and a binder.

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