JP6919119B2 - A compressed solid pharmaceutical composition containing a γ-aminobutyric acid derivative substituted at the 3-position. - Google Patents

Description

The present invention is a solid pharmaceutical composition or compressed solid pharmaceutical composition containing a derivative of γ-aminobutyric acid (GABA), preferably a solid pharmaceutical composition or compressed solid containing a γ-aminobutyric acid derivative substituted at the 3-position. The present invention relates to a pharmaceutical composition and a method for producing the solid pharmaceutical composition or a compressed solid pharmaceutical composition.
The present invention is a solid pharmaceutical composition or a compressed solid pharmaceutical composition that stably retains a derivative of γ-aminobutyric acid (GABA), preferably a compressed solid pharmaceutical composition that stably retains a γ-aminobutyric acid derivative substituted with a 3-position. The present invention relates to a composition and a method for producing the solid pharmaceutical composition or the compressed solid pharmaceutical composition.

The present invention does not cause the bitterness of a derivative of γ-aminobutyric acid (GABA), preferably a γ-aminobutyric acid derivative in which the 3-position is substituted, is excellent in elution of the derivative, maintains sufficient hardness, and is molded. A solid pharmaceutical composition or a compressed solid pharmaceutical composition having excellent properties, low adhesiveness, good powder flow, sufficient storage stability of the derivative, and capable of producing a high-quality pharmaceutical preparation, and the said The present invention relates to a method for producing a solid pharmaceutical composition or a compressed solid pharmaceutical composition.

式Ｉ プレガバリンの構造式

式ＩＩ ガバペンチンの構造式

式ＩＩＩ バクロフェンの構造式 Pregabalin, gabapentin, and baclofen are known as typical pharmaceuticals for γ-aminobutyric acid derivatives. The structures of pregabalin, gabapentin, and baclofen are, respectively, in the following formulas I to III, respectively.

Formula I Structural formula of pregabalin

Formula II Structural formula of gabapentin

Equation III Structural formula of baclofen

Pregabalin is marketed in Japan as a hard capsule under the trade name "Lyrica" by Pfizer for the treatment of neuropathic pain and pain associated with fibromyalgia. According to Lyrica's interview form, its expiration date is three years.
Gabapentin is marketed in Japan as tablets and syrups under the trade name "Gabapent" by Pfizer for the treatment of epilepsy. According to the "Gabapentin" interview form, both gabapentin tablets and syrups have a three-year expiration date.

In Japan, baclofen is sold as tablets for the treatment of spastic paralysis under the trade name of "Rioresal" by Novartis and "Gabalon" by Daiichi Sankyo Co., Ltd. Baclofen is marketed by Daiichi Sankyo Co., Ltd. as a liquid for intrathecal injection for the treatment of severe spastic paralysis caused by cerebrospinal diseases. According to the interview form, Rioresal tablets are valid for 3 years, Gavalon intrathecal injections are valid for 3 years, and Gavalon tablets are valid for 5 years.

Pregabalin and gabapentin are GABA derivatives that increase the lipophilicity of gamma-aminobutyric acid (GABA) to cross the blood-brain barrier. Pregabalin and gabapentin have a structure similar to gamma-aminobutyric acid (GABA), but _{their binding to GABA (GABA A} , GABA _B , benzodiazepine) receptors and their inhibitory effect on GABA metabolism and reuptake Not allowed. In addition, it does not have actions such as potential-dependent sodium channel blockade, opioid receptor activation, NMDA receptor blockade, cyclooxygenase inhibition, and monoamine reuptake inhibition, which are the mechanisms of action of existing analgesics.

Voltage-gated calcium channels are classified into P-type, Q-type, N-type, L-type, R-type, and T-type based on electrophysiological differences. Each of these is composed of five subunits, α1, α2, β, δ, and γ.
Of these, N-type calcium channels are thought to release neurotransmitters and affect pain sensitization. Pregabalin and gabapentin combine with the α2δ subunit, an auxiliary subunit of N-type calcium channels, to reduce the influx of calcium into nerve endings and are excitatory neurotransmitters that depend on elevated intracellular calcium ion levels. Suppresses the release of calcium.

On the other hand, calcium inhibitors, which are mainly used as therapeutic agents for hypertension, act on L-type calcium channels and exert their effects. Therefore, pregabalin and gabapentin, which antagonize only N-type calcium channels, affect blood pressure and cardiac function. It does not affect.

Both pregabalin and gabapentin are first-line drugs for neuropathic pain. Pregabalin and gabapentin are N-type voltage-gated when primary nociceptive neurons such as C fibers and Aδ fibers that transmit pain sensation in the skin project onto the glio-like substance of the posterior horn of the spinal cord to form synapses with secondary neurons. It binds to the α2δ subunit of the calcium channel to inhibit the influx of calcium into nerve endings and suppress the release of excitatory neurotransmitters, thereby producing an analgesic effect on neuropathy pain. Pregabalin has been shown to have a statistically significant analgesic effect in clinical trials in patients with postherpetic neuralgia and painful diabetic neuropathy.

The analgesic potency of gabapentin and pregabalin is 1: 5, and gabapentin should be taken in 5 to 6 times the amount of pregabalin. Both pregabalin and gabapentin have side effects of drowsiness, light-headedness, falls, peripheral edema, and weight gain, so fine-tuning of the dose is required.

The nerve endings of the GABAergic nervous system are called inhibitory nervous systems because they hyperpolarize postsynaptic cells and suppress the generation of action potentials.
Gabapentin suppresses nervous system overactivity by activating GABA transporters present at the nerve endings of the GABAergic nervous system, which are widely distributed in the central nervous system, and maintaining and enhancing the function of the GABAergic nervous system. Therefore, it can be used for the treatment of epilepsy.

Baclofen _{acts as an agonist of GABA B} receptor and has a muscle relaxant effect, so that it has an analgesic effect on pain caused by spasticity in multiple sclerosis, spinal cord injury, cerebrospinal disease and the like.

There is a difference in the pharmacokinetics of pregabalin and gabapentin, where gabapentin is absorbed by the L-amino acid transporter, while pregabalin is absorbed by either the D- or L-amino acid transporter. Therefore, the bioavailability of gabapentin decreases at high doses and it is difficult to predict the blood concentration, but pregabalin has a bioavailability of 90% or more and shows dose-dependent pharmacokinetics, so the blood concentration. Is easy to predict. In addition, while gabapentin reaches its peak in blood concentration about 3 hours after administration, pregabalin reaches its peak in about 1 hour, so that the effect can be obtained quickly.

Regarding excretion, pregabalin does not bind to plasma proteins and is not metabolized in the liver, so it is unlikely to cause drug interactions. In addition, 99% of the urinary excretion of pregabalin is unchanged. The half-life of plasma concentrations of pregabalin and gabapentin is approximately 6 hours regardless of dose increase or repeated administration. The absorption of pregabalin and gabapentin is largely unaffected by diet and is not metabolized in the liver, so it does not increase or inhibit hepatic enzymes, so it is a drug with very little drug interaction. The systemic clearance of pregabalin in healthy adults is 60-100 mL / min, and the average systemic clearance of gabapentin is 116 mL / min, both of which are consistent with the glomerular filtration rate and the urinary excretion rate of unchanged form. There is a report that it was almost 100%.

The most common side effects of pregabalin and gabapentin are drowsiness and light-headedness. The frequency increases as the dose increases and as the elderly age. The frequency of side effects of pregabalin is around 20% in domestic studies up to approval. Pregabalin has also been reported to suddenly lose consciousness. As another side effect of pregabalin, edema has been reported in about 15%.

The frequency of side effects of gabapentin is about 59% in domestic studies up to approval. Other side effects of gabapentin were headache (about 9%), diplopia (about 5%), and malaise (about 4%).
The frequency of side effects of baclofen is about 37% in domestic studies up to approval. The main side effects were drowsiness (about 10%), nausea (about 5%), loss of appetite (about 3%), weakness (about 7%), and light-headedness (3%).

Pregabalin and gabapentin are less likely to cause harmful interactions with other drugs, but it should be noted that the combined use of pregabalin and opioids has been reported to enhance respiratory depression by opioids.

These γ-aminobutyric acid derivatives have common properties based on a common structure, and even when formulated, there are common problems based on the common structure.

Japanese Patent Application Laid-Open No. 2000-034227 (Patent Document 1) describes that γ-aminobutyric acid derivatives such as gabapentin, pregabalin, and baclofen are extremely bitter drugs and have extremely poor compressibility and fluidity. ing. Further, in Patent Document 1, from the viewpoint of safety, the permissible content of lactam compound during the expiration date is 1.0% or less, and many auxiliaries react with gabapentin, pregavalin or baclofen over time. Lactam (an intramolecular dehydration condensation product of amino groups and carboxyl groups existing in the molecule of a compound having a γ-aminobutyric acid structure) is formed, and the more compacted the compound, the more accelerated the dehydration condensation reaction. It has been described that the use of water or organic solvents in the chemicals further accelerates. The structures of the lactam form of pregabalin, the lactam form of gabapentin, and the lactam form of baclofen are as shown in the following formulas IV to VI, respectively.

式ＩＶ プレガバリンのラクタム体の構造式

式Ｖ ガバペンチンのラクタム体の構造式

式ＶＩ バクロフェンのラクタム体の構造式

Equation IV Structural formula of the lactam body of pregabalin

Formula V Structural formula of the lactam body of gabapentin

Formula VI Structural formula of the lactam body of baclofen

As a solution to the above problem, Patent Document 1 blends γ-aminobutyric acid derivative with ethylene glycol, propylene glycol, butylene glycol, sorbitol, glycerin and fatty acid esters thereof as stabilizers. Therefore, we have proposed a stabilized solid composition of γ-aminobutyric acid derivative.
The same description is given to Japanese Patent Application Laid-Open No. 2003-055211 (Patent Document 2), which is a divisional application of Patent Document 1, and Japanese Patent Application Laid-Open No. 2004-043506 (Patent Document 3), which is a divisional application thereof.

Japanese Patent Application Laid-Open No. 2000-034226 (Patent Document 4) also describes the same problems as those of Patent Documents 1 to 3, and as a solution to the problem, γ-aminobutyric acid is obtained by adding an amino acid to the γ-aminobutyric acid derivative. It is described that the amino group and carboxyl group of the derivative can be blocked to stabilize the γ-aminobutyric acid derivative in the aqueous state and the solid state.

Japanese Patent Application Laid-Open No. 2009-514847 (Patent Document 5) also describes that the pregabalin preparation may form a lactam form by dehydration condensation of an amino group and a carboxyl group existing in the molecule of pregabalin. Further, in Patent Document 5, since pregabalin is absorbed in the small intestine and the ascending colon and is difficult to be absorbed beyond the right colic curve, a sustained release preparation that simply releases the active ingredient over 6 hours or more is used after 6 hours. After that, it is described that it cannot be a sustained release preparation taken once a day because it moves beyond the right colonic flexure and becomes difficult to be absorbed.

As a solution to this, Patent Document 5 contains pregabalin, polyvinyl acetate, povidone, and crosslinked povidone so that it stays in the stomach for a long period of time and continuously releases pregabalin while staying in the stomach. We are proposing a sustained-release pharmaceutical preparation that is taken once a day.

Japanese Patent Application Laid-Open No. 2014-521639 (Patent Document 6) also states that the average absorption window of pregabalin is 6 hours or less, and as a solution thereof, pregabalin by "containing pregabalin or a salt thereof and hydroxypropylmethyl cellulose". The first release control phase for the purpose of controlling the release and improving the floating property and the second release control phase having both the swelling property and the floating property by "containing polyethylene oxide as the swelling polymer" are uniformly made. We are proposing a dispersed, sustained-release tablet.

In Japanese Patent Application Laid-Open No. 2003-504324 (Patent Document 7), as a means for solving the problem of producing coated granules in which the taste is masked and the active ingredient is immediately released, first, sodium carboxymethyl cellulose (sodium carmellose) and cloth are used. Disintegrants such as povidone and carboxymethyl starch are first dried and mixed with the active ingredient powder, wet granulated with a binder, and then film disintegrants such as sodium carboxymethyl cellulose, crospovidone and carboxymethyl starch and a coating agent. It is proposed to spray and coat with the containing suspension and then dry.

Then, in Example 3 of Patent Document 7, granules containing pregabalin, crospovidone, acesulfame potassium, precipitated silica, ethyl cellulose and crospovidone are mixed with mannitol, crospovidone, aspartame, fragrance and magnesium stearate and tableted. A quick-disintegrating tablet is described.
In Example 3 of Patent Document 7, there is a description that taste masking and dissolution characteristics have been confirmed, but there is no description about storage stability.

WO2015 / 007890 (Patent Document 8) proposes capsules containing pregabalin and vitamin B12 in order to prevent vitamin B deficiency from occurring when taking pregabalin, resulting in nerve damage and anemia.

WO2015 / 114656 (Patent Document 9) describes that pregabalin is absorbed only in the upper gastrointestinal tract.
Therefore, Patent Document 9 proposes a tablet that adheres to the gastric mucosa as a solution to the problem of preparing a once-daily sustained release preparation of pregabalin. Various film-coated tablets containing pregabalin, microcrystalline cellulose, magnesium stearate, and polyethylene glycol, tragacanth, polymethacrylate derivative, or polyethylene oxide as mucosal adhesive additives in the direct formulation of Example 1 of Patent Document 9. Is described.
However, Patent Document 9 does not describe that these preparations are actually manufactured, nor does it describe that any test has been performed.

WO2015 / 114655 (Patent Document 10) describes that pregabalin is absorbed only in the upper gastrointestinal tract.
Therefore, in Patent Document 10, as a solution to the problem of producing a once-daily sustained release preparation of pregavalin, by adding a low-density additive, the tablet is fragmented for a period of stay in the stomach. We are proposing tablets that maintain the "physical unity" that maintains the original shape without having to, and that maintain the "hydraulic equilibrium state" in which the tablets float in the gastric fluid without sinking or passing through the pylorus. .. The direct formulation of Example 1 of Patent Document 10 describes various film-coated tablets containing pregabalin, microcrystalline cellulose, colloidal silicon dioxide, and ethyl cellulose.
However, Patent Document 10 does not describe that these preparations are actually produced, nor does it describe that any test has been performed.

EP2343055 (Patent Document 11) describes pregabalin or a pharmaceutically acceptable salt thereof, colloidal silicon dioxide, and phosphoric acid as a solution to the problem of producing a stable preparation containing pregabalin, particularly a stable capsule. We propose a solid formulation containing calcium hydrogen hydrogen and corn starch. It is described that the capsule of Example 1 of Patent Document 11 was composed of these components and had good elution and stability even after 6 months under the condition of 40 ° C. and 75% relative humidity. Has been done.
However, Patent Document 11 does not describe that the compressed solid preparation is produced.

According to Japanese Patent Application Laid-Open No. 2011-173881 (Patent Document 12), dogs have stronger gastric muscles than humans, and the length of the gastrointestinal tract is only about half that of humans. It is stated that the production of release tablets is difficult.
Patent Document 12 uses a high-molecular-weight or high-viscosity polymer sufficient to withstand the strength of the gastrointestinal tract of a dog as a solution thereof, and the tablet settles on the bottom of the stomach of a dog and rapidly hydrates. Then, we are proposing tablets that are stored in the stomach for a long time.

Claims 1 to 19 of Patent Document 12 are not inventions that specify an active ingredient. However, claim 20 of Patent Document 12 describes pregabalin, amoxicillin, and tramadol as applicable active ingredients, and Example 3 of Patent Document 12 describes pregabalin and hypromellose as a high molecular weight or high viscosity polymer. Tablets containing 2208 are described. Similarly, Example 4 of Patent Document 12 describes tablets containing pregabalin and polyethylene oxide WSR N-60K NF as a high molecular weight or high viscosity polymer.

And FIG. 3 of Patent Document 12 describes the sustained release dissolution profile of the pregabalin tablets of Example 3 and Example 4. Furthermore, FIG. 8 of Patent Document 12 shows the time course of plasma pregabalin concentration when the pregabalin tablets and release capsules of Examples 3 and 4 were administered once to dogs.
However, Patent Document 12 does not describe the storage stability of the compressed solid preparation containing pregabalin.

Japanese Patent Application Laid-Open No. 2008-528494 describes (a) gabapentin or pregabalin coated with a pH-independent soluble polymer and (b) pH-independent in order to formulate gabapentin or pregabalin in a sustained-release formulation. We propose a composition containing gabapentin or pregabalin coated with a sex-insoluble polymer and (c) gabapentin or pregabalin coated with a pH-dependent soluble polymer.

Japanese Patent Application Laid-Open No. 2013-535477 (Patent Document 14) describes that pregabalin is absorbed only in the upper intestine, and a matrix-forming agent, a swelling agent, and buoyancy for the sustained release formulation of pregabalin. We propose a formulation that not only swells in the stomach but also floats in the stomach or settles in the stomach and stays in the stomach by containing pregabalin in a matrix containing the agent or precipitant. ..

According to Japanese Patent Application Laid-Open No. 2010-524991 (Patent Document 15), a pregabalin preparation that can be taken by lactose-intolerant patients who cannot decompose saccharides such as lactose due to lack of lactose-degrading enzyme and the like, resulting in diarrhea when lactose is ingested. Therefore, we have proposed a pregabalin-containing pharmaceutical composition that does not require amino acids other than pregabalin for stabilization of pregabalin and essentially does not contain saccharides such as lactose.

According to Japanese Patent Application Laid-Open No. 2002-522375 (Patent Document 16), gabapentin and pregabalin tend to decompose in an aqueous solution to form a lactam by intramolecular cyclization, and gabapentin and pregabalin have bitterness. Have been described.

As a solution thereof, Patent Document 16 dissolves a polymer such as Eudragit E, aminoethylmethacrylate copolymer, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, and celluloseacetophthalate in an organic solvent such as acetone, ethanol, and isopropanol. It is proposed that the coated particles be prepared by spraying on the particle surface of gabapentin or pregavalin, and if necessary, mixed with other additives and tableted.

According to WO2011 / 107812 (Patent Document 17), as a solution to the problem that GABA derivatives such as pregabalin tend to form lactams by intramolecular dehydration condensation of amino groups and carboxyl groups, a GABA derivative of pregabalin is prepared. , Isomalt, hydrogenated maltulose, lactitol, maltitol, isomaltitol and other polysaccharides, or maltotriitol, maltotriitol, Maltoteroitol, a hydrogenated polysaccharide obtained by hydrolysis of starch and subsequent hydrogenation, cellobiitol, cellulose, xylobiitol, xylotiitol, It is proposed to add inulotriitol or hydrogenated polysaccharides obtained by hydrolysis of cellulose, xylans, fructans and subsequent hydrogenation. ing.

However, Examples 1 to 5 of Patent Document 17 are merely examples of a mixed state (Example 1) and a capsule (Examples 2 to 5), and moreover, the talc form in Examples 1 to 3 is actually used. The only additives measured for the production of were lactose hydrate, talc, silicon dioxide (Aerosil 200P), isomalt (galenIQ960), partially pregelatinized starch, and corn starch.
Patent Document 17 does not describe that the compressed solid preparation was produced, and of course, the storage stability of the compressed solid preparation in the state of the compressed solid preparation has not been examined. Further, Patent Document 17 does not examine the effect of D-sorbitol and D-mannitol on the storage stability of a compressed solid preparation of pregabalin.

Huda & Toshnival (Non-Patent Document 1) describes that pregabalin is a fiercely bitter drug.
Non-Patent Document 1 proposes to formulate a complex of Kyon T134, which is a weak cation exchange resin, and pregabalin in order to mask the bitter taste of pregabalin in an orally disintegrating tablet of pregabalin.
Non-Patent Document 1 does not describe the storage stability of pregabalin.

Japanese Unexamined Patent Publication No. 2000-034227 Japanese Unexamined Patent Publication No. 2003-055211 Japanese Unexamined Patent Publication No. 2004-043506 Japanese Unexamined Patent Publication No. 2000-034226 Special Table 2009-514847 Japanese Patent Application Laid-Open No. 2014-521639 Special Table 2003-504324 WO2015 / 007890 Pamphlet WO2015 / 114656 Pamphlet WO2015 / 114655 Pamphlet EP2343055 Japanese Unexamined Patent Publication No. 2011-173881 Japanese Unexamined Patent Publication No. 2008-528494 Special Table 2013-535477 Special Table 2010-524991 Special Table 2002-522375 Gazette WO2011 / 107812 Pamphlet

Huda & Toshniwal, International Journal of Drug Delivery, Vol. 5, 2013, pp. 56-62, Formulation taste massed orodisper tablet of Pregabalin.

However, in any of the above-mentioned publicly known documents, cellulosic additives other than hydroxypropyl-substituted cellulose are added to lactams over time in solid preparations or compressed solid preparations containing γ-aminobutyric acid derivatives such as gabapentin, pregabalin, and baclofen. It is not described that it promotes the production of and impairs storage stability. In addition, in any of the above-mentioned known documents, magnesium aluminometasilicate, light anhydrous silicic acid, hydrous silicon dioxide, titanium oxide, povidone, crospovidone, macrogol, sucrose fatty acid ester, stearic acid, gelatin starch partial pregelatinization. It is described that starch and calcium dihydrogen phosphate promote the production of lactams over time in solid preparations or compressed solid preparations containing γ-aminobutyric acid derivatives such as gabapentin, pregabalin, and baclofen, and impair storage stability. It has not been.

Further, in any of the above-mentioned known documents, the hardness of a compressed solid preparation containing a γ-aminobutyric acid derivative such as gabapentin, pregabalin, baclofen, etc. over time is determined by pregelatinized starch, sucrose, gum arabic, gelatin, and D-sorbitol. It is not stated that it is impaired.

In addition, in any of the above-mentioned publicly known documents, lactams are produced over time in compressed solid preparations containing γ-aminobutyric acid derivatives such as gabapentin, pregabalin, and baclofen by the impact of tableting, not simply by consolidation. It is not stated that it is promoted and the storage stability is impaired, and that once the tablet is beaten, the production of lactams over time remains promoted even when the lactams are crushed to release the consolidation state.

Further, neither of the above documents describes that lactams are produced to the same extent even if the strength of tableting pressure is changed, and contains cellulosic additives other than hydroxypropyl-substituted cellulose. It is not stated that in compressed solid formulations containing γ-aminobutyric acid derivatives, "the more compacted" the production of lactams does not "accelerate".

Further, in any of the above-mentioned publicly known documents, sugar alcohols such as erythritol, mannitol, xylitol, isomalt, reduced starch syrup, reduced palatinose, reduced maltose water candy, and maltitol, and carboxymethyl groups such as hydroxypropyl starch and sodium starch glycolate are included. Alternatively, starch modified with a hydroxypropoxyl group suppresses the formation of lactams over time in solid preparations or compressed solid preparations containing γ-aminobutyric acid derivatives such as gabapentin, pregavalin, and bacrophen to improve storage stability. There is no mention of what to do.

Further, in any of the above-mentioned publicly known documents, the lactam form over time in a solid preparation or a compressed solid preparation containing a γ-aminobutyric acid derivative such as gabapentin, pregavalin, baclofen, etc., by being sealed and stored in an aluminum laminate bag or the like. It is not described that the formation is promoted and the storage stability is impaired, and a solid preparation or a compressed solid preparation containing a γ-aminobutyric acid derivative is crimped with an aluminum sheet with polyvinyl chloride, polypropylene, polyethylene or the like. It is not described that the formation of lactams over time is suppressed by storing in the resulting airtight blister package.

Further, in any of the above-mentioned publicly known documents, when the granules for tableting for a compressed solid preparation containing a γ-aminobutyric acid derivative such as gabapentin, pregavalin, and baclofen are produced by stirring granulation, the compressed solid preparation is used. When the hardness is impaired over time and the granules for tableting for a compressed solid preparation containing a γ-aminobutyric acid derivative such as gabapentin, pregavalin, and bacrophen are produced by fluidized layer granulation, the compression thereof. It is not stated that the hardness of the solid preparation is not impaired over time.

Further, none of the above-mentioned publicly known documents describes that the dissolution property of the solid preparation or the compressed solid preparation containing the γ-aminobutyric acid derivative such as gabapentin, pregabalin, and baclofen is not good.
Further, neither of the above-mentioned publicly known documents describes that γ-aminobutyric acid derivatives such as gabapentin, pregabalin, and baclofen have high adhesiveness and a large friction coefficient.

Further, none of the above-mentioned publicly known documents describes that γ-aminobutyric acid derivatives such as gabapentin, pregabalin, and baclofen are acicular crystals having a length of nearly 1 mm and are bulky.

Further, in any of the above-mentioned publicly known documents, a compressed solid preparation containing a γ-aminobutyric acid derivative such as gabapentin, pregabalin, and baclofen has poor compressibility and is prone to locking disorders such as capping, sticking, and lamination. Is not listed.

Further, in any of the above-mentioned publicly known documents, it is difficult to achieve both storage stability, dissolution property, and maintenance of tablet hardness in a compressed solid preparation containing a γ-aminobutyric acid derivative such as gabapentin, pregabalin, and baclofen. It is not stated that there is.

Therefore, an object of the present invention is to provide a solid preparation or a compressed solid preparation containing a γ-aminobutyric acid derivative such as gabapentin, pregabalin, baclofen, etc., which has good storage stability.
An object of the present invention is particularly a storage-stable solid preparation or compressed solid containing a γ-aminobutyric acid derivative such as gabapentin, pregabalin, baclofen, etc., which has a lactam content of 1.0% or less within the expiration date. To provide a formulation.

An object of the present invention is also to provide a packaging form of a solid preparation or a compressed solid preparation containing a γ-aminobutyric acid derivative such as gabapentin, pregabalin, baclofen, etc., which has good storage stability.

Another object of the present invention is gabapentin, in which the hardness of a compressed solid preparation containing a γ-aminobutyric acid derivative such as gabapentin, pregabalin, baclofen is not easily impaired over time, and the hardness is maintained sufficiently throughout the period until the expiration date. , Pregabalin, baclofen and the like, to provide a compressed solid preparation containing a γ-aminobutyric acid derivative.

An object of the present invention is further to the properties of γ-aminobutyric acid derivatives such as pregabalin, gabapentin, and baclofen, which have high adhesiveness, a large coefficient of friction, bulky properties, and extremely poor compressibility and fluidity. Regardless of this, it is an object of the present invention to provide a solid preparation containing a γ-aminobutyric acid derivative or a compressed solid preparation, in which the powder before compression has good fluidity and can be stably produced with good yield.

An object of the present invention is to provide a solid preparation or a compressed solid preparation having a good dissolution of the active ingredient of a solid preparation or a compressed solid preparation containing a γ-aminobutyric acid derivative such as gabapentin, pregabalin, baclofen, etc., which disintegrates rapidly. To provide.

An object of the present invention is also to provide a compressed solid preparation containing a γ-aminobutyric acid derivative such as gabapentin, pregabalin, baclofen, etc., which does not substantially cause locking disorders such as capping, sticking, and lamination.
An object of the present invention is to further provide a solid preparation or a compressed solid preparation that masks the bitterness of γ-aminobutyric acid derivatives such as pregabalin, gabapentin, and baclofen.

An object of the present invention is also to provide a solid preparation or a compressed solid preparation containing a γ-aminobutyric acid derivative such as gabapentin, pregabalin, baclofen, etc., which has good content uniformity.
An object of the present invention is also to provide a solid preparation or a compressed solid preparation containing a γ-aminobutyric acid derivative, which can solve one, two, three, or four or more of the above-mentioned problems at the same time. Is.

As a result of diligent research to provide a solid pharmaceutical composition or a compressed solid pharmaceutical composition containing a γ-aminobutyric acid derivative such as pregabalin, gabapentin, and baclofen, the present inventor is the first to have the above-mentioned problems. After recognizing and repeating trial and error to solve this problem, he found the solution by himself based on his insight, and completed the present invention.
Specifically, the present invention is as follows.

[1]
Contains one or more active ingredients selected from the group consisting of compounds having a γ-aminobutyric acid structure and pharmaceutically acceptable salts thereof, and is selected from cellulosic additives other than hydroxypropyl-substituted celluloses 1, 2 , Or a solid formulation or a compressed solid formulation that does not contain three or more cellulosic additives or has a formulation structure in which the active ingredient does not come into contact with the cellulosic additive.

[2]
Contains one or more active ingredients selected from the group consisting of compounds having a γ-aminobutyric acid structure and pharmaceutically acceptable salts thereof, crystalline cellulose, cellulose acetate, carmellose, carmellose calcium, carmellose sodium, carme Loin potassium, croscarmellose sodium, croscarmellose calcium, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, hypromellose acetate succinate, cellulose acetate, phthalate acetate, hypromellose phthalate, carboxymethyl ethyl cellulose, It does not contain 1, 2, or 3 or more cellulosic additives selected from the group consisting of methyl cellulose, ethyl cellulose, microcrystalline cellulose, powdered cellulose, lactose / crystalline cellulose spherical granules, or the active ingredient is the above-mentioned cellulose. The solid preparation or compressed solid preparation according to [1], which has a preparation structure that does not come into contact with system additives.

[3]
Contains one or more active ingredients selected from the group consisting of pregabalin, gabapentin, baclofen and pharmaceutically acceptable salts thereof, crystalline cellulose, cellulose acetate, carmellose, carmellose calcium, carmellose sodium, carmellose potassium. , Croscarmellose sodium, croscarmellose calcium, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, hypromellose acetate succinate, cellulose acetate, phthalate acetate, hypromellose phthalate, carboxymethyl ethyl cellulose, methyl cellulose, Does not contain 1, 2, or 3 or more cellulosic additives selected from the group consisting of ethyl cellulose, microcrystalline cellulose, powdered cellulose, lactose / crystalline cellulose spherical granules, or the active ingredient is the above-mentioned cellulose-based additive. The solid preparation or compressed solid preparation according to [1] or [2], which has a preparation structure that does not come into contact with an object.

[4]
Consists of magnesium aluminometasilicate, light anhydrous silicic acid, hydrous silicon dioxide, titanium oxide, povidone, crospovidone, macrogol, sucrose fatty acid ester, stearic acid, gelatin, starch, partially pregelatinized starch, and calcium dihydrogen phosphate. One or more activities selected from the group consisting of compounds having a γ-aminobutyric acid structure and pharmaceutically acceptable salts thereof that do not contain one, two, or three or more additives selected from the group. The solid preparation or compressed solid preparation according to any one of [1] to [3], which has a preparation structure in which the component does not come into contact with the above-mentioned additive.

[5]
The solid preparation or compressed solid preparation according to any one of [1] to [4], which does not contain 1, 2, or 3 or more additives selected from the group consisting of pregelatinized starch, sucrose, and gum arabic. ..

[6]
The solid preparation or compressed solid preparation according to any one of [1] to [5], which contains hydroxypropyl-substituted cellulose.

[7]
Any one of [1] to [6] containing one or more components selected from starch modified with a carboxymethyl group or a hydroxypropoxyl group or a pharmaceutically acceptable salt thereof, and a sugar alcohol. The solid preparation or compressed solid preparation described in the section.

[8]
The solid preparation or compression according to any one of [1] to [7], which contains starch modified with a carboxymethyl group or a hydroxypropoxyl group or a pharmaceutically acceptable salt thereof, and a sugar alcohol. Solid formulation.

[9]
The solid preparation or compressed solid preparation according to any one of [1] to [8], which contains one or more modified starches selected from the group consisting of sodium carboxymethyl starch and hydroxypropyl starch.

[10]
[1] to [9] containing 1, 2, or 3 or more sugar alcohols selected from the group consisting of erythritol, mannitol, xylitol, isomalt, reduced starch syrup, reduced palatinose, reduced maltose starch syrup, maltitol, and sorbitol. ] The solid preparation or the compressed solid preparation according to any one of the items.

[11]
The solid preparation or compressed solid preparation according to any one of [1] to [10], which is an immediate release property.
[12]
The solid preparation or compressed solid preparation according to any one of [1] to [11], which is not hermetically packaged.
[13]
The solid preparation or compressed solid preparation according to any one of [1] to [12], which is airtightly packaged.

[14]
The solid preparation or compressed solid preparation according to any one of [1] to [13], which is airtightly packaged using a blister package using polyvinyl chloride, polypropylene, or polyethylene.
[15]
The solid preparation or compressed solid preparation according to any one of [1] to [14], which is a tablet.
[16]
The solid preparation or compressed solid preparation according to any one of [1] to [15], which is a film-coated tablet.

[17]
The solid preparation or compressed solid preparation according to any one of [1] to [16], which has a hardness of 20 N or more.
[18]
The solid preparation or compressed solid preparation according to any one of [1] to [17], which contains hydroxypropyl-substituted cellulose having a viscosity of a 2% aqueous solution measured at 20 ° C. of 2 to 400 mPa · s.

[19]
The solid preparation or compressed solid according to any one of [1] to [18], wherein the content of hydroxypropyl-substituted cellulose per compressed solid preparation is 1 to 15% by mass of the total mass of the compressed solid preparation. pharmaceutical formulation.

[20]
The amount ratio of hydroxypropyl-substituted cellulose to starch modified with a carboxymethyl group or hydroxypropoxyl group is 0.1 to 10 parts by mass of carboxymethyl group or hydroxypropoxyl with respect to 1 part by mass of hydroxypropyl-substituted cellulose. The solid preparation or compressed solid preparation according to any one of [1] to [19], which is a starch modified with a group.

[21]
Wet granulated product containing one or more active ingredients selected from the group consisting of a compound having a γ-aminobutyric acid structure and a pharmaceutically acceptable salt thereof, hydroxypropyl-substituted cellulose, and optionally any additive. The solid preparation or compressed solid preparation according to any one of [1] to [20], which comprises.

[22]
Flow layer granulation containing one or more active ingredients selected from the group consisting of a compound having a γ-aminobutyric acid structure and a pharmaceutically acceptable salt thereof, hydroxypropyl-substituted cellulose, and optionally any additive. The solid preparation or compressed solid preparation according to any one of [1] to [21], which contains a substance.

[23]
The method for producing a solid preparation or a compressed solid preparation according to any one of [1] to [22], which comprises the following steps:
(1) A step of mixing one or more active ingredients selected from a compound having a γ-aminobutyric acid structure or these pharmaceutically acceptable salts with an arbitrary additive.
(2) A step of spraying a hydroxypropyl-substituted cellulose solution to granulate the mixture.
(3) Arbitrarily, a step of mixing the granulated product with one or more arbitrary additives or the granulated product.

[24]
The method for producing a solid preparation or a compressed solid preparation according to any one of [1] to [23], which comprises the following steps.
(1) A step of mixing one or more active ingredients selected from a compound having a γ-aminobutyric acid structure or these pharmaceutically acceptable salts with an arbitrary additive.
(2) A step of spraying a hydroxypropyl-substituted cellulose solution to granulate the mixture.
(3) Optionally, a step of mixing the granulated product with one or more optional additives or granulated products containing starch modified with a carboxymethyl group.
[25]
The method for producing a solid preparation or a compressed solid preparation according to any one of [1] to [24], which comprises the following steps.
(1) One or more active ingredients selected from compounds having a γ-aminobutyric acid structure or pharmaceutically acceptable salts thereof, such as magnesium aluminometasilicate, light anhydrous silicic acid, hydrous silicon dioxide, titanium oxide, and the like. Selected from the group consisting of cellulosic additives other than povidone, crospovidone, macrogol, sucrose fatty acid ester, stearic acid, gelatin, starch, partially pregelatinized starch, calcium dihydrogen phosphate, and hydroxypropyl substituted cellulose 1 The step of mixing with any additive that does not contain 2, or 3 or more additives,
(2) A step of spraying a hydroxypropyl-substituted cellulose solution to granulate the mixture.
(3) Arbitrarily, a step of mixing the granulated product with one or more arbitrary additives or the granulated product.
[26]
A solid preparation or a compressed solid preparation produced by the production method according to any one of [23] to [25].

Although the compressed solid preparation of the present invention is a compressed solid preparation containing a γ-aminobutyric acid derivative or a pharmaceutically acceptable salt thereof, the formation of lactams over time triggered by the impact of tableting There is almost no. The solid preparation or compressed solid preparation of the present invention can maintain the production of lactams at 1.0% or less for 6 months or more under the storage condition of 40 ° C. and 75% relative humidity, and the period until the expiration date of 3 years. It is stable and preserved through. In addition, the compressed solid preparation of the present invention can maintain the production of lactam at 1.0% or less even after it is divided or crushed to make it in an uncompressed state.

According to the packaging form of the compressed solid preparation of the present invention, although it is a compressed solid preparation containing a γ-aminobutyric acid derivative or a pharmaceutically acceptable salt thereof, the time lapse caused by the impact of tableting is generated. There is almost no generation of typical lactam. According to the packaging form of the solid preparation or the compressed solid preparation of the present invention, the storage is stable throughout the period up to the expiration date of 3 years, and the production of lactams can be kept at 1.0% or less.

The compressed solid preparation of the present invention hardly decreases in hardness with time. The compressed solid preparation of the present invention can maintain sufficient hardness throughout the period from production to the expiration date of 3 years.
The solid preparation or compressed solid preparation of the present invention does not cause a decrease in elution with time. Sufficient elution can be maintained throughout the period from production to the expiration date of 3 years. In addition, the compressed solid preparation of the present invention rapidly disintegrates.

Although the γ-aminobutyric acid derivative has high adhesiveness, a large coefficient of friction, and bulky properties, and has extremely poor compression moldability and fluidity, the solid preparation or compressed solid preparation of the present invention is compressed. The previous powder has good fluidity, is less likely to cause locking problems such as capping, sticking, and lamination, and can be stably produced with good yield.
The solid preparation or compressed solid preparation of the present invention can mask the bitterness of the γ-aminobutyric acid derivative.
The solid preparation or compressed solid preparation of the present invention has good content uniformity.
The compressed solid preparation of the present invention is smaller than a capsule having the same active ingredient content, and is less likely to adhere to the throat and is easy to swallow.
The compressed solid preparation of the present invention can be film-coated and can be divided.
The solid preparation or compressed solid preparation of the present invention can mask the bitterness of the γ-aminobutyric acid derivative and at the same time has good dissolution property.
When the solid preparation or the compressed solid preparation of the present invention is an orally disintegrating tablet, it has good orally disintegrating property and an oral texture (mouth feel).
The solid preparation or compressed solid preparation of the present invention has a refreshing feeling of ingestion.
The solid preparation or compressed solid preparation of the present invention can simultaneously exert one, two, three, or four or more of the above-mentioned effects.

It is a figure which shows the example of the manufacturing flow of this invention. (Example 14) It is a figure of the elution rate with respect to purified water of the prototype tablet which dry-coated the main drug granule with calcium stearate (Example 15). It is a scanning electron micrograph of the prototype tablet T-1 after dry coating with calcium stearate, coating with Eudragit E (1), and coating with D-mannitol (2) (implementation). Example 17). The prototype tablet S-1 (“prototype 75 mg tablet” in the figure) is sealed in an aluminum bag, stored under accelerated conditions of 40 ° C. and 75% relative humidity, and the results of measuring the formation of lactams over time are shown. It is a figure (Example 18). In order to confirm the storage stability of the prototype tablet S-1 over time, the prototype tablet S-1 is sealed in an aluminum bag, stored under accelerated conditions of 40 ° C. and 75% relative humidity, and before the start of storage (in the figure). The elution rate with respect to purified water was measured after 0.5 months of storage (“4075-0.5M” in the figure) and 1 month after storage (“4075-1M” in the figure). It is a figure which shows the result (Example 19).

In the present invention, the solid preparation is not only a compressed solid preparation but also a solid preparation such as a powder, a granule, a fine granule, a dry syrup, a capsule in which granules are filled in a capsule, a wet tablet, and a heat-melt extrusion molded product. say. The solid product is a superordinate concept of the compressed solid product.

In the present invention, the pharmaceutical structure in which the active ingredient does not come into contact with the additive refers to a physical or chemical pharmaceutical structure in which the active ingredient and the additive do not come into contact with each other and cause a chemical change. The pharmaceutical structure in which the active ingredient does not come into contact with the additive is, for example, in a pharmaceutical product containing a plurality of granules or granules (hereinafter, referred to as “granule or the like”), which contains granules or the like containing the active ingredient and the additive. Since either or both of the granules and the like are coated with a coating agent, the active ingredient and the additive do not come into contact with each other to cause a chemical change, which is a physical or chemical pharmaceutical structure. Examples of a preparation containing a plurality of granules include a tablet containing a plurality of granules, a capsule containing a plurality of granules, a powder containing a plurality of granules, and a granule containing a plurality of granules. , Dry syrup containing a plurality of granules and the like. Further, for example, a pharmaceutical structure in which the active ingredient is present in either the inner core or the outer shell of the nucleated tablet and the additive is present in the other one is also a pharmaceutical structure in which the active ingredient does not come into contact with the additive. Similarly, a pharmaceutical structure in which the active ingredient is present in one of the two-layer tablets and the additive is present in the other is also a pharmaceutical structure in which the active ingredient does not come into contact with the additive. A formulation structure in which the active ingredient does not come into contact with an additive that impairs storage stability is also a formulation structure in which the active ingredient does not come into contact with an additive that impairs storage stability, for example, by not containing an additive that impairs storage stability. be. The formulation structure in which the active ingredient does not come into contact with the cellulosic additive is, for example, a cellulosic addition in addition to a physical or chemical formulation structure in which the active ingredient and the cellulose additive do not come into contact with each other to cause a chemical change. There is a formulation structure in which the active ingredient and the cellulosic additive do not come into contact with each other because the substance is not contained. Similarly, the active ingredients are magnesium aluminometasilicate, light anhydrous silicic acid, hydrous silicon dioxide, titanium oxide, povidone, crospovidone, macrogol, sucrose fatty acid ester, stearic acid, gelatin, starch, partially pregelatinized starch, In addition to the physical or chemical formulation structure in which these additives and the active ingredient do not come into contact with each other and cause no chemical change, the formulation structure selected from the group consisting of calcium dihydrogen phosphate does not come into contact with the additives. In addition, there is a structure in which the active ingredient does not come into contact with these additives because they are not contained.

The solid or compressed solid product of the present invention is a solid or compressed solid product containing a γ-aminobutyric acid derivative or a pharmaceutically acceptable salt thereof and containing no cellulosic additives other than hydroxypropyl-substituted cellulose. be.
Here, the γ-aminobutyric acid derivative is not particularly limited as long as it is a compound having a structure of γ-aminobutyric acid. The compound having a γ-aminobutyric acid structure is preferably a γ-aminobutyric acid derivative in which the 3-position of γ-aminobutyric acid is substituted, and pregabalin, gabapentin, or baclofen is more preferable.

Due to their structural characteristics, γ-aminobutyric acid derivatives all have the common characteristic that intramolecular amino groups and carboxyl groups are easily dehydrated and condensed to form lactams. It has a common problem in that the production of lactams within the expiration date must be kept at 1.0% or less, and such a problem can be solved in common by the problem-solving means of the present invention. It is a thing.

The pharmaceutically acceptable salt of the γ-aminobutyric acid derivative is not particularly limited as long as it can be formulated.
The cellulose skeleton refers to a polymer in which an arbitrary number (n) of structural units are linked, such as the formula VII below.

式ＶＩＩ セルロース骨格

Formula VII Cellulose Skeleton

Hydroxypropylcellulose (hereinafter, also referred to as "HPC".) And is a cellulose obtained by substituting a part of the alcohol of glucose residues Cellulose hydroxypropoxyl group (-OC 3 H _{6 OH),} dry weight in 53.4% to 77.5% of the cellulose is a hydroxypropoxyl group. HPC is obtained by etherifying the hydroxyl groups of cellulose with propylene oxide. Unlike cellulose, HPC is soluble in water and alcohols. HPC becomes a viscous liquid when water is added, and is used as a film coating agent because of its high film-forming ability. HPC is also used as a binder for tablets and granules.

As for HPC, for example, products of various grades are commercially available from Nippon Soda Co., Ltd. under the trade names of HPC-SSL, HPC-SL, HPC-L, HPC-M, and HPC-H.
HPC-SSL is a grade for film coating and granulation / bonding. The viscosity of a 2% aqueous solution measured at 20 ° C. is 2 to 2.9 mPa · s, and the molecular weight measured by the GPC method is about 40 kDa. Two types of HPC-SSL are commercially available: a normal particle type having a 50% particle size (D50) of 85 to 185 μm and an ultrafine particle type having a 50% particle size (D50) of 20 μm.

HPC-SL is a grade for film coating and granulation / bonding. The viscosity of a 2% aqueous solution measured at 20 ° C. is 3 to 5.9 mPa · s, and the molecular weight measured by the GPC method is about 100 kDa. Two types of HPC-SL are commercially available: a normal particle type having a 50% particle size (D50) of 85 to 185 μm and a fine particle type having a 50% particle size (D50) of 80 to 110 μm.

HPC-L is a grade for film coating and granulation / bonding. The viscosity of a 2% aqueous solution measured at 20 ° C. is 6 to 10 mPa · s, and the molecular weight measured by the GPC method is about 140 kDa. Two types of HPC-L are commercially available: a normal particle type having a 50% particle size (D50) of 85 to 185 μm and a fine particle type having a 50% particle size (D50) of 80 to 110 μm.

HPC-M is a grade for granulation / binding and sustained release preparation, and the viscosity of a 2% aqueous solution measured at 20 ° C. is 150 to 400 mPa · s, and the molecular weight measured by the GPC method is about 620 kDa. Two types of HPC-M are commercially available: a normal particle type having a 50% particle size (D50) of 85 to 185 μm and a fine particle type having a 50% particle size (D50) of 80 to 110 μm.

HPC-H is a grade for sustained release preparation, and the viscosity of a 2% aqueous solution measured at 20 ° C. is 1000 to 4000 mPa · s, and the molecular weight measured by the GPC method is about 910 kDa. HPC-H includes a normal particle type having a 50% particle size (D50) of 85 to 185 μm and an ultrafine particle type having a 50% particle size (D50) of 20 μm.

The grade of HPC used in the solid preparation or compressed solid preparation of the present invention is preferably HPC-SSL, HPC-SL, HPC-L, or HPC of a grade corresponding to HPC-M, and corresponds to HPC-SL or HPC-L. HPC of the grade to be used is more preferable, and HPC of the grade corresponding to HPC-L is particularly preferable. Therefore, the viscosity of the 2% aqueous solution of HPC used in the solid preparation or the compressed solid preparation of the present invention measured at 20 ° C. is preferably 2 to 400 mPa · s, more preferably 3 to 10 mPa · s. Particularly preferably, it is 6 to 10 mPa · s.
As the particle size of HPC used in the solid preparation or the compressed solid preparation of the present invention, a normal particle type having a 50% particle size (D50) of 85 to 185 μm is preferable.

式ＶＩＩＩ ヒドロキシプロピルセルロースの構造

Structure of Formula VIII Hydroxypropyl Cellulose

Low-substituted hydroxypropylcellulose (hereinafter, also referred to as "L-HPC".) And is a cellulose obtained by substituting a part of the alcohol of glucose residues Cellulose hydroxypropoxyl group (-OC 3 H _{6 OH)} Te, cellulose containing dry weight 5.0% 16.0% of hydroxypropoxy _{(-OC 3} H 6 OH). L-HPC contains 0.1-0.4 hydroxypropyl groups per unit of glucose glucose in cellulose. HPC and L-HPC differ in the substitution rate due to the hydroxypropoxyl group, but other points are common. The difference in properties between HPC and L-HPC is that HPC is water-soluble, whereas L-HPC is insoluble in water, but absorbs water and swells. Taking advantage of this property, L-HPC can be used as a disintegrant for oral solid pharmaceutical preparations. Further, since L-HPC is fibrous, it has an effect of increasing the hardness of tablets, and since the kneaded product with water has a binding property, it can also be used as a binder.

In this specification, the cellulose substituted with hydroxypropoxyl group (-OC 3 H _{6 OH),} regardless the percentage of the substitution, hydroxypropyl-substituted cellulose (hereinafter also referred to as "HP-substituted celluloses.") And Call. In the present specification, HPC and L-HPC are treated as different substances, and the term hydroxypropyl-substituted cellulose (or "HP-substituted cellulose") is used as a superordinate concept including both HPC and L-HPC.
The dry weight% of the hydroxypropoxyl group of the hydroxypropyl-substituted cellulose used in the present invention is preferably 4.0% to 80.0%, more preferably 5.0% to 77.5%, and further. It is preferably 53.0% to 81.0%, even more preferably 53.4% to 77.5%, and particularly preferably 50.0% to 75.0%.

Cellulose-based additives other than hydroxypropyl-substituted cellulose promote the formation of lactams over time in solid preparations or compressed solid preparations containing compounds having a γ-aminobutyric acid structure, and impair their storage stability. Therefore, in the solid preparation or the compressed solid preparation of the present invention, the compound having a γ-aminobutyric acid structure is one, two, or three or more cellulosic additives selected from cellulosic additives other than hydroxypropyl-substituted cellulose. It is characterized by not touching.

Here, a solid preparation or a compressed solid preparation in which the compound having a γ-aminobutyric acid structure does not come into contact with one, two, or three or more cellulosic additives selected from cellulosic additives other than hydroxypropyl-substituted cellulose is preferable. The aspects are as follows.

The solid preparation or compressed solid preparation of the present invention preferably does not contain, or does not contain at all, 1, 2, or 3 or more cellulosic additives selected from cellulosic additives other than hydroxypropyl-substituted cellulose. When the solid preparation or compressed solid preparation of the present invention contains a cellulosic additive other than hydroxypropyl-substituted cellulose, a compound having a γ-aminobutyric acid structure and a cellulosic additive other than hydroxypropyl-substituted cellulose are used. However, it is preferable that the structure does not come into contact with each other. Specific examples of the structure in which the compound having a γ-aminobutyric acid structure and the cellulosic additive other than hydroxypropyl-substituted cellulose do not come into contact include a compound having a γ-aminobutyric acid structure or a compound having a γ-aminobutyric acid structure. It is preferable to coat the granulated product. Alternatively, as a specific example of the structure in which the compound having a γ-aminobutyric acid structure and the cellulosic additive other than hydroxypropyl-substituted cellulose do not come into contact with each other, a cellulosic additive other than hydroxypropyl-substituted cellulose or a cellulose other than hydroxypropyl-substituted cellulose It is preferable to coat the granulated product containing the system additive. Both a compound having a γ-aminobutyric acid structure or a compound having a γ-aminobutyric acid structure, and a granulated product containing a cellulosic additive other than hydroxypropyl-substituted cellulose or a cellulosic additive other than hydroxypropyl-substituted cellulose. Is more preferred. As a specific example of a structure in which a compound having a γ-aminobutyric acid structure and a cellulosic additive other than hydroxypropyl-substituted cellulose do not come into contact with each other, a compound having a γ-aminobutyric acid structure is contained in the inner core and hydroxypropyl-substituted cellulose is used. A nucleated tablet containing a cellulosic additive other than that in the outer nucleus, or a nucleated tablet containing a compound having a γ-aminobutyric acid structure in the outer nucleus and containing a cellulosic additive other than hydroxypropyl-substituted cellulose in the inner nucleus. Tablets are preferred.

Specific examples of cellulosic additives other than hydroxypropyl-substituted cellulose include crystalline cellulose, cellulose acetate, carmellose, carmellose calcium, carmellose sodium, carmellose potassium, croscarmellose sodium, croscarmellose calcium, hydroxyethyl cellulose, and hydroxy. Ethylmethyl cellulose, hydroxypropyl methyl cellulose, hypromellose acetate succinate, cellulose acetate, cellulose acetate, hypromellose phthalate, carboxymethyl ethyl cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose, powdered cellulose, lactose / crystalline cellulose spherical granules Can be mentioned.

Therefore, the solid preparation or compressed solid preparation of the present invention includes crystalline cellulose, cellulose acetate, carmellose, carmellose calcium, carmellose sodium, carmellose potassium, croscarmellose sodium, croscarmellose calcium, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, A group consisting of hydroxypropylmethyl cellulose, hypromellose acetate succinate, cellulose acetate, phthalate acetate, hypromellose phthalate, carboxymethyl ethyl cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose, powdered cellulose, lactose / crystalline cellulose spherical granules. One, two, or three or more cellulosic additives selected from the above are not in contact with a compound having a γ-aminobutyric acid structure.

Therefore, the solid preparation or compressed solid preparation of the present invention includes crystalline cellulose, cellulose acetate, carmellose, carmellose calcium, carmellose sodium, carmellose potassium, croscarmellose sodium, croscarmellose calcium, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, A group consisting of hydroxypropylmethyl cellulose, hypromellose acetate succinate, cellulose acetate, phthalate acetate, hypromellose phthalate, carboxymethyl ethyl cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose, powdered cellulose, lactose / crystalline cellulose spherical granules. It is characterized by not containing 1, 2, or 3 or more cellulosic additives selected from.

The solid preparation or compressed solid preparation of the present invention includes crystalline cellulose, cellulose acetate, carmellose, carmellose calcium, carmellose sodium, carmellose potassium, croscarmellose sodium, croscarmellose calcium, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl. Select from the group consisting of methyl cellulose, hypromellose acetate succinate, cellulose acetate, phthalate acetate, hypromellose phthalate, carboxymethyl ethyl cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose, powdered cellulose, lactose / crystalline cellulose spherical granules. It is particularly preferable that it does not contain any of the cellulosic additives to be produced.

Most preferably, the solid or compressed solid preparation of the present invention is characterized by containing no cellulosic additives other than hydroxypropyl-substituted cellulose.

Magnesium aluminometasilicate, light anhydrous silicic acid, hydrous silicon dioxide, titanium oxide, povidone, crospovidone, macrogol, sucrose fatty acid ester, stearic acid, and gelatin, starch, partially pregelatinized starch, calcium dihydrogen phosphate In a solid preparation or a compressed solid preparation containing a γ-aminobutyric acid derivative, the formation of lactams over time is promoted, and the storage stability thereof is impaired. Therefore, the solid preparation or the compressed solid preparation of the present invention is characterized by containing no one, two, or three or more additives selected from these additives.

Magnesium aluminate metasilicate is commercially available under the trade name of Neucillin (trademark, Fuji Chemical Industries, Ltd.).

By simply adding a small amount (for example, 1.7%) of pregelatinized starch, sucrose, gum arabic, and gelatin to the compressed solid preparation containing the γ-aminobutyric acid derivative, the compressed solid preparation is added at 40 ° C. and 75% relative humidity 7 The hardness of the tablet after storage for days becomes zero.
Therefore, the compressed solid preparation of the present invention is characterized by containing 1.7% or more of 1, 2, or 3 or more additives selected from the group consisting of pregelatinized starch, sucrose, gum arabic, and gelatin. do. More preferably, the compressed solid preparation of the present invention is characterized by containing no one, two, or three or more additives selected from the group consisting of pregelatinized starch, sucrose, gum arabic, and gelatin. More preferably, the compressed solid preparation of the present invention is characterized by containing no additive selected from the group consisting of pregelatinized starch, sucrose, gum arabic, and gelatin.

The solid preparation or compressed solid preparation of the present invention may contain hydroxypropyl-substituted cellulose. The hydroxypropyl-substituted cellulose is preferably HPC or L-HPC.
When HPC is used as the hydroxypropyl-substituted cellulose, it is desirable to use it as a granulation solution for the main drug granules. The granulation solution containing hydroxypropyl-substituted cellulose is preferably used as an aqueous solution, an ethanol solution, or a mixed solvent solution thereof.

It is desirable that the γ-aminobutyric acid derivative or a pharmaceutically acceptable salt thereof, which is the active ingredient of the solid preparation or the compressed solid preparation of the present invention, is wet-granulated while spraying a hydroxypropyl-substituted cellulose solution. Here, as the hydroxypropyl-substituted cellulose, HPC or L-HPC is preferable, and HPC is more preferable.

The γ-aminobutyric acid derivative or a pharmaceutically acceptable salt thereof, which is the active ingredient of the solid preparation or the compressed solid preparation of the present invention, can be produced by a fluidized bed granulation method while spraying a hydroxypropyl-substituted cellulose solution. desirable. Here, as the hydroxypropyl-substituted cellulose, HPC or L-HPC is preferable, and HPC is more preferable.

The solid preparation or compressed solid preparation of the present invention may contain hydroxypropyl-substituted cellulose, and good hardness can be maintained by adding hydroxypropyl-substituted cellulose. Further, the solid preparation or the compressed solid preparation of the present invention can maintain good dissolution property by adding L-HPC. However, if the amount of hydroxypropyl-substituted cellulose is too large, the amount of lactam is increased over time. Therefore, it is desirable that the amount of hydroxypropyl-substituted cellulose in the solid preparation or the compressed solid preparation of the present invention is within a predetermined range.

The content of hydroxypropyl-substituted cellulose per solid preparation or compressed solid preparation of the present invention is preferably 1.4 to 14.8% by mass (about 1 to about 15% by mass), and more preferably 1. It is 4 to 8.8% by mass (about 1 to about 9% by mass), more preferably 1.7 to 8.4% by mass (about 1 to about 8% by mass), and even more preferably 1.9. It is ~ 4.4% by mass (about 2 to about 4% by mass), and most preferably 4.2 to 4.6% by mass.
Here, HPC is more preferable as the hydroxypropyl-substituted cellulose, and the content of HPC per solid preparation or compressed solid preparation of the present invention is preferably 1.4 to 9.6% by mass (about 1 to about 10%). Mass%), more preferably 1.7 to 8.4 mass% (about 2 to about 8 mass%), still more preferably 1.5 to 5.9 mass% (about 2 to about 6 mass%). ), More preferably 1.9 to 4.4% by mass (about 2 to about 4% by mass), and most preferably 4.2 to 4.6% by mass.

The formation of lactams in the solid or compressed solids of the present invention is suppressed by containing one or more components selected from the group consisting of starch modified with a carboxymethyl group or a hydroxypropoxyl group, and a sugar alcohol. can do. Therefore, the solid preparation or the compressed solid preparation of the present invention contains one or more components selected from the group consisting of starch modified with a carboxymethyl group, starch modified with a hydroxypropoxyl group, and a sugar alcohol. Is desirable.

The solid preparation or compressed solid preparation of the present invention can suppress the formation of lactams over time by containing starch modified with a carboxymethyl group or a hydroxypropoxyl group. The preferred modified starch for suppressing the production of lactams over time is hydroxypropyl starch or starch modified with a carboxymethyl group, and the starch modified with a carboxymethyl group is sodium carboxymethyl starch. A salt (hereinafter, may be referred to as "CMS / Na") is preferable. The sodium salt of carboxymethyl starch is also known as sodium starch glycolate, and is sold under the trade name of Primogel ™, for example.

In the solid preparation or compressed solid preparation of the present invention, a wet granule containing a γ-aminobutyric acid derivative or a pharmaceutically acceptable salt thereof is separately prepared (hereinafter, may be referred to as “base drug granule”. ), This is preferably mixed with a composition containing starch modified with a carboxymethyl group (hereinafter, may be referred to as "post-additive (post-tenkabutsu)") and tableted. The wet granulated product is more preferably a fluidized layer granulated product. In addition, the component used by mixing with the main ingredient granules is sometimes called "post-additive (post-tenkabutsu)".

Examples of preferable sugar alcohols in the solid preparation or compressed solid preparation of the present invention include mannitol, sorbitol, erythritol, xylitol, isomalt, oligosaccharide alcohol, reduced starch syrup, reduced palatinose, reduced maltose starch syrup, and maltitol. As the more preferable sugar alcohol used in the solid preparation or the compressed solid preparation of the present invention, sorbitol, isomalt, D-mannitol, reduced maltose starch syrup, and maltitol are more preferable, and reduced maltose starch syrup or D-mannitol is particularly preferable.

Here, isomalt is α-D-glucopyranose-1,6-sorbitol (disaccharide in which glucose and sorbitol are bound) and α-D-glucopyranoside-1,6-mannitol (disaccharide in which glucose and mannitol are bound). ) Is a mixture of isomalts mixed in a ratio of 1: 1. Isomalt includes sugar coating type (for example, BENEO-Palatinit's galenIQ980), direct hit type (for example, the same company's galenIQ720), troche type (for example, the same company's galenIQ990), and capsule filling type (for example, the same company's galenIQ960). There are various types such as a wet granulation type (for example, galenIQ800 of the same company), and the isomalt used in the present invention is preferably a wet granulation type isomalt.

The solid preparation or compressed solid preparation containing the γ-aminobutyric acid derivative of the present invention contains one or more components selected from the group consisting of starch modified with a carboxymethyl group or a hydroxypropoxyl group, and a sugar alcohol. This makes it possible to suppress the formation of lactams over time after compression. In the solid preparation or compressed solid preparation of the present invention, one or more components selected from the group consisting of starch modified with a carboxymethyl group or a hydroxypropoxyl group and a sugar alcohol may be added to the main ingredient granules. It may be added in the post-additive. When added to the main drug granules, wet granulation is preferable with the binding γ-aminobutyric acid derivative of the main drug granules or a pharmaceutically acceptable salt thereof, and fluidized bed granulation is more preferable. When added to a post-additive, it can be used as a powder by mixing with other additives.

The solid preparation or compressed solid preparation of the present invention preferably contains a wet granulated product, and the wet granulated product can contain any additive if desired. Here, any additive that may be contained is not particularly limited as long as it is an additive other than the unfavorable additives listed below. That is, cellulosic additives other than hydroxypropyl-substituted cellulose, magnesium aluminometasilicate, light anhydrous silicic acid, hydrous silicon dioxide, titanium oxide, povidone, crospovidone, macrogol, sucrose fatty acid ester, stearic acid, gelatin, starch. , Partially pregelatinized starch, calcium dihydrogen phosphate, sucrose, or additives other than gum arabic are not particularly limited, and excipients, disintegrants, binders, lubricants, colorants, pH adjusters, Examples thereof include surfactants, stabilizers, flavoring agents, fragrances, fluidizing agents, coating bases, coating additives and the like. Unless otherwise specified, these additives are used in amounts commonly used in the pharmaceutical field.

Examples of excipients are carbohydrates such as lactose, mannitol, xylitol, erythritol, sorbitol, martitol, fructose, lactose, dextrose, dextrin / dextrate, maltodextrin and saccharides for compression; calcium citrate, calcium phosphate, calcium carbonate. , Inorganic salts such as dicalcium phosphate and calcium sulfate.

Preferable examples of the disintegrant include sodium carboxymethyl starch, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl starch and the like. Of these, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose are more preferable.

Preferable examples of the binder include hydroxypropyl cellulose.

Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, sodium stearyl fumarate and the like. Of these, magnesium stearate and calcium stearate are more preferable.

Preferable examples of colorants include carotenoids, iron oxides, chlorophyll, and colorants. Examples of colorants also include edible pigments red Nos. 2 and 3, edible pigments yellow Nos. 4 and 5, edible pigments green No. 3, edible pigments blue Nos. 1 and 2, these. Examples include food coloring aluminum lake, iron sesquioxide and yellow iron sesquioxide.

Suitable examples of pH adjusters include citric acid, magnesium carbonate, magnesium oxide, magnesium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, Examples thereof include sodium acetate. These may be used alone or in combination of two or more.

Preferable examples of the surfactant include sodium lauryl sulfate, sodium stearate, polyoxyethylene sorbitan monooleate and the like.

Preferable examples of the stabilizer include ascorbic acid, sodium edetate, erythorbic acid, tocopherol and the like.

Preferable examples of the flavoring agent include acidulants such as citric acid, malic acid, acetic acid, tartaric acid, fumaric acid and ascorbic acid, and sweeteners such as saccharin and aspartame.

Preferable examples of the fragrance include menthol, peppermint oil, orange oil, lemon oil and the like.

Preferable examples of the fluidizing agent include talc and the like.

Preferable examples of the coating base include sugar coating bases, water-soluble film coating bases, enteric film coating bases, sustained release film coating bases and the like.

As the sugar coating base, for example, a sugar alcohol such as erythritol is used, and one or more selected from talc, precipitated calcium carbonate, pullulan, carnauba wax and the like may be used in combination.

Examples of the water-soluble film coating base include hydroxypropyl cellulose; synthetic polymers such as polyvinyl acetal diethylaminoacetate and aminoalkyl methacrylate copolymer E; and polysaccharides such as pullulan.

Examples of the enteric film coating base include acrylic acid-based polymers such as methacrylic acid copolymer L, methacrylic acid copolymer LD, and methacrylic acid copolymer S; and natural products such as cellac.

Examples of the sustained-release film coating base include acrylic acid-based polymers such as aminoalkyl methacrylate copolymer RS and ethyl acrylate / methyl methacrylate copolymer suspension.

Preferable examples of coating additives are fluidizers such as talc and / or colorants such as iron sesquioxide, yellow iron sesquioxide; plasticizers such as propylene glycol, triethyl citrate, castor oil, polysorbates; Examples thereof include organic acids such as citric acid, tartaric acid, malic acid and ascorbic acid.

The above-mentioned additives may be used by mixing two or more kinds in an appropriate ratio.

When the solid preparation or compressed solid preparation of the present invention contains starch modified with a carboxymethyl group or a hydroxypropoxyl group, by adding more starch modified with a carboxymethyl group or a hydroxypropoxyl group, , The formation of lactam form can be suppressed, and good dissolution property can be obtained. On the other hand, by adding more starch modified with a carboxymethyl group or a hydroxypropoxyl group, the hardness tends to decrease with time.

Therefore, when the solid preparation or the compressed solid preparation of the present invention contains starch modified with a carboxymethyl group or a hydroxypropoxyl group, the amount of starch modified with a carboxymethyl group or a hydroxypropoxyl group is predetermined. It is preferably within the range of. More preferably, the amount of starch modified with a carboxymethyl group is preferably within a predetermined range, and even more preferably, the amount of carboxymethyl starch is more preferably within a predetermined range, even more preferably. It is particularly preferable that the amount of CMS / Na is within a predetermined range.

The amount of starch modified with a carboxymethyl group or a hydroxypropoxyl group per solid preparation or compressed solid preparation of the present invention is preferably 2.2% by mass to 4.6% by mass, and more preferably 3. It is .3% by mass to 4.5% by mass, and more preferably 4.2% by mass to 4.6% by mass.

By adding a larger amount of HPC in the solid preparation or the compressed solid preparation of the present invention, it is possible to suppress a decrease in tablet hardness over time. On the other hand, in order to minimize the production of lactams over time by tableting, it is better to have less HPC.
When the solid preparation or compressed solid preparation of the present invention contains hydroxypropyl-substituted cellulose and starch modified with a carboxymethyl group or a hydroxypropoxyl group, the hydroxypropyl-substituted cellulose and carboxymethyl group or hydroxypropoxyl It is desirable that the mass ratio of the starch modified with the group is within a predetermined range.

When the solid preparation or compressed solid preparation of the present invention contains both HP-substituted cellulose and starch modified with a carboxymethyl group or a hydroxypropoxyl group, the hydroxypropyl-substituted cellulose and a carboxymethyl group or a hydroxypropoxyl group are used. The amount ratio of the starch modified with is 1 part by mass of hydroxypropyl substituted cellulose, preferably 0.1 to 10 parts by mass of starch modified with a carboxymethyl group or a hydroxypropoxyl group. More preferably, it is starch modified with 0.25 to 4.0 parts by mass of carboxymethyl group or hydroxypropoxyl group, and further preferably 0.25 to 2.3 parts by mass of carboxymethyl group or hydroxypropoxyl. Group-modified starch, more preferably 0.75 to 2.3 parts by mass of carboxymethyl group or hydroxypropoxyl group-modified starch, even more preferably 0.25 to 1.3. It is a starch modified with a carboxymethyl group or a hydroxypropoxyl group by mass, and most preferably a starch modified with 0.75 to 1.3 parts by mass of a carboxymethyl group or a hydroxypropoxyl group.

Here, HPC is more preferable as the hydroxypropyl-substituted cellulose, and when the solid preparation or compressed solid preparation of the present invention contains starch modified with a carboxymethyl group or a hydroxypropoxyl group, HPC and a carboxymethyl group or The amount ratio of the hydroxypropoxyl group-modified starch is preferably 0.1 to 10 parts by mass of carboxymethyl group or hydroxypropoxyl group-modified starch with respect to 1 part by mass of HPC. , More preferably 0.25 to 4.0 parts by mass of carboxymethyl group or hydroxypropoxyl group, still more preferably 0.25 to 2.3 parts by mass of carboxymethyl group or hydroxypropoxy. It is a starch modified with a ru group, more preferably 0.75 to 2.3 parts by mass of a carboxymethyl group or a hydroxypropoxyl group, and even more preferably 0.25 to 1. It is a starch modified with 3 parts by mass of carboxymethyl group or hydroxypropoxyl group, and most preferably 0.75 to 1.3 parts by mass of carboxymethyl group or hydroxypropoxyl group modified starch.

Further, as the starch modified with a carboxymethyl group or a hydroxypropoxyl group, starch modified with a carboxymethyl group is preferable, CMS or CMS / Na is more preferable, and CMS / Na is particularly preferable. Therefore, when CMS or CMS / Na is contained in the solid preparation or compressed solid preparation of the present invention, the amount ratio of CMS or CMS / Na to HPC is preferably 0 with respect to 1 part by mass of HPC, respectively. .1 to 10 parts by mass of CMS or CMS · Na, more preferably 0.25 to 4.0 parts by mass of CMS or CMS · Na, still more preferably 0.25 to 2.3 parts by mass. It is CMS or CMS · Na, more preferably 0.75 to 2.3 parts by mass of CMS or CMS · Na, and even more preferably 0.25 to 1.3 parts by mass of CMS or CMS · Na. Most preferably, it is 0.75 to 1.3 parts by mass of CMS or CMS · Na.

It is desirable that the solid preparation or the compressed solid preparation of the present invention contains both starch modified with a carboxymethyl group or a hydroxypropoxyl group and a sugar alcohol.

Since pregabalin is rapidly absorbed, acts rapidly, and is rapidly excreted without being metabolized, the solid preparation or compressed solid preparation of the present invention may be an immediate release solid preparation or a compressed solid preparation. It is desirable and even more desirable is an immediate release tablet. Here, the immediate release solid preparation or compressed solid preparation refers to a solid preparation or a compressed solid preparation that elutes 85% or more within 15 minutes in the dissolution test solution of the Japanese Pharmacopoeia. The test solutions of the Japanese Pharmacopoeia used for confirming the dissolution property of the present invention are the dissolution test first solution (pH 1.2), the acetic acid / sodium acetate buffer solution (pH 4.0), and the dissolution test second solution (pH 6.8). ), And each elution test solution of water. The solid preparation or compressed solid preparation of the present invention may be a chewable tablet, a film-coated tablet, or a sugar-coated tablet.

Alternatively, instead of the compressed solid preparation of the present invention, the granules or powder before compression may be used as they are.
The solid preparation or compressed solid preparation of the present invention is stable over the period up to the expiration date, and the amount of lactam compound generated within the expiration date is 1.0% or less, preferably 0.5% or less.
The expiration date of the solid or compressed solid product of the present invention is at least 3 years from the date of manufacture, preferably 5 years from the date of manufacture.

The solid preparation or compressed solid preparation of the present invention is not sealed and packaged using a material for sealing and packaging using a material that is impervious to gas (for example, an aluminum laminated bag), but is made of polyvinyl chloride, polypropylene, polyethylene, etc. By airtightly packaging in a container made of a gas permeable material, the formation of lactam is suppressed. For example, the solid formulation or compressed solid formulation of the present invention can be more stable by airtightly packaging a material such as polyvinyl chloride, polypropylene, polyethylene, etc. in PTP packaging (blister packaging) in which an aluminum sheet is crimped. can. Polyvinylidene chloride can also be used as the packaging material for airtight packaging. In this case, since it is more permeable to gas than polyvinyl chloride, polypropylene, and polyethylene, the storage stability of the γ-aminobutyric acid derivative is maintained. Therefore, it is disadvantageous compared to polyvinyl chloride, polypropylene, and polyethylene, but it has an advantage in that the storage stability of the γ-aminobutyric acid derivative can be maintained in a high humidity environment.

In the present invention, the closed packaging means a packaging in which solid foreign substances are not mixed under normal handling, transportation or storage. Paper bags, boxes, etc. are sealed.
In the present invention, the airtight packaging means a packaging in which solid or liquid foreign matter does not invade but gas must pass through in a normal handling, transportation or storage state. Most plastic packaging belongs to airtight packaging.

In the present invention, the sealed packaging means packaging that does not allow gas to enter under normal handling, transportation, or storage conditions. Ampoules, vials and aluminum laminated bags are sealed packaging.
In the present invention, airtight packaging, airtight packaging, and airtight packaging are concepts that do not overlap with each other, and airtight packaging and airtight packaging are excluded from airtight packaging.

The airtight packaging used in the present invention is preferably an airtight packaging that is not impermeable to gas. For example, a gas-impermeable material such as a cyclic olefin polymer or a cyclic olefin copolymer is not preferable as the packaging material of the present invention. The material for the airtight packaging used for packaging the solid preparation or the compressed solid preparation of the present invention is preferably a material such as polyvinyl chloride, polypropylene, or polyethylene.

The compressed solid preparation of the present invention can maintain a hardness of preferably 20 N or more, more preferably 25 N or more, still more preferably 30 N or more, still more preferably 35 N or more, and most preferably 40 N or more during the expiration date.

A preferred method for producing a solid or compressed solid product of the present invention includes the following steps.
(1) A step of mixing one or more active ingredients selected from γ-aminobutyric acid derivatives or pharmaceutically acceptable salts thereof together with any additive.
(2) A step of spraying a hydroxypropyl-substituted cellulose solution to granulate the mixture.
(3) Optionally, a step of mixing the granulated product with starch modified with at least a carboxymethyl group,
(4) Arbitrarily, a step of producing a solid preparation by compressing the mixture obtained in (3) above.

Here, any additive in the step (1) is a cellulosic additive (however, hydroxypropyl-substituted cellulose may be used), magnesium aluminometasilicate, light anhydrous silicic acid, hydrous silicon dioxide, and titanium oxide. , Crospovidone, povidone, gum arabic, macrogol, sucrose fatty acid ester, stearic acid, gelatin, calcium dihydrogen phosphate, starch, pregelatinized starch, partially pregelatinized starch, one or more selected from the group consisting of sucrose. It is preferable not to use additives. The optional additive in step (1) is preferably a sugar alcohol, and examples of particularly preferable sugar alcohols include mannitol, sorbitol, erythritol, xylitol, oligosaccharide alcohol, reduced water candy, reduced palatinose, reduced maltsaccharide water candy and maltitol. One or more sugar alcohols selected from the group consisting of tall, more preferably one or two or more sugar alcohols selected from the group consisting of mannitol, oligosaccharide alcohol, reduced maltitol sugar candy and maltitol. , More preferably a reduced maltitol maltitol. In addition, in order to prevent nerve damage due to vitamin B deficiency, vitamin Bs, especially vitamin B12, may be contained as an optional additive, but even if vitamin Bs are used in combination, nerve damage due to vitamin B deficiency may be contained. Therefore, it is possible to prepare a preparation to which vitamin Bs (particularly vitamin B12) are not added.

Further, in the step of spraying and granulating the hydroxypropyl-substituted cellulose solution in step (2), fluidized bed granulation is preferable, and γ-aminobutyric acid derivative and pharmaceuticals are used by fluidized bed granulation instead of stirring granulation. By spraying the hydroxypropyl-substituted cellulose solution onto the salt which is acceptable to the product, the physical properties of the drug substance can be canceled and good tableting property (moldability, adhesiveness) can be ensured. Therefore, the step (2) is preferably "a step of spraying the mixture with a hydroxypropyl-substituted cellulose solution to granulate the fluidized bed".

Further, the hydroxypropyl-substituted cellulose in the step (2) is more preferably hydroxypropyl cellulose from the viewpoint of suppressing the formation of lactams over time and suppressing the decrease in hardness over time. Therefore, it is more preferable that the step (2) is "a step of spraying the mixture with a hydroxypropyl cellulose solution to granulate the fluidized bed".

The present invention includes a solid preparation or a compressed solid preparation produced by the above-mentioned production method.

In all of the following examples, the drug substance of pregabalin was 0.1% impurities, 2.2 μm for D10 (10% integrated particle size), 13.1 μm for D50 (also 50% particle size), and D90 (also 50% particle size). A free drug substance having a particle size of 89.4 μm (90% particle size) was used.
The angle of repose of the pregabalin drug substance was 50 ° to 55 °, and a large coefficient of friction was observed.

It was also found that the pregabalin drug substance adhered to the polyethylene bag containing the drug substance in a large amount and had high adhesion.
In addition, the pregabalin drug substance had a loose bulk density of 0.2 g / mL, indicating that it was bulky.

Formulation change test ;
A combination change test of pregabalin drug substance and additives was conducted.
After mixing the pregavalin drug substance and the additive in a mass ratio of 1: 1, store them under the conditions of 30 ° C. 75% relative humidity, 40 ° C. 75% relative humidity, and 60 ° C. without humidity control. The mass ratio (%) of the mass of the lactam body after storage for 2 weeks to the mass of the initial pregavalin drug substance was measured (Table 1). The measurement was performed in 1 or 2 stations.

The lactam form was quantified by high performance liquid chromatography using a column in which a stainless steel tube having an inner diameter of 4.6 mm and a length of 25 cm was filled with 5 μm octadecylsilylated silica gel. The mobile phase is detected at an OD of 210 nm at a flow rate of 1 mL / min using a mixed solvent (*) of mobile phase A and mobile phase B, the relative retention time is confirmed with a standard lactam of pregabalin, and pregabalin is internally standardized. The peak with a relative retention time of 2.7 when used as a substance was identified as a lactam form. The quantification of the lactam form was calculated based on the sub-peak area of 0.15 g of pregabalin with a relative retention time of 2.7. Below, in all the tests, the lactam body was quantified by the same method.

* Mixed solvent:
Mobile phase A: 5.28 g of diammonium hydrogen phosphate was dissolved in 1000 mL of water, phosphoric acid was added to adjust the pH to 6.5, and 800 mL of this solution was added with 200 mL of methanol.
Mobile phase B: Acetonitrile / methanol mixed solution (9: 1)
Mixing ratio: 0-10 minutes (A: B = 98: 2), 10-21 minutes (A: B = linear concentration gradient changing from 98: 2 to 80:20), 21-45 minutes (A: B =) 80:20)

Additives subject to the compounding change test were lactose hydrate [Pharmatose ™ 200M, DFE Pharma], corn starch [Nissho Corn Starch ™, Nippon Foods Chemicals Co., Ltd.], D-mannitol [Mannit]. P (trademark), Mitsubishi Corporation Food Tech Co., Ltd.], Crystalline cellulose [Theoras PH-101 (trademark), Asahi Kasei Co., Ltd.], Crystalline cellulose [Theoras KG-802 (trademark), Asahi Kasei Co., Ltd.], Isomalt [galenIQ800 (trademark)) ), BENEO-Palatinit GmbH], Crosspovidon [Kollidon CL-F ™, BASF Japan Co., Ltd.], Crosspovidon [Polyplasmone Ultra-10 ™, Ashland Inc. ], Light Silica Silica [Adsolider 101 ™, Freund Sangyo Co., Ltd.], Hydroxypropyl Cellulose [HPC-L ™ Normal Particle Type, Nippon Soda Co., Ltd.], Povidon [K30, BASF Japan Co., Ltd.], Stear Magnesium acid [Taipei Chemical Industries, Ltd.], Calcium stearate [Taipei Chemical Industries, Ltd.], Sucrose fatty acid ester [Sanei Gen FFI Co., Ltd.], Tarku [Risplan (trademark), Sanei Gen FFI Co., Ltd.] Co., Ltd.], Hypromerose [TC-5R, Shin-Etsu Chemical Industries, Ltd.], Macrogol 6000 [Sanyo Chemical Industries, Ltd.], Titanium oxide [A-HR, Freund Sangyo Co., Ltd.], Hydrous silicon dioxide B type [Freund Sangyo Co., Ltd.] Company] was used.

* Isomalt is a mixture of 6-O-α-D-glucoppyranosyl-D-sorbitol and 1-O-α-D-glucoppyranosyl-D-mannitol dihydrate in a ratio of 1: 1.

As can be seen from Table 1, extremely significant amounts of lactams were confirmed by mixing the pregabalin drug substance powder with either hydrous silicon dioxide or light anhydrous silicic acid and placing it in a dry condition at 60 ° C. for 2 weeks. Regarding titanium oxide, crystalline cellulose, hypromellose, and crospovidone, it was confirmed that a remarkable amount of lactam was produced by mixing any of these with the powder of the pregabalin drug substance and leaving it in a drying condition at 60 ° C. for 2 weeks. With regard to crystalline cellulose, the formation of a certain amount of lactam was confirmed after storage for 2 weeks in the same manner under each storage condition of 30 ° C. and 75% relative humidity and 40 ° C. and 75% relative humidity.

For povidone, macrogol 6000, and sucrose fatty acid ester, a medium amount of lactam was produced when any of these was mixed with the powder of the pregavalin drug substance and placed in a dry condition at 60 ° C. for 2 weeks (after 2 weeks). At this time, the povidone group was 0.293%, the macrogol 6000 group was 0.420%, and the sucrose fatty acid ester group was 0.366%.) For talc, corn starch, and isomalt, by mixing one of these with the powder of the pregavalin drug substance and placing it in a dry condition at 60 ° C for 2 weeks, the amount is about 10 times higher than the initial value, albeit in a relatively small amount. The formation of lactam was confirmed (at 2 weeks, 0.215% in the talc group, 0.222% in the corn starch group, 0.234% in the isomalt group).

On the other hand, even if the powder of the pregabalin drug substance was left alone at 60 ° C. for 2 weeks, almost no lactam was produced. For magnesium stearate, calcium stearate, hydroxypropyl cellulose, lactose hydrate, and D-mannitol, even if one of these is mixed with pregabalin drug substance powder and left at 60 ° C for 2 weeks, most of the lactams are present. No lactam was produced, or the amount of lactam produced was negligible.

While the combination of cellulosic additives such as crystalline cellulose and hypromellose with pregabalin produces a significant amount of lactam, it is said that only a very small amount of hydroxypropyl cellulose is produced. It was amazing.

Combination change test (when kneaded) ;
A combination change test of pregabalin drug substance and additives was conducted.
The powder of each additive is added so as to have a mass ratio of 1.125 parts by mass of the additive to 75 parts by mass of the pregavalin drug substance and kneaded with water in a mortar, and then a sample dryer (Fuji Tokushu Kogyo Co., Ltd.) , Model number FHB-10-1) was dried at 60 ° C. for 1 hour, and the whole amount was sieved with a No. 30 mesh to prepare a sample (specimen name: W4 to W13). The fluidity of these samples was confirmed visually and by the angle of repose measurement method, and evaluated on a scale of 5: very good (◎), good (○), slightly bad (△ +), bad (△), and very bad (×). bottom. In addition, the same granules were stored under the condition of 60 ° C. without humidity control, and the mass ratio (%) of the mass of the lactam form at the start of storage and after storage for 3 days to the mass of the initial pregabalin drug substance was measured. (Table 2). The measurement was performed in a series.

In addition, pregabalin drug substance (specimen name: W1), sample in which only pregabalin drug substance is kneaded with purified water (specimen name: W2), and sample in which only pregabalin drug substance is kneaded with absolute ethanol (sample name: W3) are also available. The mass ratio (%) of the mass of the lactam body to the mass of the initial pregabalin drug substance was measured at the start of storage and after storage for 3 days under the condition of no humidity control at 60 ° C. Table 2). The measurement was performed in a series.
In addition, the fluidity of the contents of 75 mg of Lyrica (trademark) capsules was confirmed, and the sample (specimen name: L13994) that was tableted as it was was stored for 3 days under the condition of no humidity control at 60 ° C. The mass ratio (%) of the mass of the lactam form after storage to the mass of the initial pregabalin drug substance was measured (Table 2). The measurement was performed in a series.

Additives subject to the compounding change test are hydroxypropyl cellulose [HPC-L (trademark) normal particle type, Nippon Soda Co., Ltd.], D-mannitol [mannitol P (trademark), Mitsubishi Corporation Food Tech Co., Ltd.], Isomalt [galenIQ800 ™, BENEO-Palatinit GmbH], D-sorbitol [Merck Co., Ltd.], concentrated glycerin [Merck Co., Ltd.], propylene glycol [BASF Japan Co., Ltd.], Macrogol 400 [Sanyo Kasei Kogyo Co., Ltd.], They were reduced malt sugar water candy [Amarti MR100 (trademark), Mitsubishi Corporation Food Tech Co., Ltd.], xylitol [Saneigen FFI Co., Ltd.], and erythritol [Saneigen FFI Co., Ltd.].

As can be seen from Table 2, the fluidity of the obtained granules was obtained by kneading, drying and sieving the powder of the pregabalin drug substance together with an aqueous solution of concentrated glycerin, propylene glycol, macrogol 400 or xylitol. The fluidity of the granules and the contents of the Lyrica ™ capsule 75 mg itself was "very bad (x)".
Granules obtained by kneading, drying and sieving the bulk powder of the pregavalin drug substance without additives, granules obtained by kneading, drying and sieving with purified water, and kneading, drying and sieving with anhydrous ethanol All of the granules obtained by passing were "bad (Δ)".

The fluidity of the granules obtained by kneading, drying and sieving the powder of the pregabalin drug substance together with the aqueous solution of erythritol was “slightly poor (Δ+)”.
The fluidity of the granules obtained by kneading, drying and sieving the powder of the pregabalin drug substance together with an aqueous solution of either isomalt or D-sorbitol was “good (◯)”.

The fluidity of the granules obtained by kneading, drying, and sieving the powder of the pregabalin drug substance together with an aqueous solution of hydroxypropyl cellulose, D-mannitol, or reduced maltose starch syrup was "very good (◎)". rice field.

Regarding the formation of lactam, the granules obtained by kneading, drying and sieving the powder of the pregavalin drug substance together with the hydroxypropyl cellulose aqueous solution are placed in a drying condition of 60 ° C. for 3 days, and the powder of the pregavalin drug substance. Is mixed with powder of D-mannitol, isomalt, D-sorbitol, concentrated glycerin, propylene glycol, macrogol 400, reduced maltose candy, xylitol, or erythritol, and water is added for kneading, drying, and sieving. When the obtained granules were placed in a dry condition of 60 ° C. for 3 days, lactams were produced very little or very little.

On the other hand, it was confirmed that a remarkable amount of lactam was produced by placing the prototype tablet, which was obtained by manually pressing the contents of 75 mg of Lyrica ™ capsule as it was, under a drying condition of 60 ° C. for 3 days or 2 weeks. Granules obtained by kneading, drying and sieving only the pregabalin drug substance powder to produce almost no lactam, and kneading, drying and sieving the pregabalin drug substance powder with purified water or absolute ethanol. When placed in a drying condition of 60 ° C. for 3 days, almost no lactam form was produced, and in the state of 75 mg of Lyrica ™ capsule, the lactam form during the storage period should be within an acceptable range. In consideration of the above, it was understood that the impact of tableting significantly increased the production of lactams when left in a drying condition of 60 ° C. for 3 days or 2 weeks (Table 2).

Prototype of compressed solid preparation ;
A prototype of a compressed solid preparation containing pregabalin was carried out.

The additives used were hydroxypropyl cellulose [HPC-L (trademark) normal particle type, Nippon Soda Co., Ltd.], low-substituted hydroxypropyl cellulose [LH-11 (trademark), Shin-Etsu Chemical Industry Co., Ltd.], aluminum metasilicate. Magnesium Acidate [Neucillin ™, Fuji Chemical Industry Co., Ltd.], Crystalline Cellulose [Theoras KG-802 ™, Asahi Kasei Co., Ltd.], Carmellose Calcium [ECG-505 ™, Gotoku Yakuhin Co., Ltd.], Cross Carme Sodium loin [Ac-Di-Sol ™, Wilbur Ellis Co., Ltd.], partially pregelatinized starch [PCS ™, Asahi Kasei Co., Ltd.], corn starch [Nissho Corn Starch ™, Nippon Foods Chemicals Co., Ltd.] , Calcium dihydrogen phosphate [Taipei Chemical Industry Co., Ltd.], D-mannitol [Mannit P (trademark), Mitsubishi Corporation Food Tech Co., Ltd.], D-mannitol for direct hit [Pertec M100 (trademark), Merck Millipore Corporation] , D-Sorbitol [Merck Co., Ltd.], Granulated lactose hydrate [Dilactos S (trademark), Freund Sangyo Co., Ltd.], Isomalt [galenIQ800 (trademark), BENEO-Palatinit GmbH], Calcium stearate [Taipei Chemical Industry Co., Ltd.] ], Magnesium stearate [Taipei Chemical Industry Co., Ltd.].

Prototype tablets were prepared using the amount of the main ingredient and additives for 8000 tablets according to Table 3. Specifically, 600 g of the pregavalin drug substance and 8000 times the amount of powder per tablet of the "additives in the granulating solution" shown in Table 3 are weighed and the fluidized bed (FD-MP-01 type) is used. , Paulec), and 800 g of purified water was granulated at a speed of 12 g / min at an intake temperature of 80 ° C. and an exhaust temperature of 30 ° C. for about 67 minutes while spraying. As for the amount of "additives in the granulation solution", for example, when 4 mg of D-mannitol was added per tablet, 32 g of D-mannitol was added. However, when hydroxypropyl cellulose is not added as a powder and 4 mg of hydroxypropyl cellulose is added per tablet, 800 g of a 4 mass% HPC aqueous solution prepared in advance is added at a speed of 12 g / min. Granulation was performed while spraying at an intake temperature of 80 ° C. and an exhaust temperature of 30 ° C. for about 67 minutes. Similarly, when 2 mg of hydroxypropyl cellulose is added per tablet, 400 g of 4 mass% HPC aqueous solution is sprayed at a rate of 12 g / min at an intake temperature of 80 ° C. and an exhaust temperature of 30 ° C. for about 33 minutes. When granulating while adding 8 mg of hydroxypropyl cellulose per tablet, 1600 g of 4 mass% HPC aqueous solution was added at a speed of 12 g / min at an intake temperature of 80 ° C. and an exhaust temperature of 30 ° C. for about 133 minutes. Granulated while spraying. The obtained granulated product was dried as it was at 80 ° C. for 5 minutes using a fluidized bed, and sieved through a mesh 30 filter. Add the post-additives shown in Table 3 to the granulated product after drying and sieving in an amount of 8000 times the amount per tablet, mix, and beat using a single-shot tableting machine (AUTOTAB-500, Ichihashi Seiki). The tablet was tableted at a tablet pressure of 0.8 t. The mass per tablet obtained as a result was as shown in Table 3.

Hardness of the prototype compressed solid formulation:
The hardness of the prototype compressed solid preparation immediately after the trial production was measured using a hardness measuring machine (KHT-20N, Fujiwara Seisakusho). The measurement results are as shown in Table 3.
As shown in Table 3, regarding the hardness of tablets, after adding D-sorbitol to the main drug granules and granulating with a granulation solution (that is, water) that does not contain hydroxypropyl cellulose, crystalline cellulose and L- are added as post-additives. When HPC and calcium stearate are added (specimen name: MP5-1-1), and when the main drug granules are granulated with an HPC aqueous solution and then partially pregelatinized starch, L-HPC and calcium stearate are added as post-additives. (Sample name: MP2-9-1) and the case where granulated lactose hydrate, L-HPC and calcium stearate are added as post-additives after granulating the main drug granules with an aqueous HPC solution (Sample name: MP2- In 7-1), the hardness was less than 30 N. However, in all the samples other than these, sufficient hardness of 30 N or more could be obtained.

Storage stability of the prototype compressed solid formulation:
Each compressed solid preparation was stored at 40 ° C. and 75% relative humidity for 1 week, 2 weeks, or 4 weeks. However, the contents of the Lyrica ™ capsule 75 mg were stored as they were at 40 ° C. and 75% relative humidity without locking. Similarly, some of the pregabalin drug substances were stored as is at 40 ° C. and 75% relative humidity without locking.

When only the drug substance was tableted (specimen name: drug substance + 0.4t, drug substance + 0.8t, drug substance + 1.2t), no lactam was generated at the start of storage regardless of the strength of the tableting pressure. The lactam body did not increase at all even after 1 week of storage. From this, it was found that the increase in lactams over time is not caused only by tableting, but only when tableted with a specific additive.

Similarly, when the contents of 75 mg of Lyrica (trademark) capsules are stored at 40 ° C. and 75% relative humidity without tableting (specimen name: Lyrica (trademark)), the amount of lactam at the start of storage is 0. Despite a value of .342%, there was no increase in lactams after 2 and 4 weeks of storage. On the other hand, in Example 2, when the content of 75 mg of Lyrica ™ capsule was directly tableted and stored under 60 ° C. drying conditions for 3 days and 14 days (specimen name: L13994), at the start of storage. Lactam hydration contained in the contents of 75 mg of Lyrica ™ capsules, considering that a marked increase in lactam was observed despite the similar amount of lactam. It was found that pregabalin tableting with substances, corn starch, and talc was the cause of lactam formation over time by tableting.

When magnesium aluminometasilicate (Neucillin) is added as a post-additive as an additive that is present at the time of tableting and triggers the formation of lactams over time, the amount of lactams at the start of storage is 0.066%. After storage at 40 ° C. and 75% relative humidity for 1 week, a remarkable amount of 1.270% of lactam was produced (specimen name MP2-2-1). When magnesium aluminometasilicate (neucillin) was added as a post-additive, the amount of lactam produced was the same amount of partially pregelatinized starch (specimen name MP2-9-1) and phosphorus instead of magnesium aluminometasilicate. Calcium dihydrogen acid (specimen name MP2-6-1), corn starch (specimen name MP2-8-1), direct hit D-mannitol (specimen name MP2-4-1), granulated lactose hydrate (specimen) It was an order of magnitude higher than the amount of lactam produced when D-sorbitol (specimen name MP2-5-1), isomalto (specimen name MP2-3-1), and isomalto (specimen name MP2-5-1) were added. ..

Similarly, when 41 mg of crystalline cellulose is added per tablet as a post-additive, a significant amount of lactam body over time is obtained after storage at 40 ° C. and 75% relative humidity for 2 weeks and 4 weeks as compared with the start of storage. (Specimen names 75-M1, 75-M2, 75-M3). The amount of lactams produced over time after storage at 40 ° C. and 75% relative humidity for 2 weeks was 0.164% higher than when 10.5 mg of crystalline cellulose was added per tablet (specimen name). Compare 75-M2 with sample name MP2-1-1).

Even among the group to which 41 mg of crystalline cellulose was added per tablet as a post-additive, the larger the amount of hydroxypropyl cellulose added to the main drug granules, the more the lactam body after storage under the condition of 40 ° C. and 75% relative humidity for 2 weeks. Increased (specimen names 75-M1, 75-M2, 75-M3).

Even when carmellose calcium (specimen name MP2-1-2) or croscarmellose sodium (specimen name MP2-1-3), which are cellulosic additives, are added as post-additives, the relative humidity is 40 ° C. and 75%. Under the conditions, the amount of lactam after storage for 1 week was increased as compared with the start of storage.

However, even when 10.5 mg of crystalline cellulose was added per tablet as a post-additive, D-mannitol (specimen name MP3-1-1 (lactam body increased by 0.089%)) was added to the main drug granules. Or D-sorbitol (specimen name MP4-1-1 (lactam body increased by 0.018%), MP5-1-1 (lactam body increased by 0.039%), MP6-1-1 (lactam body increased by 0.039%). When these were added (02% increase)), the increase in lactams after storage under the condition of 40 ° C. and 75% relative humidity for 1 week was the case when these were not added (specimen name MP2-1-1 (lactam). The body increased by 0.12%)) was suppressed.

Similarly, even when crystalline cellulose and croscarmellose sodium are added together as a post-additive, D-sorbitol (specimen name MP2-1-3-5-3 (specam name: MP2-1-3-5-3 (lactam form is 0.)) is added to the post-additive. 031% increase), MP2-1-3-5-1 (Lactam form increased by 0.032%), MP2-1-3-5 (Lactam form increased by 0.019%), MP2-1-3-5 When -2 (lactam body increased by 0.024%) and MP2-1-3-5-4 (lactam body increased by 0.011%) were added, under the condition of 40 ° C. and 75% relative humidity. The increase in lactams after storage for 1 week was suppressed as compared with the case where these were not added (specimen name MP2-1-3 (lactams increased by 0.087%)).

Partially pregelatinized starch (specimen name MP2-9-1 (lactam body increased by 0.088%)), granular corn starch (specimen name MP2-8-1 (lactam body increased by 0.080%)) as post-additives Or, when calcium dihydrogen phosphate (specimen name MP2-6-1 (quantum body increased by 0.085%)) was added, the condition was 40 ° C. and 75% relative humidity compared to the start of storage. There was a clear increase in lactam after storage for 1 week.

On the other hand, when only HPC was added to the main drug granules and no cellulosic additive other than L-HPC was added as a post-additive, partially pregelatinized starch (specimen name MP2-9-) was added as a post-additive. 1), Granular corn starch (specimen name MP2-8-1), or calcium dihydrogen phosphate (specimen name MP2-6-1) is not added, but under the condition of 40 ° C. and 75% relative humidity for 1 week. There was no increase in lactams due to storage (specimen name MP2-5-1 (apparently a 0.019% decrease in lactams)) or very slight (specimen name MP2-3-1). (Lactam body increased by 0.030%), MP2-7-1 (Lactam body increased by 0.042%), MP2-4-1 (Lactam body increased by 0.050%). Specimen name MP2-5-1, MP2-3-1, MP2-7-1, MP2-4-1 are each sample with sample name MP2-5-1 as a post-additive other than L-HPC and calcium stearate. Contains D-sorbitol, MP2-3-1 contains isomalt, MP2-7-1 contains lactose hydrate, and MP2-4-1 contains D-mannitol. Unless a cellulose-based additive other than L-HPC is added, the formation of lactams over time does not occur even when tableting, and HPC, L-HPC, D-sorbitol, D-mannitol, lactose water It was found that the addition of Japanese products and isomalt did not cause the formation of lactams over time by tableting.

Disintegration of the prototype compressed solid formulation:
About compressed solid preparation of sample names MP-2-2-1, MP2-1-2, MP2-1-3, MP2-1-1, MP4-1-1, MP2-8-1, MP2-5-1 Only, according to the dissolution test method specified in the Japanese Pharmacopoeia, the disintegration time with respect to water in the vessel was measured using the paddle method under the condition of 50 revolutions per minute.
As a result, as shown below, it was found that the disintegration within 30 minutes required for the uncoated tablets by the Japanese Pharmacopoeia was achieved for all the samples, and that they had sufficiently fast disintegration.

Specimen name MP-2-2-1:
After granulating 75 mg of pregabalin per tablet using a 4% aqueous HPC solution (HPC per tablet is 4 mg), 10.5 mg of magnesium aluminometasilicate per tablet (neucillin) per tablet. When 10 mg of L-HPC and 0.5 mg of calcium stearate per tablet were added, mixed, and tableted at a pressure of 0.8 t, the disintegration time was 12 minutes.

Specimen name MP2-1-2:
After granulating 75 mg of pregabalin per tablet using a 4% aqueous HPC solution (HPC per tablet is 4 mg), 10.5 mg of crystalline cellulose per tablet, 10 mg of carmellose calcium per tablet, The disintegration time was 11 minutes when 0.5 mg of calcium stearate was added per tablet, mixed, and tableted at a pressure of 0.8 t.

Specimen name MP2-1-3:
After granulating 75 mg of pregabalin per tablet using a 4% aqueous HPC solution (4 mg of HPC per tablet), 10.5 mg of crystalline cellulose per tablet and 10 mg of croscarmellose sodium per tablet. The disintegration time was 2.5 minutes when 0.5 mg of calcium stearate was added per tablet, mixed, and tableted at a pressure of 0.8 t.

Specimen name MP2-1-1: 1
After granulating 75 mg of pregabalin per tablet using a 4% aqueous HPC solution (HPC per tablet is 4 mg), 10.5 mg of crystalline cellulose per tablet, and 10 mg of L-HPC per tablet, The disintegration time was 13 minutes when 0.5 mg of calcium stearate was added per tablet, mixed, and tableted at a pressure of 0.8 t.

Specimen name MP4-1: 1:
75 mg of pregabalin per tablet and 4 mg of D-sorbitol per tablet are mixed, and 4% HPC aqueous solution is sprayed on the mixture to obtain 4 mg of HPC per tablet, and then granulated, and then per tablet. Disintegration time is 5.5 minutes when 10.5 mg of crystalline cellulose, 10 mg of L-HPC per tablet, and 0.5 mg of calcium stearate per tablet are added, mixed, and tableted at a pressure of 0.8 t. Met.

Specimen name MP2-8-1:
After granulating 75 mg of pregavalin per tablet using 4% aqueous HPC solution (HPC per tablet is 4 mg), 10.5 mg of granulated corn starch per tablet (granulated cornstarch) per tablet. When 10 mg of L-HPC and 0.5 mg of calcium stearate per tablet were added, mixed, and tableted at a pressure of 0.8 t, the disintegration time was 9.5 minutes.

Specimen name MP2-5-1:
After granulating 75 mg of pregabalin per tablet using a 4% aqueous HPC solution (4 mg of HPC per tablet), 10.5 mg of D-sorbitol per tablet and 10 mg of L-HPC per tablet. The disintegration time was 6.5 minutes when 0.5 mg of calcium stearate was added per tablet, mixed, and tableted at a pressure of 0.8 t.

Prototype of compressed solid preparation ;
A prototype of a compressed solid preparation was made by tableting only the granulated product containing pregabalin.

The additives used were hydroxypropyl cellulose [HPC-L (trademark) normal particle type, Nippon Soda Co., Ltd.], D-mannitol [mannitol P (trademark), Mitsubishi Corporation Foodtech Co., Ltd.], D-sorbitol [Merck]. Co., Ltd.].

Prototype tablets were prepared using the amount of the main ingredient and additives for 8000 tablets according to Table 4. Specifically, for samples with sample names starting with 75-MP, 600 g of pregavalin drug substance and "additives in granulation solution" (D-mannitol or D-sorbitol; HPC) shown in Table 4 8000 times the amount of powder per tablet (added in the granulation solution) was weighed and put into a fluidized layer (FD-MP-01 type, Paulec), and 800 g of a 4 mass% hydroxypropyl cellulose aqueous solution. Was granulated at a speed of 12 grams per minute at an intake temperature of 80 ° C. and an exhaust temperature of 30 ° C. while spraying for about 67 minutes. For example, when adding 4 mg of D-mannitol per tablet, 32 g of D-mannitol was added. The obtained granulated product was dried as it was at 80 ° C. for 5 minutes using a fluidized bed, and sieved through a mesh 30 filter. The granulated product after drying and sieving was locked with a single-shot locking machine (AUTOTAB-500, Ichihashi Seiki) at the locking pressure shown in Table 4. The mass per tablet obtained as a result was as shown in Table 4. When "-" is displayed in the pressing pressure column, it means that the tablet is not locked.

Since each tablet of the sample with the sample name: 75-M3 contains 8 mg of hydroxypropyl cellulose, 1600 g of a 4 mass% hydroxypropyl cellulose aqueous solution is exhausted at a speed of 12 g / min at an intake temperature of 80 ° C. Granulation was carried out at a temperature of 30 ° C. while spraying for about 133 minutes, and a trial tablet was prepared in the same manner as above except for the above.

Storage stability of the prototype compressed solid formulation:
As shown in Table 4, each granulated or compressed solid preparation was stored at 40 ° C. and 75% relative humidity for 7 or 14 days. The contents of 75 mg of Lyrica ™ capsules were stored as is at 40 ° C. and 75% relative humidity without locking.

The content of the Lyrica ™ capsule 75 mg had a large amount of lactam at the start of storage, but the amount of lactam after storage at 40 ° C. and 75% relative humidity for 14 days did not increase at all. On the other hand, in Example 2, when the content of 75 mg of Lyrica ™ capsule was directly tableted and stored under 60 ° C. drying conditions for 3 days and 14 days (specimen name: L13994), at the start of storage. Considering that a marked increase in lactam was observed despite similar amounts of lactam in the lactam, the increase in lactam was the content of 75 mg of Lyrica ™ capsules. It was understood that it progresses over time triggered by the impact of tableting together with lactam hydrate, corn starch, and talc contained in.

For pregabalin granules containing HPC, D-mannitol, and D-sorbitol, no increase in lactam was observed after storage at 40 ° C. and 75% relative humidity for 7 days, unless locked. That is, 75 mg of pregavalin was granulated and dried using a 4% HPC aqueous solution (HPC per tablet was 4 mg) (specimen names: 75-MP2-40, 75-MP2-45), and 4% HPC. And D-mannitol aqueous solution (HPC and D-mannitol per tablet are 4 mg each), and 75 mg of pregavalin was granulated and dried (specimen names: 75-MP3-40, 75-MP3-45). Pregabalin 75 mg was granulated and dried using a 4% aqueous solution of HPC and D-sorbitol (HPC and D-sorbitol per tablet were 4 mg each) (specimen names: 75-MP4-40, 75-MP4). In −45), the amount of increase in lactams after storage at 40 ° C. and 75% relative humidity for 7 days was 0.012% or less, and no increase in lactams was observed. From this, it was understood that the increase in lactams progressed over time triggered by the impact of locking with a predetermined additive.

When pregabalin granules containing HPC, D-mannitol, and D-sorbitol were tableted, the amount of lactams at the start of storage increased slightly compared to the case without tableting. The increase in lactams due to storage at 40 ° C. and 75% relative humidity for 7 days was negligible. That is, 75 mg of pregavalin was granulated using a 4% HPC aqueous solution (HPC per tablet was 4 mg), dried, and then tableted at 0.4 t, 0.8 t, and 1.2 t (specimen name 75-). Use MP2-04, 75-MP2-08, 75-MP2-12), 4% HPC and D-mannitol (4 mg each of HPC and D-mannitol per tablet) to granulate and dry 75 mg of pregavalin. After that, the tablets were locked at 0.4t, 0.8t, 1.2t (specimen name, sample name 75-MP3-04, 75-MP3-08, 75-MP3-12), and 4% HPC and D-. Pregabalin 75 mg was granulated using sorbitol (HPC and D-sorbitol per tablet were 4 mg each), dried, and then tableted at 0.4 t, 0.8 t, and 1.2 t (specimen name 75-MP4). -04, 75-MP4-08, 75-MP4-12), the amount of increase in lactam form after storage at 40 ° C. and 75% relative humidity for 7 days was 0.026% or less, and lactam. The increase in body was negligible. In addition, no clear association was found between the striking pressure and the amount of increase in lactam.

From this, even if HPC is added to a compressed solid preparation containing a γ-aminobutyric acid derivative or a pharmaceutically acceptable salt thereof, the formation of lactams over time triggered by the impact of tableting occurs. It turned out not.

Further, even if D-mannitol or D-sorbitol is added to a compressed solid preparation containing a γ-aminobutyric acid derivative or a pharmaceutically acceptable salt thereof, the lactam form over time generated by the impact of tableting It was found that almost no generation occurred.

Prototype of compressed solid preparation ;
A prototype of a compressed solid preparation containing pregabalin was carried out.

The additives used were hydroxypropyl cellulose [HPC-L (trademark) normal particle type, Nippon Soda Co., Ltd.], low-substituted hydroxypropyl cellulose [LH-11 (trademark), Shin-Etsu Chemical Industry Co., Ltd.], reduced malt sugar water candy. [Amalti MR100 ™, Mitsubishi Shoji Food Tech Co., Ltd.], Crystalline Cellulose [Theoras KG-802 ™, Asahi Kasei Co., Ltd.], Croscarmellose Sorb [Ac-Di-Sol ™, Wilbur Ellis Co., Ltd.] ], D-mannitol for direct hitting [Partec M200 (trademark), Merck Millipore Corporation], D-sorbitol [Merck Co., Ltd.], granulated lactose hydrate [Dilactos S (trademark) Freund Sangyo Co., Ltd.], Erythritol [Sanei] Source FFI Co., Ltd.] and calcium stearate [Taipei Chemical Industry Co., Ltd.].

Prototype tablets were prepared using the amount of the main ingredient and additives for 8000 tablets according to Table 5. Specifically, the fluidized layer (FD-MP-01 type) is weighed 8000 times the amount per tablet of 600 g of the pregavalin drug substance and the "additive (powder) of the granulated portion" shown in Table 5. , Paulec), and a 4 mass% HPC aqueous solution was granulated while spraying at a speed of 12 g / min at an intake temperature of 80 ° C. and an exhaust temperature of 30 ° C. As for the amount of "additive (powder) for granulated portion", when 4 mg of D-sorbitol is added per tablet, 32 g of D-sorbitol is added as powder, and 7 mg of reduced maltose water candy is added per tablet. In some cases, 56 g of reduced maltose syrup was added in powder form, and in the case of adding 7 mg of erythritol per tablet, 56 g of erythritol was added in powder form. Regarding the spray amount and spray time of the HPC aqueous solution, when 4 mg of HPC is added per tablet, 800 g of 4 mass% HPC aqueous solution is sprayed and granulated for about 67 minutes, and 6 mg of HPC is added per tablet. In some cases, 1200 g of 4% by mass HPC aqueous solution is sprayed for about 100 minutes to granulate, and when 8 mg of HPC is added per tablet, 1600 g of 4% by mass of HPC aqueous solution is sprayed for about 133 minutes. Granulated while doing. The obtained granulated product was dried as it was at 80 ° C. for 5 minutes using a fluidized bed, and sieved through a mesh 30 filter. Add the post-additives shown in Table 5 to the granulated product after drying and sieving in an amount of 8000 times the amount per tablet, mix, and beat using a single-shot tableting machine (AUTOTAB-500, Ichihashi Seiki). The tablet was tableted at a tablet pressure of 0.8 t. The mass per tablet obtained as a result was as shown in Table 5.

As shown in Table 5, a 4% HPC solution was used so as to have a content of 4 mg, 6 mg or 8 mg per tablet, and D-sorbitol was used as an additive for the granulated portion containing pregabalin, and reduced. Maltose starch syrup and erythritol were examined. As the cellulosic additive in the post-additive, each sample contained 2 mg of croscarmellose sodium per tablet. In addition, each sample of sample names: MP7-1 (1), MP7-2 (1), MP7-3 (1), and MP8-2 (1) further contained 10 mg of crystalline cellulose per tablet. ..

Hardness of the prototype compressed solid formulation:
The hardness of the prototype compressed solid preparation immediately after the trial production was measured using a hardness measuring machine (KHT-20N, Fujiwara Seisakusho). The measurement results are as shown in Table 5.
As shown in Table 5, the hardness of all the prototype tablets was 66 N or more at the start of storage, which was sufficient.

However, when the prototype tablets using D-sorbitol as an additive for the granulated portion were stored at 40 ° C. and 75% relative humidity for 3 days, the hardness was reduced to about 20 N or less (specimen name MP7-1). (1), MP7-2 (1) to (5), MP7-3 (1)). On the other hand, when the prototype tablets using reduced maltose starch syrup or erythritol as an additive for the granulated portion were stored at 40 ° C. and 75% relative humidity for 3 days, the hardness was maintained over 40 N (specimen name MP8). -2 (1) to (5), MP9-2 (3)).

Storage stability of the prototype compressed solid formulation:
Each compressed solid preparation was stored at 40 ° C. and 75% relative humidity for 7 days.
Trial tablets using D-sorbitol as an additive for the granulated portion had more than doubled the amount of lactams when stored at 40 ° C and 75% relative humidity for 7 days, but still the lactams after storage. The amount was 0.1% or less, and the amount of lactam compound increased by storing at 40 ° C. and 75% relative humidity for 7 days was 0.057% or less (specimen names MP7-1 (1), MP7-). 2 (1) to (5), MP7-3 (1)). From this, it was found that even if crystalline cellulose and / or sodium croscarmellose is contained in the post-additive, if D-sorbitol is contained in the granulated portion, the increase in the lactam form can be sufficiently suppressed. ..

On the other hand, in the trial tablet using reduced maltose starch syrup or erythritol as an additive for the granulated portion, the amount of lactam after storage at 40 ° C. and 75% relative humidity for 7 days is about 0.145% or less, and 40 ° C. The amount of lactams increased by storage at 75% relative humidity for 7 days was 0.072% or less ((1) to (5), MP9-2 (3) of sample names MP8-2). From this, even if crystalline cellulose and / or sodium croscarmellose is contained in the post-additive, if the granulated portion contains reduced maltose starch syrup or erythritol, the increase in lactam can be sufficiently suppressed. all right.

Disintegration of the prototype compressed solid formulation:
Specimen name: Only for compressed solid preparations of MP7-1 (1), MP7-2 (1), MP7-3 (1), MP8-2 (2), paddle according to the dissolution test method specified in the Japanese Pharmacopoeia. Using the method, the decay time with respect to water in the vessel was measured under the condition of 50 revolutions per minute.
As a result, as shown below, it was found that the disintegration within 30 minutes required for the uncoated tablets by the Japanese Pharmacopoeia was achieved for all the samples, and that they had sufficiently fast disintegration.

Specimen name MP7-1 (1):
After granulating 75 mg of pregabalin per tablet and 4 mg of D-sorbitol per tablet using a 4% aqueous HPC solution (HPC per tablet is 4 mg), 10 mg of crystalline cellulose per tablet (KG802). ), 2 mg of croscarmellose sodium per tablet and 1 mg of calcium stearate per tablet were added and mixed, and the disintegration time was 4 minutes when the tablet was beaten at a pressure of 0.8 t.

Specimen name MP7-2 (1):
After granulating 75 mg of pregabalin per tablet and 4 mg of D-sorbitol per tablet using a 4% aqueous HPC solution (HPC per tablet is 6 mg), 10 mg of crystalline cellulose per tablet (KG802). ), 2 mg of croscarmellose sodium per tablet and 1 mg of calcium stearate per tablet were added and mixed, and the disintegration time was 8 minutes when the tablet was beaten at a pressure of 0.8 t.

Specimen name MP7-3 (1):
After granulating 75 mg of pregabalin per tablet and 4 mg of D-sorbitol per tablet using a 4% aqueous HPC solution (8 mg HPC per tablet), 10 mg of crystalline cellulose per tablet (KG802). ), 2 mg of croscarmellose sodium per tablet and 1 mg of calcium stearate per tablet were added and mixed, and the disintegration time was 15 minutes when the tablet was beaten at a pressure of 0.8 t.

Specimen name MP8-2 (2):
After granulating 75 mg of pregabalin per tablet and 7 mg of reduced maltose starch syrup per tablet using a 4% aqueous HPC solution (HPC per tablet is 6 mg), 10 mg of D for direct beating per tablet. -Mannitol (Pertec M200), 2 mg of croscarmellose sodium per tablet, and 1 mg of calcium stearate per tablet were added and mixed, and the disintegration time was 7 minutes when tableted at a pressure of 0.8 t. ..

Summary of Example 5:
As described above, in the preparation containing crystalline cellulose and / or sodium croscarmellose as a post-additive, the disintegration time was sufficiently fast. However, the prototype tablet using D-sorbitol as an additive for the granulated portion had good storage stability when stored at 40 ° C. and 75% relative humidity for 7 days, while at 40 ° C. and 75% relative humidity. The hardness decreased significantly after storage for 3 days. Trial tablets using reduced maltose starch syrup or erythritol as an additive for the granulated portion have good storage stability when stored at 40 ° C. and 75% relative humidity for 7 days, and at 40 ° C. and 75% relative humidity for 3 days. The hardness after storage was also good.

Prototype of compressed solid preparation ;
A prototype of a compressed solid preparation containing pregabalin was made using the main drug granules containing 1%, 2%, or 3% of water.

The additives used were hydroxypropyl cellulose [HPC-L (trademark) normal particle type, Nippon Soda Co., Ltd.], reduced maltose water candy [Amarti MR100 (trademark), Mitsubishi Corporation Foodtech Co., Ltd.], crystalline cellulose [Theoras KG- 802 (trademark), Asahi Kasei Co., Ltd.], croscarmellose sodium [Ac-Di-Sol (trademark), Wilbur Ellis Co., Ltd.], calcium stearate [Taipei Chemical Industry Co., Ltd.].

Prototype tablets were prepared using the amount of the main ingredient and additives for 8000 tablets according to Table 6. Specifically, 600 g of the pregavalin drug substance and 56 g of the reduced maltose starch syrup were weighed and put into a fluidized bed (FD-MP-01 type, Paulec), and 800 g of a 4% hydroxypropyl cellulose aqueous solution was added at a speed of 12 g / min. Granulation was performed while spraying at an intake temperature of 80 ° C. and an exhaust temperature of 30 ° C. for about 67 minutes. The obtained granulated product was dried as it was at 80 ° C. using a fluidized bed, and the obtained granulated product was measured for water content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). It was dried to 1%, 2%, or 3%. Then, it was sieved with a filter of mesh 30. Add the post-additives shown in Table 6 to the granulated product after drying and sieving in an amount of 8000 times the amount per tablet, mix, and beat using a single-shot tableting machine (AUTOTAB-500, Ichihashi Seiki). The tablet was tableted at a tablet pressure of 0.8 t. The mass per tablet obtained as a result was as shown in Table 6.

Storage stability of the prototype compressed solid formulation:
Storage stability of the main ingredient granules themselves using the main ingredient granules containing 1%, 2%, or 3% water, storage of tableting granules in which the main ingredient granules are mixed with crystalline cellulose, croscarmellose sodium, and calcium stearate. Stability and each of the prototype tablets in which the granules for tableting were tableted at 0.8 ton were stored at 40 ° C. and 75% relative humidity for 7 days.

As a result, in each of the main drug granules having a water content of 1%, 2% and 3%, the amount of increase in the lactam form due to storage at 40 ° C. and 75% relative humidity for 7 days was 0 in each case without tableting. The water content was 0.014%, 0.015%, and 0.015%, whereas it was 0.035%, 0.042%, and 0.035% when tableted. Regardless, it was reconfirmed that the impact of tableting caused an increase in lactam body over time. On the other hand, the increase in lactams over time in the main drug granules, the tableting granules, and the prototype compressed solid preparation did not change depending on the water content of the main drug granules.

Prototype of compressed solid preparation ;
We investigated a pregabalin preparation that can maintain the hardness of tablets even after storage under accelerated conditions.

The additives used were hydroxypropyl cellulose [HPC-L (trademark) normal particle type, Nippon Soda Co., Ltd.], reduced malt sugar water candy [Amalti MR100 (trademark), Mitsubishi Corporation Food Tech Co., Ltd.], pregelatinized starch [Nissho]. Kagaku Co., Ltd.], sucrose [Merck Co., Ltd.], Arabic rubber [Saneigen FFI Co., Ltd.], gelatin [Saneigen FFI Co., Ltd.], stearic acid [Taipei Chemical Industry Co., Ltd.], starch Sodium glycolate [Primogel ™, DFE Pharma], croscarmellose sodium [Ac-Di-Sol ™, Wilbur Ellis Co., Ltd.], calcium stearate [Taipei Chemical Industry Co., Ltd.].

200 prototype tablets were prepared using a mortar according to Table 7. Specifically, 15 g of pregavalin and 1.4 g of reduced maltose water candy were mixed in a dairy pot, and each aqueous solution for granulation (0.3 g HPC, 0.3 g pregelatinized starch, 0.3 g sucrose, 0.3 g) was mixed. After adding (6 g aqueous solution containing arabic rubber or 0.3 g of gelatin), granulate in a dairy pot and dry in a dryer at 80 ° C. (electric constant temperature dryer, Kayagaki Medical Science Industry Co., Ltd.) to obtain the obtained product. The granulated product was dried until the water content became 1% or less while measuring the water content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). Then, it was sieved with a filter of mesh 30. The granulated product after drying and sieving was weighed for 100 tablets, and the post-additives shown in Table 7 were added in an amount 100 times the amount per tablet and mixed, and a single-shot tableting machine (AUTOTAB-500, Ichihashi Seiki) was used to lock the tablet at a tableting pressure of 0.8 ton. The mass per tablet obtained as a result was as shown in Table 7.

For the prototype tablet containing stearic acid, 15 g of pregavalin and 1.4 g of reduced maltose starch syrup were mixed in a dairy pot, 1.6 g of stearic acid powder was added, and a dryer at 80 ° C. (electric constant temperature dryer, Kayagaki). Granulation was performed while heating and melting at Medical Science Industry Co., Ltd.). Then, it was sieved with a filter of mesh 30. Add the post-additives shown in Table 7 to the granulated product after sieving in an amount 100 times the amount per tablet, mix, and use a single-shot tableting machine (AUTOTAB-500, Ichihashi Seiki) to apply the tableting pressure. It was locked at 0.8 ton. The mass per tablet obtained as a result was as shown in Table 7.

As shown in Table 7, for each of the prototype tablets of sample names: N3-4 to N3-8, the type and amount of post-additives were fixed to 2 mg of croscarmellose sodium per tablet and 1 mg of calcium stearate per tablet. Then, after fixing the amount of reduced maltose starch syrup to be added as powder to the granulated granules to 7 mg per tablet, the additives to be added by dissolving in the granulated liquid were changed in various ways, and the relative humidity was 40 ° C. and 75%. We examined the increase in tablet hardness and lactam after storage in.

Specimen name: For only one group of N3-9, 7 mg of reduced starch sugar candy per tablet was added as a powder to the granulated granules, and 1.5 mg of HPC per tablet was dissolved in the granulation solution for granulation. Granulate by spraying with the liquid, add 2 mg of sodium starch glycolate and 1 mg of calcium stearate per tablet as post-additives, mix and then tablet to prepare a prototype tablet. Specimen name: Contrast with N3-4 prototype tablets.

Specimen name: The prototype tablet of N4-1 examined the possibility of melt granulation using stearic acid. As an ingredient per tablet, instead of 1.5 mg of HPC per tablet used in the prototype tablet of sample name: N3-4, 8 mg of stearic acid per tablet of the prototype tablet of sample name: N4-1 was used. Since it was added, the prototype tablet with the sample name: N3-4 and the prototype tablet with the sample name: N4-1 were compared.

Hardness of the prototype compressed solid formulation:
The hardness of the prototype compressed solid preparation immediately after the trial production was measured using a hardness measuring machine (KHT-20N, Fujiwara Seisakusho). The measurement results are as shown in Table 7.
As shown in Table 7, the hardness of all the prototype tablets was 25 N or less at the start of storage, which was not sufficient as the hardness at the start of storage. From this, it was found that the hardness of the tablets was lowered when 7 mg of reduced maltose starch syrup was added to the granules of the main ingredient.

In addition, when 1.5 mg of pregelatinized starch is added per tablet together with 7 mg of reduced maltose starch syrup per tablet as an additive for the granulated portion (specimen name N3-5), 1.5 mg of white sugar per tablet is also added. (Sample name N3-6), 1.5 mg of gum arabic per tablet (Sample name N3-7), and 1.5 mg of gelatin per tablet (Sample name) In N3-8), the hardness of the tablet after storage at 40 ° C. and 75% relative humidity for 7 days decreased to 0 (zero) N. From this, it was found that at least when pregelatinized starch, sucrose, gum arabic or gelatin was added to the granulated portion, the hardness of the tablet during the expiration date could not be maintained.

On the other hand, when 1.5 mg of HPC per tablet and 7 mg of reduced maltose starch syrup per tablet were used as additives in the granulation solution (specimen names N3-4, N3-9), the temperature was 75% relative to 40 ° C. The hardness of the tablets after storage at humidity for 7 days was maintained at about 10 N, and it was found that the hardness of the pregavalin tablets during the period of use may be maintained by adding HPC to the granulated portion.

In the case of melt granulation using 8 mg of stearic acid per tablet and 7 mg of reduced maltose water candy per tablet as additives in the granulation liquid (specimen name N4-1), 25 N tablets at the start of storage. Since it had a hardness and could maintain a hardness of 17N even after being stored at 40 ° C. and 75% relative humidity for 7 days, the hardness of the pregavalin preparation was increased by melt granulation in which stearic acid was added to the granulated part, and at the same time. It was found that the tablet hardness during storage is unlikely to decrease.

Storage stability of the prototype compressed solid formulation:
Each compressed solid preparation is stored at 40 ° C. and 75% relative humidity, and is subjected to a high-speed liquid chromatogram using a column filled with 5 μm octadecylsilylated silica gel in a stainless steel tube having an inner diameter of 4.6 mm and a length of 25 cm after 7 days. And the lactam body after 14 days was quantified.

When melt granulation is performed by adding 7 mg of reduced maltose starch syrup per tablet and 8 mg of stearic acid per tablet as an additive for the granulated portion (specimen name N4-1), the lactam content at the start of storage is 0. The lactam content increased to 0.437% after storage at 40 ° C. and 75% relative humidity for 14 days, while it was .064%, and over time due to melt granulation with the addition of stearic acid. An increase in lactam was observed.

Similarly, when 1.5 mg of gelatin per tablet is added together with 7 mg of reduced maltose starch syrup per tablet as an additive for the granulated portion (specimen name N3-8), it is stored at 40 ° C. and 75% relative humidity for 14 days. The lactam content increased to 0.176%, and an increase in lactam over time was observed with the addition of gelatin.

When 1.5 mg of HPC per tablet is added together with 7 mg of reduced maltose starch syrup per tablet (specimen name N3-4), 1.5 mg of pregelatinized starch is also added per tablet as an additive for the granulated portion. (Sample name N3-5), 1.5 mg of maltose per tablet (Sample name N3-6), and 1.5 mg of arabic rubber per tablet (Sample name N3-). In 7), the lactam content after storage at 40 ° C. and 75% relative humidity for 14 days was between 0.103% and 0.124%, which was due to storage at 40 ° C. and 75% relative humidity for 14 days. Since the amount of increase in lactam was also 0.042% to 0.067%, a slight increase in lactam over time was observed.

On the other hand, the additives in the granulation solution were 1.5 mg of HPC per tablet and 7 mg of reduced maltose starch syrup per tablet, and 2 mg of sodium starch glycolate per tablet and 1 mg per tablet as post-additives. When calcium stearate was used (specimen name N3-9), the lactam content after storage at 40 ° C. and 75% relative humidity for 14 days remained at 0.066%, and 14 at 40 ° C. and 75% relative humidity. Since the increase in lactam form due to storage for days was only 0.028%, it is preferable to use sodium starch glycolate as a post-additive, and in comparison with the sample name: N3-4, etc., the post-additive It was found that the addition of croscarmellose sodium was not preferable for maintaining storage stability.

Prototype of compressed solid preparation ;
The storage stability of the prototype compressed solid preparation was examined.

The additives used were hydroxypropyl cellulose [HPC-L (trademark) normal particle type, Nippon Soda Co., Ltd.], D-sorbitol [Merck Co., Ltd.], reduced malt sugar water candy [Amarti MR100 (trademark), Mitsubishi Corporation Food Tech Co., Ltd.) Company], Erythritol [Saneigen FFI Co., Ltd.], Crystalline cellulose [Theoras KG-802 (trade), Asahi Kasei Co., Ltd.], Croscarmellose sodium [Ac-Di-Sol (trademark), Wilbur Ellis Co., Ltd. Company], calcium stearate [Taipei Chemical Industry Co., Ltd.], magnesium stearate [Taipei Chemical Industry Co., Ltd.], low-substituted hydroxypropyl cellulose [LH-11 ™, Shin-Etsu Chemical Industry Co., Ltd.].

Prototype tablets were prepared using the amount of the main ingredient and additives for 8000 tablets according to Table 8. Specifically, the fluidized layer (FD-MP-01) is weighed 8000 times the amount per tablet of 600 g of the pregavalin drug substance and "additives added as powder into granulated granules" shown in Table 8. The 4% by mass HPC aqueous solution prepared in advance for granulation was granulated at a speed of 12 grams per minute at an intake temperature of 80 ° C. and an exhaust temperature of 30 ° C. while spraying. .. The spray amount and spray time of the HPC aqueous solution are such that when 4 mg of HPC is added per tablet, 800 g of 4 mass% HPC aqueous solution is sprayed for about 67 minutes to granulate, and when 6 mg of HPC is added per tablet. Granulated while spraying 1200 g of a 4 mass% HPC aqueous solution for about 100 minutes, and when 8 mg of HPC was added per tablet, granulated while spraying 1600 g of a 4 mass% HPC aqueous solution for about 133 minutes. The amount of "additives added as powder to granulated granules" is 8 g of D-sorbitol added as powder when 1 mg of D-sorbitol is added per tablet, and 4 mg of D-sorbitol per tablet. When adding, 32 g of D-sorbitol was added in powder form, and when adding 7 mg of D-sorbitol per tablet, 56 g of D-sorbitol was added in powder form. Reduced maltose starch syrup and erythritol were also added in powder form in the same manner. The obtained granulated product was dried as it was at 80 ° C. using a fluidized bed, and the obtained granulated product was measured for water content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). It was dried to 1%. Then, it was sieved with a filter of mesh 30. Add the post-additives shown in Table 8 to the granulated product after drying and sieving in an amount of 8000 times the amount per tablet, mix, and beat using a single-shot tableting machine (AUTOTAB-500, Ichihashi Seiki). The tablet was tableted at a tablet pressure of 0.8 t. The mass per tablet obtained as a result was as shown in Table 8.

As shown in Table 8, in the prototype tablets whose sample name starts with N, a 4% HPC solution was used as the granulation solution so that the HPC content per tablet was 4 mg, and the granulated portion containing pregavalin was added. As a substance, D-sorbitol, reduced maltose starch syrup, or erythritol was added as a powder so as to be 1 mg, 4 mg, or 7 mg per tablet. The post-additive had a composition containing 10 mg of crystalline cellulose per tablet, 2 mg of sodium croscarmellose per tablet, and 1 mg of calcium stearate per tablet.

For prototype tablets whose sample name starts with M, a 4% HPC solution was used as the granulation solution so that each tablet contained 4 mg of HPC, and D-sorbitol was used as an additive for the granulated portion containing pregabalin. It was added as a powder so as to be 4 mg per tablet.

As for the post-additive, as shown in Table 8, the amount of crystalline cellulose and calcium stearate per tablet was fixed, and the amount of L-HPC was changed to 10 mg or 2 mg per tablet (specimen name MP4-1-1). 1 and MP4-1-2).

Alternatively, as the post-additive, as shown in Table 8, the amount of croscarmellose and calcium stearate per tablet was fixed, and the amount of crystalline cellulose was changed to 5 mg, 10 mg, or 20 mg per tablet (sample). Names MP4-2-1, MP4-2-2, and MP-4-2-3).

Furthermore, in the prototype tablets whose sample name starts with 75, the post-additives are fixed to 41 mg of crystalline cellulose per tablet, 10 mg of L-HPC per tablet, and 1.5 mg of magnesium stearate per tablet. The granulation solution used for producing granulated products containing pregavalin was granulated by increasing or decreasing the amount of 4% HPC solution so as to have an HPC content of 2 mg, 4 mg or 8 mg per tablet (specimen name MP75). -M1, 75-M2, and 75-M3).

Hardness of the prototype compressed solid formulation:
The hardness of the prototype compressed solid preparation immediately after the trial production was measured using a hardness measuring machine (KHT-20N, Fujiwara Seisakusho). The measurement results are as shown in Table 8.
As shown in Table 8, the hardness of all the prototype tablets was about 30 N or more at the start of storage, and had sufficient hardness.

Storage stability of the prototype compressed solid formulation:
Each compressed solid preparation was stored at 40 ° C. and 75% relative humidity, and the amount of lactam was quantified after 7, 14, or 28 days.

When only 4 mg of HPC per tablet was added as an additive for the granulated portion, and 10 mg of crystalline cellulose, 2 mg of croscarmellose sodium, and 1 mg of calcium stearate were added as post-additives (specimen name: N1). The amount of lactam in the trial tablet increased with time, and the amount of increase in lactam after storage at 40 ° C. and 75% relative humidity for 2 weeks was 0.320%. From this, it can be seen that the amount of lactam is increased over time by tableting pregabalin together with cellulosic additives such as crystalline cellulose and croscarmellose sodium.

On the other hand, when 1 mg, 4 mg, or 7 mg of erythritol was added per tablet in addition to 4 mg of HPC per tablet as an additive for the granulated portion, the mixture was stored at 40 ° C. and 75% relative humidity for 2 weeks. Although the amount of increase in lactam in the trial tablet over time was suppressed to 0.182% to 0.191%, no effect proportional to the amount of erythritol added was observed (specimen name: N4-1). , N4-2, N4-3).

When 1 mg, 4 mg, or 7 mg of reduced maltose starch syrup was added per tablet in addition to 4 mg of HPC per tablet as an additive for the granulated portion, the increase in lactam in the prototype tablet over time was added. The larger the amount of reduced maltose starch syrup, the more suppressed it was, and the amount of increase in lactam in the prototype tablet over time due to storage at 40 ° C. and 75% relative humidity for 2 weeks was when 1 mg of reduced maltose starch syrup was added per tablet. 0.202% was 0.139% when 4 mg of reduced maltose starch syrup was added per tablet, and 0.134% when 7 mg of reduced maltose starch syrup was added per tablet. Therefore, in the sample to which 4 mg or 7 mg of reduced maltose starch syrup was added per tablet, the amount of lactam was maintained at a smaller amount than when the same amount of erythritol was added (sample names: N3-1, N3-). 2, N3-3).

When 1 mg, 4 mg, or 7 mg of D-sorbitol was added per tablet in addition to 4 mg of HPC per tablet as an additive for the granulated portion, the increase in lactam in the prototype tablet over time was added. The larger the amount of D-sorbitol, the more it was suppressed, and the amount of increase in lactam in the trial tablet over time due to storage at 40 ° C and 75% relative humidity for 2 weeks was obtained when 1 mg of D-sorbitol was added per tablet. 0.178% was 0.103% when 4 mg of D-sorbitol was added per tablet. When 7 mg of D-sorbitol was added per tablet, the absolute amount of lactam was only 0.137% after storage at 40 ° C. and 75% relative humidity for 2 weeks (since there is no data at the start of storage). The amount of lactam body increased over time is unknown). Thus, samples supplemented with 1 mg, 4 mg, or 7 mg of D-sorbitol per tablet were able to maintain a much smaller amount of lactam than when the same amount of reduced maltose starch syrup was added (). Specimen name: N2-1, N2-2, N2-3).

4 mg of HPC per tablet and 4 mg of D-sorbitol per tablet were added as additives for the granulated portion, and 10 mg of crystalline cellulose per tablet and 1 mg of calcium stearate per tablet as post-additives, and 1 mg of calcium stearate per tablet. When 2 mg of L-HPC was added (specimen name: MP4-1-2), the amount of increase in lactam in the trial tablet over time due to storage at 40 ° C. and 75% relative humidity for 2 weeks was 0.076. The amount of increase in lactam in the trial tablet over time due to storage at 40 ° C. and 75% relative humidity for 2 weeks when the amount of L-HPC of the sample was changed to the same amount of croscarmellose sodium. Compared with 103% (specimen name: N2-2), the amount of lactam produced over time could be maintained even smaller. From this, it was found that croscarmellose sodium is not preferable and L-HPC is preferable for suppressing the increase of lactams over time triggered by the impact of tableting.

Moreover, even if the amount of L-HPC of MP4-1-2 was increased from 2 mg per tablet to 10 mg per tablet, the amount of lactam produced over time was almost the same (specimen name N4-1-1). 1). From this, it was found that L-HPC does not significantly affect the increase of lactams over time.

4 mg HPC per tablet and 4 mg D-sorbitol per tablet were added as additives for the granulated portion, and 10 mg crystalline cellulose per tablet and 2 mg croscarmellose sodium per tablet as post-additives, and 1 A sample (specimen name: MP4-2-2) containing 1 mg of calcium stearate per tablet was added afterwards compared to the amount of lactam (0.158%) after storage at 40 ° C. and 75% relative humidity for 2 weeks. After storing a sample (specimen name 4-2-1) in which the amount of crystalline cellulose of a product was reduced to 5 mg per tablet at 40 ° C. and 75% relative humidity for 2 weeks, the amount of lactam was reduced to 0.150%. The amount of lactam form after storing a sample (specimen name 4-2-3) in which the amount of crystalline cellulose as a post-additive was increased to 20 mg per tablet at 40 ° C. and 75% relative humidity for 2 weeks was 0.132%. Increased to. From this, it was found that by tableting pregabalin together with crystalline cellulose, the amount of lactams increased over time, and the greater the amount of crystalline cellulose added, the greater the amount of lactams produced over time. ..

Only 2 mg, 4 mg or 8 mg of HPC per tablet was added as an additive for the granulated portion, and 41 mg of crystalline cellulose per tablet was added as a post-additive, 10 mg of L-HPC per tablet, and 1.5 mg per tablet. The amount of lactam produced by storing the samples (specimen names 75-M1, 75-M2, 75-M3) to which magnesium stearate was added at 40 ° C. and 75% relative humidity for 2 weeks was 2 mg of HPC per tablet. The addition was 0.337%, the addition of 4 mg of HPC per tablet was 0.387%, and the addition of 8 mg of HPC per tablet was 0.428%. It was a formulation far from practical use. From this, it was found that when 41 mg of crystalline cellulose was added per tablet, basically too much lactam body was produced over time. In addition, since the amount of lactam produced over time tended to increase slightly when the amount of HPC added was large, the amount of lactam produced over time was acceptable if the amount of HPC was up to a certain level. Even if it is within the range, it was found that a small amount of HPC is preferable for suppressing the production of lactams over time.

Disintegration of the prototype compressed solid formulation:
Only for the compressed solid preparation with the sample name MP4-1-1, the disintegration time with respect to water in the vessel is measured using the paddle method according to the dissolution test method specified in the Japanese Pharmacopoeia under the condition of 50 rotations per minute. bottom.
As a result, as shown below, the sample with the sample name: MP4-1-1 has achieved the disintegration within 30 minutes required for the uncoated tablets by the Japanese Pharmacopoeia, and has sufficiently fast disintegration property. all right.

Specimen name MP4-1: 1:
After granulating 75 mg of pregabalin per tablet and 4 mg of D-sorbitol per tablet using a 4% aqueous HPC solution (HPC per tablet is 4 mg), 10 mg of crystalline cellulose per tablet (KG802). ), 10 mg of L-HPC per tablet and 1 mg of calcium stearate per tablet were added, mixed, and tableted at a pressure of 0.8 t, and the disintegration time was 5.5 minutes.

Prototype of compressed solid preparation ;
The hardness and amount of lactams of various prototype tablets were examined in order to establish a formulation of a pregabalin preparation that can maintain hardness when stored at 40 ° C. and 75% relative humidity and is stable in storage. In the prototype of Example 9, crystalline cellulose was not used because it causes an increase in lactams over time.

The additives used were hydroxypropyl cellulose [HPC-L (trademark) normal particle type, Nippon Soda Co., Ltd.], D-mannitol [Mannitol P (trademark), Mitsubishi Corporation Foodtech Co., Ltd.], D-sorbitol [Merck]. Co., Ltd.], Reduced malt sugar candy [Amarti MR100 (trademark), Mitsubishi Corporation Food Tech Co., Ltd.], Erythritol [Saneigen FFI Co., Ltd.], Isomalt [galenIQ800 (trademark), BENEO-Palatinit GmbH], Crosscarme They were sodium loin [Ac-Di-Sol ™, Wilbur Ellis Co., Ltd.] and calcium stearate [Taipei Chemical Industry Co., Ltd.].

Prototype tablets were prepared using the amount of the main ingredient and additives for 8000 tablets according to Table 9. Specifically, 600 g of the pregavalin drug substance and 8000 times the amount per tablet of "additives added as powder in granulated granules" shown in Table 9 are weighed and powdered into a fluidized layer (FD-MP). -01 type, Paulec) and prepared for granulation in advance with 4% by mass HPC aqueous solution at a speed of 12 grams per minute at an intake temperature of 80 ° C and an exhaust temperature of 30 ° C while spraying. Granulated. The spray amount and spray time of the HPC aqueous solution are such that when 4 mg of HPC is added per tablet, 800 g of 4 mass% HPC aqueous solution is sprayed for about 67 minutes to granulate, and when 8 mg of HPC is added per tablet. Was granulated while spraying 1600 g of a 4 mass% HPC aqueous solution for about 133 minutes. The amount of "additives added as powder to granulated granules" is as follows: when 4 mg of D-sorbitol is added per tablet, 32 g of D-sorbitol is added as powder and 4 mg of D-mannitol is added per tablet. When adding 32 g of D-mannitol in powder form, when adding 7 mg of reduced maltose sorbitol per tablet, add 56 g of reduced maltose sorbitol in powder form, and when adding 7 mg of erythritol per tablet 56 g of erythritol was added in powder form. The obtained granulated product was dried as it was at 80 ° C. using a fluidized bed, and the obtained granulated product was measured for water content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). It was dried to 1%. Then, it was sieved with a filter of mesh 30. Add the post-additives shown in Table 9 to the granulated product after drying and sieving in an amount of 8000 times the amount per tablet, mix, and beat using a single-shot tableting machine (AUTOTAB-500, Ichihashi Seiki). The tablet was tableted at a tablet pressure of 0.8 t. The mass per tablet obtained as a result was as shown in Table 9.

Specimen name: In the MP2-B prototype tablet, only 4% HPC solution was used as the granulation solution so as to have an HPC content of 4 mg per tablet, and only 1 mg of calcium stearate per tablet was used as a post-additive. Added. Specimen name: In the MP2-A prototype tablet, 2 mg of croscarmellose sodium per tablet was added as a post-additive to the MP2-B prototype tablet.

In the prototype tablet of sample name: MP5, instead of granulation with the HPC solution used in the prototype tablet of sample name: MP2-A, 4 mg of D-sorbitol powder was added per tablet and water was sprayed. Granulated.
In the sample tablet of the sample name: MP3, 4 mg of D-mannitol was further added as a powder as an additive for the granulated portion containing the pregabalin of the sample tablet of the sample name: MP2-A.

In the sample tablet of the sample name: MP4, 4 mg of D-sorbitol was further added as a powder as an additive for the granulated portion containing pregabalin of the sample tablet of the sample name: MP2-A.

Specimen name: In the prototype tablets of MP7-1, MP7-3, MP8-1, MP8-3, MP9-1, and MP9-3, the post-additives were 2 mg of croscarmellose sodium per tablet and 1 mg per tablet. 4 mg of D-sorbitol (specimen names: MP7-1, MP7-3) per tablet as an additive for the granulated portion containing pregavalin fixed to calcium stearate (specimen names: MP7-1, MP7-3) Specimen name: MP8-1, MP8-3) or 7 mg of erythritol (specimen name: MP9-1, MP9-3) was added per tablet, and the amount of HPC used for granulation was 1 in each of these. The dose was 4 mg (specimen names: MP7-1, MP8-1, MP9-1) or 8 mg (specimen names: MP7-3, MP8-3, MP9-3) per tablet.

Specimen name: In the prototype tablets of MP2-A-1 and MP2-A-2, only a 4% HPC solution was used as the granulating solution so as to have an HPC content of 4 mg per tablet, and 1 as a post-additive. In addition to the post-additives of the prototype tablet (specimen name: MP2-A) to which 2 mg of croscarmellose sodium per tablet and 1 mg of calcium stearate were added per tablet, an additional 10 mg of isomalt (specimen name: MP2-A) per tablet. A-1) or 10 mg of D-sorbitol (specimen name: MP2-A-2) per tablet was post-added.

The prototype tablet of sample name: MP8-1-1 is a prototype tablet in which 7 mg of reduced maltose starch syrup is added as a powder to the granulated product of the prototype tablet of sample name: MP2-A-1. That is, in the MP8-1-1 prototype tablet, a mixture of 75 mg of pregabalin per tablet and 7 mg of reduced maltose starch syrup per tablet was mixed with a 4% HPC solution so as to have an HPC content of 4 mg per tablet. As post-additives, 2 mg of croscarmellose sodium per tablet, 1 mg of calcium stearate per tablet, and 10 mg of isomalt per tablet were added to the granulated product obtained by spraying.

The prototype tablet of sample name: MP8-3-1 is a prototype tablet in which the HPC content in the granulated product of the prototype tablet of sample name: MP8-1-1 is increased to 8 mg per tablet. That is, in the MP8-3-1 prototype tablet, a mixture of 75 mg of pregabalin per tablet and 7 mg of reduced maltose starch syrup per tablet was mixed with a 4% HPC solution so as to have an HPC content of 8 mg per tablet. As post-additives, 2 mg of croscarmellose sodium per tablet, 1 mg of calcium stearate per tablet, and 10 mg of isomalt per tablet were added to the granulated product obtained by spraying.

Specimen name: In the prototype tablet of MP8-1-2, only 4% HPC solution was used as the granulating solution so as to have an HPC content of 4 mg per tablet, and 10 mg of D- per tablet as a post-additive. 7 mg of reduced maltose starch syrup per tablet in the granulated product of a prototype tablet (specimen name: MP2-A-2) containing 2 mg of croscarmellose sodium per tablet and 1 mg of calcium stearate per tablet. It is a trial tablet to which. That is, in the MP8-1-2 prototype tablet, a mixture of 75 mg of pregabalin per tablet and 7 mg of reduced maltose starch syrup per tablet was mixed with a 4% HPC solution so as to have an HPC content of 4 mg per tablet. As post-additives, 2 mg of croscarmellose sodium per tablet, 1 mg of calcium stearate per tablet, and 10 mg of D-sorbitol per tablet were added to the granulated product obtained by spraying.

Further, the prototype tablet having the sample name MP8-3-2 was a prototype tablet in which the HPC amount of the prototype tablet having the sample name: MP8-1-2 was increased to 8 mg per tablet. That is, in the MP8-3-2 prototype tablet, a mixture of 75 mg of pregabalin per tablet and 7 mg of reduced maltose starch syrup per tablet was mixed with a 4% HPC solution so as to have an HPC content of 8 mg per tablet. As post-additives, 2 mg of croscarmellose sodium per tablet, 1 mg of calcium stearate per tablet, and 10 mg of D-sorbitol per tablet were added to the granulated product obtained by spraying.

Hardness of the prototype compressed solid formulation:
The hardness of the prototype compressed solid preparation immediately after the trial production was measured using a hardness measuring machine (KHT-20N, Fujiwara Seisakusho). The measurement results are as shown in Table 9.

As shown in Table 9, 2 mg of croscarmellose sodium per tablet and 1 mg of calcium stearate per tablet were added as post-additives to the pregabalin-containing granules granulated using only D-sorbitol without HPC. The prototype tablet (specimen name: MP5), which was added and mixed and then tableted with a tableting pressure of 0.8 t, was prepared using other HPC aqueous solutions except that the hardness at the start of storage was only 22 N. All of the prototype tablets using the granulated pregabalin-containing granules had a hardness of about 30 N or more at the start of storage, and had sufficient hardness.

However, the prototype tablets (specimen names: MP4, MP5, MP7-1, MP7-3) containing 4 mg of D-sorbitol per tablet as an additive in the granulated product have a relative humidity of 40 ° C. and 75%. After storage for 7 days, the tablet hardness decreased to less than 20 N, and the maintenance of the tablet hardness was insufficient. By increasing the content of HPC in the granulated product from 4 mg to 8 mg per tablet, the tablet hardness after storage at 40 ° C. and 75% relative humidity for 7 days is 6 N (specimen name: MP7-1) to 12.5 N. Although it increased to (specimen name: MP7-3), it was still less than 20N (specimen name MP7-3).

Similarly, even when 10 mg of D-sorbitol is added per tablet as a post-additive, the tablet hardness after storage at 40 ° C. and 75% relative humidity for 7 days decreases to 0N, and the tablet hardness is maintained. It was completely inadequate (specimen names: MP2-A-2, MP8-1-2, MP8-3-2).

Only 4% HPC solution was used as the granulation solution so that the HPC content was 4 mg per tablet, 10 mg isomalt per tablet as a post-additive, 2 mg croscarmellose sodium per tablet, and per tablet. The tablet hardness of the prototype tablet (specimen name: MP2-A-1) to which 1 mg of calcium stearate was added has a tablet hardness of 36.5 N at the start of storage, and is 40 even after storage at 40 ° C. and 75% relative humidity for 7 days. The tablet hardness of .3N was maintained.

However, when 7 mg of reduced maltose starch syrup was added per tablet as an additive in the granulated product of the prototype tablet of sample name: MP2-A-1, the tablet hardness was 60.5 N at the start of storage. After storage at 40 ° C. and 75% relative humidity for 7 days, the tablet hardness decreased to only 8.0 N (specimen name: MP8-1-1). When the HPC content in the granulated product of the above-mentioned sample name: MP8-1-1 prototype tablet was increased to 8 mg per tablet, 20.0 N was obtained even after storage at 40 ° C. and 75% relative humidity for 7 days. The tablet hardness was maintained, but the tablet hardness was still not satisfactory (specimen name: MP8-3-1).

On the other hand, a trial tablet (specimen name) in which only a 4% HPC solution was used as a granulating solution so as to have an HPC content of 4 mg per tablet, and only 1 mg of calcium stearate was added as a post-additive. : MP2-B), the prototype tablet (specimen name: MP2-A) in which 2 mg of croscarmellose sodium was added as a post-additive to the prototype tablet of MP2-B, and the prototype tablet of MP2-A. In the trial tablet (specimen name: MP3) to which 4 mg of D-mannitol was added per tablet as an additive for the granulated portion containing pregabalin, the tablet was stored at 40 ° C. and 75% relative humidity for 7 days even at the start of storage. Later, it had a sufficiently good tablet hardness of about 30 N or more.

Similarly, granulated products containing 4 mg or 8 mg of HPC per tablet, 7 mg of reduced maltose starch syrup per tablet, and 75 mg of pregabalin per tablet were granulated in a fluidized bed, and 2 mg of croscarmellose sodium per tablet was added. The prototype tablets (specimen names: MP8-1, MP8-3) after adding 1 mg of calcium stearate per tablet, mixing and tableting were approximately stored at 40 ° C. and 75% relative humidity for 7 days. It maintained an extremely good tablet hardness of 50 N or more.

Similarly, granulations containing 4 mg or 8 mg HPC per tablet, 7 mg erythritol per tablet and 75 mg pregabalin per tablet were fluidized bed granulated, and 2 mg croscarmellose sodium and 1 tablet per tablet. The prototype tablets (specimen names: MP9-1, MP9-3) that were post-added, mixed, and tableted with 1 mg of calcium stearate per tablet were 44.0 N even after being stored at 40 ° C. and 75% relative humidity for 7 days. The above-mentioned good tablet hardness was maintained.

From these experimental results, the addition of D-sorbitol significantly reduces the tablet hardness after storage under accelerated conditions, and the combined use of reduced maltose starch syrup and isomalt results in tablet hardness after storage under accelerated conditions. It was found to be significantly reduced. In addition, erythritol did not reduce the tablet hardness after storage under accelerated conditions, and unless it was used in combination with isomalt or D-sorbitol, reduced maltose starch syrup was stored under accelerated conditions by adding reduced maltose starch syrup to the main drug granulation part. It was found that the later tablet hardness was significantly improved.

Storage stability of the prototype compressed solid formulation:
Each compressed solid preparation was stored at 40 ° C. and 75% relative humidity, and the amount of lactam after 7 days was quantified by high performance liquid chromatography.

As shown in Table 9, only 4% HPC solution was used as the granulating solution so as to have an HPC content of 4 mg per tablet, and only 1 mg of calcium stearate was added and mixed as a post-additive. In the prototype tablet (specimen name: MP2-B), which was later tableted with a tableting pressure of 0.8 t, the amount of lactam was hardly increased even after storage at 40 ° C. and 75% relative humidity for 7 days.
From this, it was found that at an HPC content of 4 mg per tablet, essentially no increase in lactams was observed over time after tableting.

Only 4% HPC solution was used as the granulation solution so that the HPC content was 4 mg per tablet, and 2 mg of croscarmellose sodium per tablet and 1 mg of calcium stearate per tablet were added as post-additives. In the prototype tablet (specimen name: MP2-A), which was mixed and then tableted at a tableting pressure of 0.8 ton, the amount of lactam was significantly increased after storage at 40 ° C. and 75% relative humidity for 7 days. ..
From this, it was found that the addition of sodium croscarmellose significantly increased the production of lactams over time after tableting.

On the other hand, the prototype tablet (specimen name: MP4, MP7-1) in which 4 mg of D-sorbitol was added per tablet to the granulated product of the prototype tablet of the sample name: MP2-A over time. The increase in lactam was significantly suppressed.
From this, it was found that by adding 4 mg of D-sorbitol per tablet, the production of lactams over time after tableting can be significantly suppressed.

Then, when 4 mg of HPC per tablet was excluded from the granulated product of the prototype tablet of sample name: MP2-A, the increase of lactams over time was further slightly suppressed (specimen name: MP5), and it was contained in the granulated product. When the amount of HPC was increased to 8 mg per tablet, the degree of suppression of the increase in lactams over time decreased (specimen name: MP7-3).
From this, HPC essentially does not promote the production of lactams over time after tableting, but can slightly produce lactams over time after tableting, depending on the amount added. all right.

Similarly, a prototype tablet (specimen) in which 10 mg of D-sorbitol was added as a post-additive instead of adding 4 mg of D-sorbitol to the granulated product of the prototype tablet of the above-mentioned sample name: MP2-A (sample). Name: MP2-A-2) also significantly suppressed the increase in lactams over time.
From this, it was found that the addition of D-sorbitol can significantly suppress the production of lactams over time after tableting.

Further, a prototype tablet (specimen name: MP8-1-2) in which 7 mg of reduced maltose starch syrup is added to each granulated product of the prototype tablet of the sample name: MP2-A-2 also has a sample name: MP2. The increase in lactam over time was significantly suppressed to the same extent as the prototype tablet of -A-2.
From this, it was found that the addition of 7 mg of reduced maltose starch syrup per tablet did not promote the production of lactams over time after tableting.

Then, the significant suppression of the increase in lactams over time in the prototype tablet of sample name: MP8-1-2 was achieved by increasing the amount of HPC in the granulated product to 8 mg per tablet (specimen name: MP8). In -3-2), it remained suppressed to the same extent.
From this, it was found that HPC essentially does not promote the production of lactams over time after tableting.

Only 4% HPC solution was used as the granulation solution so that the HPC content was 4 mg per tablet, and 2 mg of croscarmellose sodium per tablet and 1 mg of calcium stearate per tablet were added as post-additives. To a trial tablet (specimen name: MP2-A) that was tableted with a tableting pressure of 0.8 ton after mixing, 4 mg of D-mannitol was added to the granulated product of this trial tablet. Tablets (specimen name: MP3) did not suppress the increase in lactams over time.
From this, it was found that 4 mg of D-mannitol per tablet did not promote or suppress the production of lactams over time after tableting.

Similarly, only 4% HPC solution was used as the granulation solution so that the HPC content was 4 mg per tablet, 2 mg croscarmellose sodium per tablet as post-additives, and 1 mg calcium stearate per tablet. To a prototype tablet (specimen name: MP2-A) that was tableted with a tableting pressure of 0.8 t after adding and mixing, 10 mg of isomalt was added to each tablet as a post-additive of the prototype tablet. With tablets (specimen name: MP2-A-1), the increase in lactams over time was only slightly suppressed.
From this, it was found that 10 mg of isomalt per tablet slightly suppressed the production of lactams over time after tableting.

On the other hand, a prototype tablet (specimen name: MP8-1-1) in which 7 mg of reduced maltose starch syrup was added to the granulated product of the prototype tablet of the sample name: MP2-A-1. ), The increase in lactams over time was significantly suppressed.
From this, it was found that the production of lactams over time after tableting can be suppressed by adding 7 mg of reduced maltose starch syrup per tablet.

Lactam over time is also present in the prototype tablet (specimen name: MP8-3-1) in which the amount of HPC in the granulated product of the prototype tablet of the sample name: MP8-1-1 is increased to 8 mg per tablet. Body growth remained significantly suppressed.
From this, it was found that HPC essentially does not promote the production of lactams over time after tableting.

Only 4% HPC solution was used as the granulation solution so that the HPC content was 4 mg per tablet, and 2 mg of croscarmellose sodium per tablet and 1 mg of calcium stearate per tablet were added as post-additives. To the trial tablet (specimen name: MP2-A) that was tableted with a tableting pressure of 0.8 ton after mixing, a trial tablet (specimen) in which 7 mg of reduced maltose water candy was added to the granulated product of this trial tablet. Name: MP8-1) did not significantly suppress the increase in lactam over time as much as the prototype tablets (specimen names: MP4, MP7-1) to which 4 mg of D-sorbitol was added, but lactam over time. The increase was suppressed to some extent.
From this, it was found that the production of lactams over time after tableting can be suppressed by adding 7 mg of reduced maltose starch syrup per tablet.

Specimen name: The prototype tablet (specimen name: MP8-3) in which the amount of HPC in the granulated product of the prototype tablet of MP8-1 is increased to 8 mg per tablet is also medium in the same manner as the prototype tablet of sample name: MP8-1. Although a degree of suppression of the increase in lactams over time was observed, the amount of lactams produced over time was slightly increased by increasing the amount of HPC in the granulated product.
From this, HPC essentially does not promote the production of lactams over time after tableting, but can slightly produce lactams over time after tableting, depending on the amount added. all right.

Only 4% HPC solution was used as the granulation solution so that the HPC content was 4 mg per tablet, and 2 mg of croscarmellose sodium per tablet and 1 mg of calcium stearate per tablet were added as post-additives. To the prototype tablet (specimen name: MP2-A) that was tableted with a tableting pressure of 0.8 ton after mixing, 7 mg of erythritol was added to the granulated product of this trial tablet (sample name: MP2-A). Specimen name: MP9-1) did not significantly suppress the increase of lactam over time as much as the trial tablet (specimen name: MP4, MP7-1) to which 4 mg of D-sorbitol was added, but lactam over time. Body growth was suppressed to some extent.
From this, it was found that by adding 7 mg of erythritol per tablet, the production of lactams over time after tableting can be suppressed to some extent.

Specimen name: The prototype tablet (specimen name: MP9-3) in which the amount of HPC in the granulated product of the prototype tablet of MP9-1 is increased to 8 mg per tablet is also medium in the same manner as the prototype tablet of sample name: MP9-1. Although a degree of suppression of the increase in lactams over time was observed, the amount of lactams produced over time was slightly increased by increasing the amount of HPC in the granulated product.
From this, HPC essentially does not promote the production of lactams over time after tableting, but can slightly produce lactams over time after tableting, depending on the amount added. all right.

From these experimental results, it was found that the amount of lactams after storage at 40 ° C. and 75% relative humidity for 7 days was significantly increased by the post-addition of croscarmellose.

This increase in lactams over time is slightly increased by increasing the amount of HPC in the granules, while the addition of D-mannitol in the granules does not change the amount of lactams. It was found that the addition of reduced maltose starch syrup or erythritol to the granulated product was moderately suppressed. In addition, this increase in lactams over time can be significantly suppressed by adding D-sorbitol to the granulated product, and by adding isomalt or D-sorbitol as a post-additive. It was found to be significantly suppressed.

However, the tablet hardness after storage at 40 ° C. and 75% relative humidity for 7 days is the tablet hardness when D-sorbitol is added to the granulated product and when D-sorbitol is added as a post-additive. I also found that I couldn't keep it. The tablet hardness after storage at 40 ° C. and 75% relative humidity for 7 days is that the tablet contains pregavalin drug substance, HPC, reduced maltose starch syrup, and isomalt as a post-additive. It turned out that the hardness could not be maintained.
Therefore, in the prototype tablets shown in Table 9, only a 4% HPC solution was used as the granulating solution so as to have an HPC content of 4 mg per tablet, and only 1 mg of calcium stearate was added as a post-additive. Except for the prototype tablet (specimen name: MP2-B), it was not possible to maintain the tablet hardness and storage stability during the expiration date.

Prototype of compressed solid preparation ;
In order to establish a formulation of a pregabalin preparation that can maintain hardness when stored at 40 ° C. and 75% relative humidity and is stable in storage, various prototype tablets were prepared to obtain the tablet hardness and lactam form. The amount was verified.

The additives used were hydroxypropyl cellulose [HPC-L (trademark) normal particle type, Nippon Soda Co., Ltd.], reduced malt sugar water candy [Amalti MR100 (trademark), Mitsubishi Corporation Food Tech Co., Ltd.], sodium starch glycolate [Primo]. Gel (trademark), Matsutani Chemical Industry], Hydroxypropyl starch [HPS-101 (trademark), Freund Sangyo Co., Ltd.], Corn starch [Nissho Corn Starch (trademark), Nippon Food Chemicals Co., Ltd.], Partially pregelatinized starch [PCS] (Trademark), Asahi Kasei Co., Ltd.], Pregelatinized starch [Amicol (trademark), Nissho Chemical], Low-substituted hydroxypropyl cellulose [LH-11 (trademark), Shin-Etsu Chemical Industry Co., Ltd.], D-mannitol for direct hitting [Partec M100 ™, Merck Millipore Corporation], croscarmellose sodium [Ac-Di-Sol ™, Wilbur Ellis Co., Ltd.], calcium stearate [Taipei Chemical Industry Co., Ltd.].

Prototype tablets were prepared using the amount of the main ingredient and additives for 8000 tablets according to Table 10. Specifically, 600 grams of pregavalin drug substance and powder of reduced maltose starch syrup were weighed and put into a fluidized layer (FD-MP-01 type, Paulec), and 4% by mass prepared in advance for granulation. The HPC aqueous solution was granulated while spraying at a speed of 12 grams per minute at an intake temperature of 80 ° C. and an exhaust temperature of 30 ° C. Regarding the spray amount and spray time of the HPC aqueous solution, when 4 mg of HPC is added per tablet, 800 g of 4 mass% HPC aqueous solution is sprayed for about 67 minutes to granulate, and 1.3 mg of HPC is added per tablet. In the case, 260 g of a 4 mass% HPC aqueous solution was sprayed for about 22 minutes for granulation. The amount of reduced maltose starch syrup added is 56 g of reduced maltose starch syrup when 7 mg of reduced maltose starch syrup is added per tablet, and 160 g of reduced maltose starch syrup when 20 mg of reduced maltose starch syrup is added per tablet. Was added in powder form. The obtained granulated product was dried as it was at 80 ° C. using a fluidized bed, and the obtained granulated product was measured for water content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). It was dried to 1%. Then, it was sieved with a filter of mesh 30. Add the post-additives shown in Table 10 to the granulated product after drying and sieving in an amount of 8000 times the amount per tablet, mix, and beat using a single-shot tableting machine (AUTOTAB-500, Ichihashi Seiki). The tablet was tableted at a tablet pressure of 0.8 t. The mass per tablet obtained as a result was as shown in Table 10.

Among the prototype tablets shown in Table 10, all the samples whose sample names start with MP10 are granulated containing 4 mg of HPC per tablet, 7 mg of reduced maltose starch syrup per tablet, and 75 mg of pregabalin per tablet. After granulating the product in a fluidized bed and drying it, in addition to 1 mg of calcium stearate per tablet, the additives shown in Table 10 were added so as to be the amount added per tablet shown in Table 10. By mixing and tableting with a tableting pressure of 0.8 t, a trial tablet capable of maintaining the tablet hardness and preventing the increase of the lactam body over time was examined.

Among the prototype tablets shown in Table 10, the samples whose sample names start with MP11 are granulated products containing 1.3 mg of HPC per tablet, 20 mg of reduced maltose starch syrup per tablet, and 75 mg of pregavalin per tablet. After granulating the fluidized bed and drying, in addition to 0.7 mg of calcium stearate per tablet and 3 mg of sodium starch glycolate per tablet, 20 mg or 40 mg of D-mannitol for direct impact was added per tablet. Then, by mixing and tableting with a tableting pressure of 0.6 t, a trial tablet capable of maintaining the tablet hardness and preventing the increase of the lactam body over time was examined.

First, in the prototype tablet of sample name: MP10-8, a granulated product containing 4 mg of HPC per tablet, 7 mg of reduced maltose starch syrup per tablet, and 75 mg of pregabalin per tablet was granulated in a fluidized bed and dried. After that, in addition to 1 mg of calcium stearate per tablet, 2 mg of sodium croscarmellose per tablet was added, mixed, and tableted at a tableting pressure of 0.8 t.

The prototype tablet of sample name: MP10-9 was produced in the same manner as the prototype tablet of sample name: MP10-8, except that the amount of croscarmellose sodium was reduced to 1 mg per tablet.

Specimen name: MP10-1 prototype tablet was the same as the MP10-8 prototype tablet, except that 4 mg of sodium starch glycolate was post-added instead of 2 mg of croscarmellose sodium per tablet. Manufactured in the same way.

The prototype tablet of sample name: MP10-2 was produced in the same manner as the prototype tablet of sample name: MP10-1, except that the amount of sodium starch glycolate was reduced to 3 mg per tablet.

Specimen name: MP10-3 prototype tablets, except that 4 mg of hydroxyprepyl starch per tablet was post-added instead of 2 mg of croscarmellose sodium per tablet. Manufactured in the same way.

Specimen name: MP10-4 prototype tablets were manufactured in the same manner as the MP10-8 prototype tablets, except that 4 mg of cornstarch per tablet was post-added instead of 2 mg of croscarmellose sodium per tablet. bottom.

Specimen name: MP10-5 prototype tablet, except that 4 mg of partially pregelatinized starch per tablet was post-added instead of 2 mg of croscarmellose sodium per tablet. Manufactured in the same way.

Specimen name: The prototype tablet of MP10-6 is the same as the prototype tablet of sample name: MP10-8, except that 4 mg of pregelatinized starch was post-added per tablet instead of 2 mg of croscarmellose sodium per tablet. Manufactured in.

Specimen name: MP10-7 prototype Tablets, except that 4 mg of low-substituted hydroxypropyl cellulose per tablet was post-added instead of 2 mg of croscarmellose sodium per tablet. Manufactured in the same way as tablets.

Specimen name: MP10-10 prototype tablet, except that 3 mg of sodium starch glycolate was post-added in addition to 2 mg of croscarmellose sodium per tablet, and the sample name: MP10-8 prototype tablet. Manufactured in the same way.

Specimen name: In the prototype tablet of MP10-11, except that 7 mg of sodium starch glycolate and 60 mg of direct-hit mannitol per tablet were post-added instead of 2 mg of croscarmellose sodium per tablet. Specimen name: Manufactured in the same manner as the prototype tablet of MP10-8.

Specimen name: In the prototype tablet of MP11-1, a granulated product containing 1.3 mg of HPC per tablet, 20 mg of reduced maltose starch syrup per tablet, and 75 mg of pregabalin per tablet was granulated in a fluidized bed and dried. After that, in addition to 1 mg of calcium stearate per tablet, 3 mg of sodium starch glycolate per tablet and 20 mg of mannitol for direct striking per tablet were added, mixed, and tableted at a tableting pressure of 0.8 t. bottom.

Specimen name: MP11-2 prototype tablet was produced in the same manner as the prototype tablet of sample name: MP11-1 except that the amount of mannitol for direct impact was increased to 40 mg per tablet.

Changes in hardness and increase in lactam form over time of the prototype compressed solid formulation:
The prototype compressed solid preparation was stored at 40 ° C. and 75% relative humidity, and the tablet hardness and the amount of lactam were measured at the start of storage and after 7 days. The measurement results are as shown in Table 10.

Granulation containing 4 mg of HPC per tablet, 7 mg of reduced maltose starch syrup per tablet, and 75 mg of pregabalin per tablet was granulated in a fluidized bed, dried, and then 2 mg of croscarmellose sodium and 1 tablet. The prototype tablet (specimen name: MP10-8), which was mixed by adding 1 mg of calcium stearate per tablet and tableted at a tableting pressure of 0.8 ton, was 39 even after being stored at 40 ° C. and 75% relative humidity for 7 days. The tablet hardness of .5N was maintained, and the amount of increase in lactam over time was also small. This result was generally consistent with the fact that the tablet hardness was maintained and the increase in lactams over time was moderate even with the prototype tablet of Example 9 (Table 9) having the same formulation and sample name: MP8-1.

From this, the formation of lactams over time after tableting by post-adding 2 mg of croscarmellose sodium per tablet was achieved by adding 7 mg of reduced maltose starch syrup per tablet to the main drug granules. It turned out that it can be suppressed to some extent.

Similarly, in the prototype tablet of the sample name: MP10-8, the amount of croscarmellose sodium added was reduced to 1 mg per tablet, and the prototype tablet (specimen name: MP10-9) also had a relative humidity of 40 ° C. and 75%. The tablet hardness was maintained even after storage for 7 days, and the amount of increase in lactam over time was even smaller.
From this, it was found that the smaller the amount of croscarmellose sodium added, the smaller the production of lactams over time after tableting.

In the trial tablet (specimen name: MP10-1) in which 4 mg of sodium starch glycolate was post-added per tablet instead of 2 mg of croscarmellose sodium per tablet in the prototype tablet of MP10-8. By storing at 40 ° C. and 75% relative humidity for 7 days, no increase in lactam was observed over time, but the tablet hardness decreased to 15.0 N.
From this, it was found that sodium starch glycolate did not promote the formation of lactams over time after tableting, but at the same time, it was found that the tablet hardness decreased over time.

Specimen name: Even a trial tablet (specimen name: MP10-2) in which the amount of sodium starch glycolate of 4 mg per tablet of the prototype tablet of MP10-1 is reduced to 3 mg per tablet is stored at 40 ° C. and 75% relative humidity for 7 days. As a result, no increase in lactam was observed over time, but the tablet hardness decreased to 20.0 N.
From this, it was found that sodium starch glycolate does not promote the formation of lactams over time after tableting, and that the tablet hardness decreases over time depending on the amount of sodium starch glycolate added. rice field.

Specimen name: MP10-8 prototype tablet (specimen name: MP10-3), 1 Trial tablet with 4 mg corn starch post-added per tablet (specimen name: MP10-4), trial tablet with post-addition of 4 mg partially pregelatinized starch per tablet (specimen name: MP10-5), 4 mg α per tablet The trial tablets (specimen name: MP10-6) to which the starch-forming starch was post-added and the trial tablets (specimen name: MP10-7) to which 4 mg of L-HPC was post-added per tablet were all at 40 ° C. and 75% relative humidity. The tablet hardness was maintained at about 38 N or more even after storage for 7 days, and the amount of increase in lactam over time was small.
Therefore, it was found that these prescriptions can both maintain the tablet hardness during the expiration date and suppress the production of lactams over time after tableting.

In the above-mentioned sample tablet of sample name: MP10-8, the trial tablet (specimen name: MP10-10) to which 3 mg of sodium starch glycolate was added after each tablet was stored at 40 ° C. and 75% relative humidity for 7 days. The subsequent increase in lactams over time was negligible, but the tablet hardness decreased to 23.8N.
From this, it was found that sodium starch glycolate did not promote the formation of lactams over time after tableting, but at the same time, it was found that the tablet hardness decreased over time.

In the above-mentioned prototype tablet with the sample name MP10-8, instead of 2 mg of croscarmellose sodium per tablet, 7 mg of sodium starch glycolate per tablet and 60 mg of mannitol for direct impact were post-added per tablet. In (Sample name: MP10-11), the amount of increase in lactam compound over time after storage at 40 ° C. and 75% relative humidity for 7 days was small, but the tablet hardness decreased to 20.5 N.
From this, it was found that sodium starch glycolate did not promote the formation of lactams over time after tableting, but at the same time, it was found that the tablet hardness decreased over time.

Granulation containing 1.3 g of HPC per tablet, 20 mg of reduced maltose syrup per tablet, and 75 mg of pregabalin per tablet by adjusting the amount of additives in the prototype tablet of MP10-11. After granulating the product in a fluidized layer and drying it, add 3 mg of sodium starch glycolate per tablet, 20 mg of D-mannitol for direct impact per tablet, and 1 mg of calcium stearate per tablet, mix, and mix, 0.8 t. The trial tablet (specimen name: MP11-1) tableted with the tableting pressure of No. 1 had a small increase in lactam over time after being stored at 40 ° C. and 75% relative humidity for 7 days, but the tablet hardness was small. Decreased to 15.0N.
From this, it was found that sodium starch glycolate did not promote the formation of lactams over time after tableting, but at the same time, it was found that the tablet hardness decreased over time.

The prototype tablet (specimen name: MP11-2) in which the amount of D-mannitol for direct hitting in the prototype tablet of the sample name: MP11-1 was increased to 40 mg per tablet was stored at 40 ° C. and 75% relative humidity for 7 days. The amount of increase in lactams over time was further slightly increased, and the tablet hardness decreased to 13.5 N.
From this, it was found that sodium starch glycolate did not promote the formation of lactams over time after tableting, but at the same time, it was found that the tablet hardness decreased over time. It was also found that D-mannitol for direct striking did not promote the formation of lactams over time after tableting, but at the same time, it was found that the tablet hardness decreased over time depending on the amount added.

Based on the above experimental results, granulated products containing 4 mg of HPC per tablet, 7 mg of reduced maltose starch candy per tablet, and 75 mg of pregabalin per tablet were granulated in a fluid layer, dried, and then 1 mg per tablet. Post-additives to be added with calcium stearate include 4 mg hydroxypropyl starch per tablet (specimen name: MP10-3), 4 mg cornstarch per tablet (specimen name: MP10-4), and 4 mg partial α per tablet. 4 mg of pregelatinized starch (specimen name: MP10-6) per tablet (specimen name: MP10-5), 4 mg of L-HPC per tablet (specimen name: MP10-7) is 75% at 40 ° C. Even after storage at relative humidity for 7 days, the tablet hardness was maintained at about 38 N or higher, and the amount of increase in lactam over time was very small. Therefore, the tablet hardness was maintained and the tablet hardness was maintained over time. It was most suitable for both prevention of lactam formation.

In addition, granulated products containing 4 mg of HPC per tablet, 7 mg of reduced maltose starch syrup per tablet, and 75 mg of pregavalin per tablet were granulated in a fluid layer, dried, and then added together with 1 mg of calcium stearate per tablet. When 4 mg of sodium starch glycolate (specimen name: MP10-1) or 3 mg of sodium starch glycolate (specimen name: MP10-2) per tablet was used as the post-additive, 40. Even after storage at 75% relative humidity for 7 days, no increase in lactam was observed over time, which was the best in terms of preventing lactam formation over time, but the maintenance of tablet hardness was insufficient. Met.

When 4 mg of sodium starch glycolate (specimen name: MP10-1) or 3 mg of sodium starch glycolate (specimen name: MP10-2) per tablet was used, the amount of sodium starch glycolate added was increased. Although a tendency for tablet hardness to decrease proportionally was observed, the prototype tablet (specimen name: MP10-1) containing 4 mg of sodium starch glycolate per tablet was 4 mg of hydroxypropyl starch (specimen name) per tablet. MP10-3) 4 mg cornstarch per tablet (specimen name: MP10-4), 4 mg partially pregelatinized starch per tablet (specimen name: MP10-5), 4 mg pregelatinized starch per tablet (specimen name MP10) -6) Good disintegration was shown as compared with the case of using 4 mg of L-HPC per tablet. That is, when the disintegration time of water and 50 rotations was confirmed with an dissolution tester, the prototype tablet (specimen name: MP10-1) containing 4 mg of sodium starch glycolate per tablet disintegrated in about 12 to 13 minutes. On the other hand, the disintegration time of the prototype tablets of MP10-3 to MP10-6 was 15 minutes or more.

From these results, it was considered necessary to further study and optimize the amount of sodium starch glycolate added in the formulation of sample name: MP10-1 or sample name: MP10-2.

Based on the results of Examples 9 and 10, the sample name of Example 9: the prototype tablet of MP2-A (specimen name: MP2 main drug granule, powder for MP2 tableting, MP2 tablet, MP2 tablet crushed product), and Specimen name of Example 10: Trial tablet in which the amount of sodium starch glycolate in the trial tablet of MP10-2 was reduced to 2 mg per tablet (specimen name: MP8-1-4 main ingredient granules, MP8-1-4 for tableting For each of the powder, MP8-1-4 tablet, MP8-1-4 tablet crushed product), the main drug granule, the tableting powder, the tablet, and the tablet crushed in a dairy pot, 40 ° C. 75% relative humidity. The amount of lactam in the state before and after storage for 7 days was examined. For the prototype tablet with the sample name: MP2 and the prototype tablet with the sample name: MP8-1--4, the tablet hardness was measured before and after storage at 40 ° C. and 75% relative humidity for 7 days.

The additives used were hydroxypropyl cellulose [HPC-L (trademark) normal particle type, Nippon Soda Co., Ltd.], reduced maltose water candy [Amarti MR100 (trademark), Mitsubishi Corporation Foodtech Co., Ltd.], sodium starch glycolate [Primo]. Gel (trademark), Matsutani Chemical Industry], croscarmellose sodium [Ac-Di-Sol (trademark), Wilbur Ellis Co., Ltd.], calcium stearate [Taipei Chemical Industry Co., Ltd.].

Prototype tablets were prepared using 8000 tablets of the active ingredient and additives according to Table 11. Specifically, for the sample with the sample name: MP8-1-4, 600 g of the pregavalin drug substance and 56 g of the powder of reduced maltose starch syrup were weighed and put into the fluidized layer (FD-MP-01 type, Paulec) in advance. 800 g of a 4 mass% HPC aqueous solution prepared for granulation was granulated at a speed of 12 g / min at an intake temperature of 80 ° C. and an exhaust temperature of 30 ° C. for about 67 minutes while spraying. Specimen name: For the MP2 sample, 600 g of the pregavalin drug substance was weighed and put into a fluidized layer (FD-MP-01 type, Paulec), and 800 g of a 4 mass% HPC aqueous solution prepared in advance for granulation was added. Granulation was carried out at a speed of 12 grams per minute at an intake temperature of 80 ° C. and an exhaust temperature of 30 ° C. while spraying for about 67 minutes.
The obtained granulated product was dried as it was at 80 ° C. using a fluidized bed, and the obtained granulated product was measured for water content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). It was dried to 1%. Then, it was sieved with a filter of mesh 30. Add the post-additives shown in Table 11 to the granulated product after drying and sieving in an amount of 8000 times the amount per tablet, mix, and beat using a single-shot tableting machine (AUTOTAB-500, Ichihashi Seiki). The tablet was tableted at a tablet pressure of 0.8 t. The mass per tablet obtained as a result was as shown in Table 11.

First, for a sample whose sample name starts with MP2, a granulated product containing 4 mg of HPC per tablet and 75 mg of pregavalin per tablet is granulated in a fluid layer and dried to produce "main drug granules". To this, 2 mg of croscarmellose sodium per tablet and 1 mg of calcium stearate per tablet were added and mixed to produce a "tablet powder", which was tableted with a tableting pressure of 0.8 tons. A prototype tablet was produced, and the tablet was crushed using a dairy pot to produce a "crushed tablet product".

For samples whose sample name starts with MP8-1-4, granules containing 4 mg of HPC per tablet, 7 mg of reduced starch sugar candy per tablet and 75 mg of pregavalin per tablet are granulated in a fluid layer and dried. Then, "main drug granules" are produced, and 2 mg of sodium starch glycolate per tablet and 1 mg of calcium stearate per tablet are added and mixed to produce "tablet powder". A prototype tablet was produced by tableting with a tableting pressure of 0.8 ton, and further pulverized using a dairy pot to produce a "crushed tablet product".

Changes in hardness and increase in lactam form over time of the prototype compressed solid formulation:
The compressed solid preparation of the prototype compressed solid preparation was stored at 40 ° C. and 75% relative humidity, and the tablet hardness and the amount of lactam were measured at the start of storage and after 7 days. The measurement results are as shown in Table 11.

The amount of lactam in the "main agent granules" (specimen name: MP2 main agent granules) obtained by granulating a granule containing 4 mg of HPC per tablet and 75 mg of pregabalin per tablet in a fluidized bed and drying it is There was almost no change before and after storage at 40 ° C. and 75% relative humidity for 7 days.

"Powder for tableting" (specimen name:: powder for tableting) obtained by adding 2 mg of croscarmellose sodium per tablet and 1 mg of calcium stearate per tablet to the "main drug granules" (specimen name: MP2 main drug granules) and mixing them. The amount of lactams (MP2 tableting powder) did not change much before and after storage at 40 ° C. and 75% relative humidity for 7 days.

However, the "tablet" (specimen name: MP2 tablet) obtained by tableting the "tablet powder" (specimen name: MP2 tableting powder) with a tableting pressure of 0.8 t is 75% at 40 ° C. Storage at relative humidity for 7 days significantly increased the amount of lactams over time. The "tablet" (specimen name: MP2 tablet) had almost no change in tablet hardness before and after storage at 40 ° C. and 75% relative humidity for 7 days, and maintained a tablet hardness of 38 N after storage for 7 days. ..

From this, it was found that the addition of croscarmellose alone did not cause the formation of lactams over time, but when the tablets were tableted, the formation of lactams over time occurred. Further, it was found that the tablet containing croscarmellose and having the sample name: MP2 was excellent in maintaining the tablet hardness.

The "tablet crushed product" (specimen name: MP2 tablet crushed product) obtained by crushing the "tablet" (specimen name: MP2 tablet) in a mortar is also aged by storing at 40 ° C. and 75% relative humidity for 7 days. The amount of lactam was significantly increased.
From this, the formation of lactams over time after tableting is not simply due to the consolidation state, but the impact of tableting promotes the formation of lactams over time, impairing storage stability, and once locking. After that, it was found that the production of lactams over time remained promoted even after crushing and releasing the consolidation state.

On the other hand, "main drug granules" obtained by fluidizing a granule containing 4 mg of HPC per tablet, 7 mg of reduced maltose starch syrup per tablet and 75 mg of pregabalin per tablet, and drying the granules (specimen name:: The amount of lactams (MP8-1--4 main drug granules) did not change much before and after storage at 40 ° C. and 75% relative humidity for 7 days.

"Powder for tableting" obtained by adding 2 mg of sodium starch glycolate and 1 mg of calcium stearate per tablet to the "main drug granules" (specimen name: MP8-1--4 main drug granules) and mixing them. The amount of lactam (specimen name MP8-1-4 powder for tableting) also hardly changed before and after storage at 40 ° C. and 75% relative humidity for 7 days.

A "tablet" (specimen name: MP8-1-4 tablet) obtained by tableting the "tablet powder" (specimen name: MP8-1-4 tableting powder) with a tableting pressure of 0.8 ton. The amount of lactams in the tablet was also almost unchanged before and after storage at 40 ° C. and 75% relative humidity for 7 days. The tablet hardness of the "tablet" (specimen name: MP8-1-4 tablet) decreased from 57.3N to 36.3N by storing at 40 ° C. and 75% relative humidity for 7 days, but the tablet hardness was still sufficient. Had.

Therefore, the prototype tablet of sample name: MP8-1-4, in which the main ingredient granules were granulated using HPC and reduced maltose starch syrup and the amount of sodium starch glycolate per tablet in the post-additive was suppressed to 2 mg, It was found that the formulation can achieve both maintenance of tablet hardness during the expiration date and suppression of lactam formation over time after tableting.

The amount of lactam in the "tablet crushed product" (specimen name: MP8-1--4 tablet crushed product) obtained by crushing the "tablet" (specimen name: MP8-1-4 tablet) in a mortar was also 40 ° C. There was almost no change before and after storage at 75% relative humidity for 7 days.
From this, it was found that if the formulation does not produce lactams over time after tableting, even if it is crushed, lactams will not be produced over time after tableting. ..

Based on the above experimental results, granules containing 4 mg of HPC per tablet, 7 mg of reduced maltose starch syrup per tablet, and 75 mg of pregabalin per tablet were granulated in a fluid layer and dried to produce "main drug granules". Then, 2 mg of sodium starch glycolate per tablet and 1 mg of calcium stearate per tablet were added and mixed to produce a "tablet powder", which was tableted at a tableting pressure of 0.8 tons. The trial tablet (specimen name: MP8-1--4) obtained in this manner showed no increase in lactams over time, and even after being stored at 40 ° C. and 75% relative humidity for 7 days, it was 36.3 N. It was found that sufficient tablet hardness can be maintained.

On the other hand, granules containing 4 mg of HPC per tablet and 75 mg of pregavalin per tablet are granulated in a fluidized bed and dried to produce "base drug granules", to which 2 mg of croscarmellose per tablet is produced. A prototype tablet (specimen name: MP2) obtained by adding and mixing sodium and 1 mg of calcium stearate per tablet to produce a "tablet powder" and tableting this with a tableting pressure of 0.8 ton. Tablets) had sufficient tablet hardness after being stored at 40 ° C. and 75% relative humidity for 7 days, but a marked increase in lactams was observed over time.

This is because the prototype tablet with the sample name "MP2 tablet" contains croscarmellose sodium, which is a cellulosic compound that causes an increase in lactams over time, and is modified with a carboxymethyl group or a hydroxypropoxyl group. It was considered that the increase of lactam compounds over time could not be suppressed because it contained neither starch nor sugar alcohol.

In addition, even in the case where the prototype tablet with the sample name "MP2 tablet" was crushed and the consolidation state was released, a remarkable increase in lactams over time was observed as in the case where the sample was not crushed. It is surprising that the increase in lactams over time in tablets is not brought about by the "consolidation" during storage, but the impact of tableting initiates the increase in lactams. It was a result.

Prototype of compressed solid preparation ;
Established a formulation of a pregabalin preparation that can maintain hardness when stored at 40 ° C. and 75% relative humidity, does not generate lactams over time after tableting, and has good dissolution properties. In order to do so, the hardness of various prototype tablets and the amount of lactam were examined under the conditions of opening the chalet and sealing the aluminum.

The additives used were hydroxypropyl cellulose [HPC-L (trademark) normal particle type, Nippon Soda Co., Ltd.], reduced maltose water candy [Amarti MR100 (trademark), Mitsubishi Corporation Foodtech Co., Ltd.], sodium starch glycolate [Primo]. Gel (trademark), Matsutani Chemical Industry], croscarmellose sodium [Ac-Di-Sol (trademark), Wilbur Ellis Co., Ltd.], calcium stearate [Taipei Chemical Industry Co., Ltd.].

Prototype tablets were prepared using 8000 tablets of the active ingredient and additives according to Table 12. Specifically, 600 g of the pregavalin drug substance and 56 g of the powder of reduced maltose starch syrup were weighed and put into a fluidized layer (FD-MP-01 type, Paulec), and 4% by mass prepared in advance for granulation. The HPC aqueous solution was granulated while spraying at a speed of 12 grams per minute at an intake temperature of 80 ° C. and an exhaust temperature of 30 ° C. The spray amount and spray time of the HPC aqueous solution are such that when 4 mg of HPC is added per tablet, 800 g of 4 mass% HPC aqueous solution is sprayed for about 67 minutes to granulate, and when 8 mg of HPC is added per tablet. Granulates while spraying 1600 g of 4 mass% HPC aqueous solution for about 133 minutes, and when adding 1.5 mg of HPC per tablet, granulates while spraying 300 g of 4 mass% HPC aqueous solution for about 25 minutes. bottom. The obtained granulated product was dried as it was at 80 ° C. using a fluidized bed, and the obtained granulated product was measured for water content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). It was dried to 1%. Then, it was sieved with a filter of mesh 30. Add the post-additives shown in Table 12 to the granulated product after drying and sieving in an amount of 8000 times the amount per tablet, mix, and beat using a single-shot tableting machine (AUTOTAB-500, Ichihashi Seiki). The tablet was tableted at a tablet pressure of 0.8 t. The mass per tablet obtained as a result was as shown in Table 12.

First, in the prototype tablet of sample name: MP8-1--3, a mixture containing 4 mg of HPC per tablet, 7 mg of reduced maltose starch syrup per tablet, and 75 mg of pregavalin per tablet was granulated in a fluidized bed and dried. After that, 1 mg of sodium starch glycolate and 1 mg of calcium stearate per tablet were added and mixed, and the tablets were tableted with a tableting pressure of 0.8 t.

The prototype tablet of sample name: MP8-1--4 was produced in the same manner as the prototype tablet of sample name: MPMP8-1-3, except that the amount of sodium starch glycolate was increased to 2 mg per tablet.

The prototype tablet with the sample name: MP8-1-5 was produced in the same manner as the prototype tablet with the sample name: MPMP8-1-3, except that the amount of sodium starch glycolate was increased to 4 mg per tablet.

Specimen name: In the prototype tablet of MP8-3-3, sample name: MPMP8-1 except that the amount of sodium starch glycolate was increased to 4 mg per tablet and the amount of HPC was increased to 8 mg per tablet. It was manufactured in the same manner as the prototype tablet of -3.

Specimen name: In the prototype tablet of N3-9, a mixture containing 1.5 mg of HPC per tablet, 7 mg of reduced maltose starch syrup per tablet, and 75 mg of pregabalin per tablet was granulated in a fluidized bed and dried. 1 mg of sodium starch glycolate and 1 mg of calcium stearate per tablet were added and mixed, and the tablets were tableted at a tableting pressure of 0.8 t.

In the prototype tablet of sample name: N3-4, sample name N3- except that 2 mg of sodium starch glycolate per tablet in the prototype tablet of sample name: N3-9 was changed to 2 mg of croscarmellose sodium per tablet. It was produced in the same manner as the prototype tablet of 9.

Dissolution of the prototype compressed solid preparation, change in hardness over time, and increase in lactam form:
Specimen name: MP8-1-3, Specimen name: MP8-1--4, Specimen name: MP8-1-5, and Specimen name: MP8-3-3 are each prototype tablets at 40 ° C. and 75% relative humidity. , The tablet was stored under open conditions and sealed in an aluminum bag, and the tablet hardness and the amount of lactam were measured at the start of storage, after 7 days and after 14 days.

Specimen name: N3-9 prototype tablet and sample name: N3-4 prototype tablet are stored at 40 ° C. and 75% relative humidity only under the conditions of opening the chalet, and the tablet hardness at the start of storage and after storage for 7 days, and The amount of lactam was measured at the start of storage, 7 days and 14 days later.
The measurement results are as shown in Table 12.

A mixture containing 4 mg of HPC per tablet, 7 mg of reduced maltose water candy per tablet and 75 mg of pregabalin per tablet was granulated in a fluidized bed, dried, and then 1 mg of sodium starch glycolate per tablet and per tablet. The prototype tablet (specimen name: MP8-1-3), which was mixed by adding 1 mg of calcium stearate and tableted at a tableting pressure of 0.8 t, was stored in a chalet open condition at 40 ° C. and 75% relative humidity for 14 days. Even after this, there was almost no increase in the lactam form over time, and the tablet hardness after storage for 7 days also maintained a good tablet hardness of 41.3 N, but the dissolution rate after 15 minutes in water. Was only 65.5%, and the dissolution property was insufficient.

Specimen name: The trial tablet (specimen name: MP8-1--4) in which 1 mg of sodium starch glycolate added afterwards in the trial tablet of MP8-1-3 was increased to 2 mg per tablet was 75% at 40 ° C. Even after 14 days of storage in relative humidity under open conditions, there was almost no increase in lactams over time, and the tablet hardness after storage for 7 days also maintained a good tablet hardness of 36.3 N. However, the dissolution rate in water after 15 minutes was only 80.5%, and the dissolution property was insufficient.

Specimen name: The trial tablet (specimen name: MP8-1-5) in which 1 mg of sodium starch glycolate added after the trial tablet of MP8-1-3 was increased to 4 mg per tablet was 75% at 40 ° C. Even after 14 days of storage in relative humidity under open petri dishes, there was almost no increase in lactams over time, and the elution rate in water after 15 minutes reached 99.0%, which was extremely good. The tablet hardness after storage in a petri dish open condition at 40 ° C. and 75% relative humidity for 7 days was lowered to 23.3N, and there was a possibility that the tablet hardness could not be maintained at 20N or more. Therefore, when the tablet hardness after storage in a petri dish open condition at 40 ° C. and 75% relative humidity for 14 days was followed, the tablet hardness was still maintained at 23.0 N, so that the tablet hardness was further reduced. I was able to confirm that it did not progress.
From this, the prototype tablet having the sample name: MP8-1-3 can maintain its hardness when stored at 40 ° C. and 75% relative humidity, and the lactam body is produced over time after tableting. It was found that it was a formulation of a pregabalin preparation that did not occur and had good dissolution properties.

Specimen name: In the prototype tablet of MP8-1--3, the amount of 1 mg of sodium starch glycolate added afterwards was increased to 4 mg per tablet, and the amount of HPC in the granulated product was increased from 4 mg to 1 tablet per tablet. The trial tablet (specimen name: MP8-3-3) whose dose was increased to 8 mg per tablet showed a slight increase in lactam over time after being stored in a chalet open condition at 40 ° C. and 75% relative humidity for 14 days. The tablet hardness after storage for 7 days also maintained 29.0 N, but the dissolution rate in water after 15 minutes was only 54.5%, and the dissolution property was insufficient.

On the other hand, the prototype tablets of the above sample names: MP8-1-3, MP8-1--4, MP8-1-5, and MP8-3-3 are sealed in an aluminum bag and placed in an environment of 40 ° C. and 75% relative humidity. When stored in, the amount of lactam after 14 days was significantly increased in all of these prototype tablets.
For this reason, it is not desirable to store tablets containing the γ-aminobutyric acid derivative in a sealed manner because it promotes the formation of lactams over time after tableting. Therefore, packaging in an airtight package rather than a sealed package. It was found that the form was desirable.

A mixture containing 1.5 mg of HPC per tablet, 7 mg of reduced maltose starch syrup per tablet, and 75 mg of pregabalin per tablet was fluidized, dried, and then 2 mg of sodium starch glycolate and 1 tablet. The prototype tablet (specimen name: N3-9), which was mixed by adding 1 mg of calcium stearate per tablet and tableted at a tableting pressure of 0.8 ton, was stored in a chalet open condition at 40 ° C. and 75% relative humidity for 14 days. Although there was almost no increase in the lactam form over time, the tablet hardness was only 20.5 N at the start of storage and decreased to 10.5 N after 7 days. The hardness was insufficient.
From this, it was found that in order to maintain the tablet hardness, the amount of HPC in the main drug granules was not sufficient at 1.5 mg per tablet, and HPC of 4 mg or more per tablet was required.

Specimen name: The prototype tablet (specimen name: N3-4) in which the post-additive of 2 mg of sodium starch glycolate was changed to 2 mg of croscarmellose sodium per tablet in the prototype tablet of N3-9 was also 40. The increase in lactams over time after storage in 75% relative humidity for 14 days under the open conditions of chalet was small, but the tablet hardness was only 21.5 N at the start of storage, and after 7 days had passed. Was lowered to 10.0 N, and the tablet hardness was insufficient.
From this, it was found that, in order to maintain the tablet hardness, the amount of HPC in the main drug granules was not sufficient at 1.5 mg per tablet, and HPC of 4 mg or more per tablet was required.

Based on the above experimental results, granulated products containing 4 mg of HPC per tablet, 7 mg of reduced maltose starch syrup per tablet, and 75 mg of pregabalin per tablet were granulated in a fluidized bed, dried, and then 4 mg per tablet. A prototype tablet (specimen name: MP8-1-5) obtained by adding and mixing sodium starch glycolate and 1 mg of calcium stearate per tablet and tableting at a tableting pressure of 0.8 ton has extremely good dissolution property. It was confirmed that even after the tablet was stored in a chalet open condition at 40 ° C. and 75% relative humidity for 14 days, almost no increase in the lactam body was observed over time, and good tablet hardness could be maintained.

However, it was found that if this is in a packaging form that is sealed using an aluminum bag or the like, a significant increase in lactams will occur over time, and therefore a sealed packaging should not be used. Usually, the preferred packaging form for maintaining the stability of the pharmaceutical preparation is (1) sealed packaging, (2) airtight packaging, and (3) sealed packaging, and since sealed packaging is the most preferable, sealed packaging is used. It was surprising that the stability of pregabalin in the pregabalin preparation was impaired.

Prototype of compressed solid preparation ;
Further various prototype tablets were prepared in order to establish a formulation of a pregabalin preparation that can maintain tablet hardness, have good dissolution property, and is stable in storage when stored at 40 ° C. and 75% relative humidity. And examined.

The additives used were hydroxypropyl cellulose [HPC-L (trademark) normal particle type, Nippon Soda Co., Ltd.], reduced malt sugar water candy [Amarti MR100 (trademark), Mitsubishi Corporation Foodtech Co., Ltd.], sodium starch glycolate [Primo]. Gel (trademark), Matsutani Chemical Industry], calcium stearate [Taipei Chemical Industry Co., Ltd.], titanium oxide [Freund Sangyo Co., Ltd.], and talc [Saneigen FFI Co., Ltd.].

Prototype tablets were prepared using 8000 tablets of the active ingredient and additives according to Table 13. Specifically, for each trial tablet of sample name: MP10S, MP10-1, MP10-2, MP10-3, MP10-4, 600 g of pregavalin drug substance and 56 g of powder of reduced maltose starch syrup are weighed and flown layer ( FD-MP-01 type, Paulec), 800 g of 4 mass% HPC aqueous solution prepared for granulation in advance at a speed of 12 g / min, intake temperature 80 ° C., exhaust temperature 30 ° C. Granulation was performed while spraying for about 67 minutes. Specimen name: For each trial tablet of MP11S, MP11-1, MP11-2, MP11-4, weigh 600 g of pregavalin drug substance and 480 g of powder of reduced maltose starch syrup and weigh a fluid layer (FD-MP-01 type, Paulec). Granulation while spraying 1400 g of a 4 mass% HPC aqueous solution prepared for granulation in advance at a speed of 12 g / min at an intake temperature of 80 ° C. and an exhaust temperature of 30 ° C. for about 117 minutes. bottom. The obtained granulated product was dried as it was at 80 ° C. using a fluidized bed, and the obtained granulated product was measured for water content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). It was dried to 1%. Then, it was sieved with a filter of mesh 30. Add the post-additives shown in Table 13 to the granulated product after drying and sieving in an amount of 8000 times the amount per tablet, mix, and beat using a single-shot tableting machine (AUTOTAB-500, Ichihashi Seiki). The tablet was tableted at a tablet pressure of 0.8 t. The masses of the uncoated tablets and film-coated tablets obtained as a result per tablet were as shown in Table 13.

The manufacturing method of each prototype tablet was as follows.
First, in the sample tablet (uncoated tablet) of sample name: MP10S, a mixture containing 4 mg of HPC per tablet, 7 mg of reduced maltose starch syrup per tablet, and 75 mg of pregavalin per tablet was granulated in a fluidized bed and dried. After that, 4 mg of sodium starch glycolate and 1 mg of calcium stearate per tablet were added and mixed, and the tablets were tableted with a tableting pressure of 0.8 t.

In the prototype tablet of sample name: MP10-1, the prototype tablet (bare tablet) of sample name: MP10S was coated with 0.9 mg of HPC per tablet and 0.1 mg of reduced maltose starch syrup per tablet.

In the prototype tablet of sample name: MP10-2, the prototype tablet (bare tablet) of sample name: MP10S was coated with 1.8 mg of HPC per tablet and 0.2 mg of reduced maltose starch syrup per tablet.

In the prototype tablet of sample name: MP10-3, in addition to the prototype tablet (FC tablet) of sample name: MP10-2, 0.8 mg of HPC per tablet and 0.1 mg of titanium oxide per tablet were added. A second layer coating with 0.1 mg talc per tablet was applied.

In the prototype tablet of sample name: MP10-4, in addition to the prototype tablet (FC tablet) of sample name: MP10-2, 1.6 mg of HPC per tablet and 0.2 mg of titanium oxide per tablet were added. A second layer coating with 0.2 mg talc per tablet was applied.

Next, in the prototype tablet (uncoated tablet) of sample name: MP11S, a mixture containing 7 mg of HPC per tablet, 60 mg of reduced maltose starch syrup per tablet, and 75 mg of pregavalin per tablet was granulated in a fluidized bed. After drying, 7 mg of sodium starch glycolate and 2 mg of calcium stearate per tablet were added and mixed, and tablets were tableted at a tableting pressure of 0.55 t.

In the prototype tablet of sample name: MP11-1, the prototype tablet (bare tablet) of sample name: MP11S was coated with 0.9 mg of HPC per tablet and 0.1 mg of reduced maltose starch syrup per tablet.

In the prototype tablet of sample name: MP11-2, the prototype tablet (bare tablet) of sample name: MP11S was coated with 1.8 mg of HPC per tablet and 0.2 mg of reduced maltose starch syrup per tablet.

In the prototype tablet of sample name: MP11-4, in addition to the prototype tablet (FC tablet) of sample name: MP11-2, 1.6 mg of HPC per tablet and 0.2 mg of titanium oxide per tablet were added. A second layer coating with 0.2 mg talc per tablet was applied.

Dissolution of the prototype compressed solid preparation, change in hardness over time, and increase in lactam form:
A mixture containing 4 mg of HPC per tablet, 7 mg of reduced maltose starch syrup per tablet and 75 mg of pregabalin per tablet was granulated in a fluidized bed, dried, and then 4 mg of sodium starch glycolate per tablet and per tablet. Trial tablets (specimen names: MP10S, MP10-1, MP10-2) having uncoated tablets (specimen name: MP10S trial tablet) that were mixed by adding 1 mg of calcium stearate and tableted at a tableting pressure of 0.8 ton. , MP10-3, MP10-4) were all stored in a chalet open condition at 40 ° C. and 75% relative humidity for 7 days, and the increase in lactams over time was negligible.

Among these, the prototype tablets having sample names: MP10S, MP10-2, and MP10-4 were 95% eluted with water after 15 minutes at the start of storage, and showed extremely good dissolution (the elution property was extremely good). Specimen name: The elution of MP10-1 and MP10-3 has not been confirmed.)

Similarly, the prototype tablets of sample names: MP10S, MP10-2, and MP10-4 were stored at 40 ° C. and 75% relative humidity for 7 days under the open condition of the chalet, respectively, in order of 20.0N, 23.0N, respectively. It had a tablet hardness of 23.0 N, which was an acceptable tablet hardness (specimen names: MP10-1 and MP10-3 have unconfirmed tablet hardness).

From these facts, the prototype tablet having the sample name: MP10S and the prototype tablet having a film coating applied thereto (specimen names: MP10-1, MP10-2, MP10-3, MP10-4) have a relative humidity of 40 ° C. and 75%. It was found that the pregabalin preparation which can maintain the tablet hardness, has good dissolution property, and is stable in storage when stored in.

A mixture containing 7 mg HPC per tablet, 60 mg reduced maltose starch syrup per tablet and 75 mg pregabalin per tablet was fluidized bed granulated, dried, and then 7 mg sodium starch glycolate per tablet and per tablet. Trial tablets (specimen names: MP11S, MP11-1, MP11-2) having uncoated tablets (specimen name: MP11S trial tablet) that were mixed by adding 2 mg of calcium stearate and tableted at a tableting pressure of 0.55 ton. , MP11-4) all had a small increase in lactams over time after being stored in a chalet open condition at 40 ° C. and 75% relative humidity for 7 days, but the above-mentioned sample names: MP10S, MP10- 1, MP10-2, MP10-3, MP10-4 were clearly more than the prototype tablets.

Among these, the prototype tablets having sample names: MP11S, MP11-2, and MP11-4 had elution ratios of 77.0% and 73.0 in order after 15 minutes with respect to water at the start of storage, respectively. The elution rate was 79.0%, which was less than 85%.

The tablet hardnesses of the prototype tablets of these sample names: MP11S, MP11-2, and MP11-4 after being stored in a relative humidity of 40 ° C. and 75% for 7 days under the conditions of opening the chalet were 30.0 N and 23. It had a tablet hardness of 0N and 23.0N, both of which were acceptable tablet hardness.

From the above experimental results, the compounding ratio of the prototype tablets containing a large amount of reduced maltose starch syrup in the main drug granules: MP11S, MP11-1, MP11-2, MP11-4 is the lactam compound over time after tableting. Although the production of starch syrup was limited to a small amount and sufficient tablet hardness could be maintained, it was found to be unfavorable in terms of elution.

Further, the tablet hardness can be maintained when the amount of HPC added is about 4.4% (4 mg per tablet) in the mass of one tablet, and the amount of sodium starch glycolate added is 4 in the mass of one tablet. It was found that good dissolution was obtained when the content was about 4% (4 mg per tablet) (specimen names: MP10-1, MP10-2, MP10-3, MP10-4). In addition, in order to suppress the production of lactams over time after tableting, it is sufficient to contain about 7.7% (7 mg per tablet) of reduced maltose starch syrup in the mass of one tablet (specimen name). : It was found that the dissolution property deteriorates when MP10-1, MP10-2, MP10-3, MP10-4) and about 40% (60 mg per tablet) of reduced maltose starch syrup are contained in the mass of one tablet. (Sample names: MP11S, MP11-1, MP11-2, MP11-4).

In this way, the comparison between the prototype tablets of the sample names: MP10S, MP10-1, MP10-2, MP10-3, and MP10-4 and the prototype tablets of the sample names: MP11S, MP11-1, MP11-2, and MP11-4. Therefore, even if the amount of reduced maltose starch syrup is increased, the increase in lactams over time after tableting is not suppressed, the decrease in tablet hardness over time is not suppressed, and the elution property is rather lowered. I found out that I would do it.

On the other hand, if the amount of reduced maltose starch syrup in the main drug granules is small, and the compounding ratio of the trial tablets of MP10S, MP10-1, MP10-2, MP10-3, and MP10-4, the increase in lactam over time is extremely small. It was found that it had extremely good dissolution property and had sufficient tablet hardness even after storage under accelerated conditions. It was found that the tablet hardness was improved by film coating.

Prototype of compressed solid preparation ;
From the results of Examples 1 to 13, the prototype tablet of the sample name: MP10S of Example 13 was determined as a prescription of a tablet containing 75 mg of pregabalin per tablet (hereinafter referred to as "75 mg tablet"), and the prototype tablet was determined. A tablet obtained by doubling the amount of each additive in the above is determined as a provisional final prescription (manufacturing prescription) of a tablet containing 150 mg (hereinafter referred to as "150 mg tablet") of pregabalin per tablet, and an accelerated test is carried out. bottom. The same additives used in Example 13 were used in the following production formulations.

As an actual production formula for 75 mg tablets, 2 batches were produced on a scale of 50,000 tablets. Specifically, 3750 g of pregavalin drug substance and 350 g of powder of reduced maltose starch syrup were weighed and put into a fluidized layer (FLO-5, Freund industry), and 5000 g of a 4 mass% HPC aqueous solution prepared in advance for granulation. Was granulated at a speed of 50 grams per minute at an intake temperature of 80 ° C. and an exhaust temperature of 30 ° C. while spraying for 100 minutes. The obtained granulated product was dried as it was at 80 ° C. using a fluidized bed, and the obtained granulated product was measured for water content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). It was dried to 1%. Then, it was sieved with a filter of mesh 30. This was repeated twice, and 400 g of sodium starch glycolate and 100 g of calcium stearate were added to the granulated product after drying and sieving for 2 batches, mixed, and used with a tableting machine (HT-P18A, Hata Iron Works). The tablet was tableted with a mass of 91 mg per tablet and a tableting pressure of 0.8 t.

As an actual production prescription for 150 mg tablets, 2 batches were produced on a scale of 25,000 tablets. Specifically, 3750 g of pregavalin drug substance and 350 g of powder of reduced maltose starch syrup were weighed and put into a fluidized layer (FLO-5, Freund industry), and 5000 g of a 4 mass% HPC aqueous solution prepared in advance for granulation. Was granulated at a speed of 50 grams per minute at an intake temperature of 80 ° C. and an exhaust temperature of 30 ° C. while spraying for 100 minutes. The obtained granulated product was dried as it was at 80 ° C. using a fluidized bed, and the obtained granulated product was measured for water content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). It was dried to 1%. Then, it was sieved with a filter of mesh 30. This was repeated twice, and 400 g of sodium starch glycolate and 100 g of calcium stearate were added to the granulated product after drying and sieving for 2 batches, mixed, and used with a tableting machine (HT-P18A, Hata Iron Works). The tablet was tableted with a mass of 182 mg per tablet and a tableting pressure of 0.8 t.

On the other hand, as a prescription of a tablet containing 25 mg of pregabalin per tablet (hereinafter referred to as "25 mg tablet"), the amount of each additive of the sample name: MP10S prototype tablet of Example 13 is simply 3 of 75 mg tablet. If it is reduced to 1/1, the mass per tablet will be only 30.3 mg, and the tablet will be too small. Therefore, for the main ingredient granules of 25 mg tablets, the content of pregabalin, HPC and reduced maltose water candy to be added Simply make it one-third the amount of 75 mg tablets (pregabalin 25 mg, HPC 1.3 mg, reduced maltose water candy 2.3 mg per tablet), while the post-additives of 25 mg tablets are simply one-third. For sodium starch glycolate, the amount is 3 mg per tablet, which is more than 1.3 mg per tablet, which is one-third, and for calcium stearate, one tablet is one-third. 0.7 mg per tablet, which is more than 0.3 mg per tablet, and tablets produced by adding 37.7 mg of D-mannitol for direct impact as a post-additive per tablet are determined as the provisional final formulation of 25 mg tablets. Then, an acceleration test was carried out.

As an actual production formula for 25 mg tablets, it is produced on a scale of 100,000 tablets, 2500 g of pregavalin drug substance and 230 g of powder of reduced maltose starch syrup are weighed and put into a fluidized layer (FLO-5, Freund industry), and granulated in advance. 3250 g of the 4 mass% HPC aqueous solution prepared for use was granulated at a speed of 50 g / min at an intake temperature of 80 ° C. and an exhaust temperature of 30 ° C. for about 65 minutes while spraying. The obtained granulated product was dried as it was at 80 ° C. using a fluidized bed, and the obtained granulated product was measured for water content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). It was dried to 1%. Then, it was sieved with a filter of mesh 30. 3770 g of D-mannitol for direct striking, 300 g of sodium starch glycolate, and 70 g of calcium stearate are added to the granulated product after drying and sieving, mixed, and used with a tableting machine (HT-P18A, Hata Iron Works). Each tablet was tableted with a mass of 70 mg and a tableting pressure of 0.8 t.

Regarding the provisional final prescriptions of the above 25 mg tablets, 75 mg tablets, and 150 mg tablets, these were manufactured on an actual production scale and detailed confirmation was performed.

Specifically, (1) presence or absence of defects in the granulation / drying process, (2) particle size distribution of dried granules, (3) mixing uniformity after addition, and (4) mixture after addition of calcium stearate (beating). Bulk density and rest angle of (tablet powder), (5) presence / absence of tableting disorder, (6) variation in mass of each tablet, (7) dissolution in water, (8) dissolution in pH 1.2 elution test solution Sex, (9) Elution to pH 4.0 elution test solution, (10) Elution to pH 6.8 elution test solution, (11) Changes in tablet hardness over time, (12) Lactam mass over time We confirmed the changes and (13) bitterness.

The specific manufacturing process of the 75 mg tablet was as follows. Regarding the production of the 25 mg tablet and the 150 mg tablet, the production process was the same except that the amount of the additive was different.

(1) Production of main drug granules 3750 g of Pregavalin drug substance powder and 350 g of reduced maltose starch syrup (Amarti MR100) were mixed using a fluidized bed granulator (FLO-5, Freund Sangyo), and 200 g of HPC was added to 4800 g. Granulation was performed while spraying a solution dissolved in water. After granulation, it is dried with a fluidized bed granulator, about 10 g is sampled, and the dry weight loss is measured using a dry weight loss measuring device (MOC-120H, manufactured by Shimadzu Corporation), and the dry weight loss is 1% or less. I confirmed that. This was repeated twice.

Subsequently, using an ND-30S granulator, sizing using a screen with a diameter of 0.5 mm, using this as the main ingredient granules, sampling about 10 g and measuring the particle size distribution of the main ingredient granules after sizing, Microtrack MT3000 Measurement was performed under dry conditions using (Microtrack Bell Co., Ltd.).

(2) Addition and mixing of post-additives (end for tableting)
The entire amount of the main drug granules produced in the above step (1) is taken out from the fluidized bed granulator, 400 g of sodium starch glycolate is added, and the mixture is mixed for 10 minutes using a V-20 mixing device (Tokuju Kosakusho). , The post-addition mixture A. As a result of confirming the mixing uniformity by sampling about 10 g from 5 places, the average value of the mixing uniformity was within 97.5% to 102.5%, and the content of each tablet was also in the range of 95% to 105%. It was confirmed that it was inside.

Further, 100 g of calcium stearate was added to the above-mentioned post-addition mixture A and mixed using a V-20 mixing device (Tokuju Kosakusho) to prepare a powder for tableting. About 60 g of the powder for tableting was sampled to measure the loose bulk density and the tap bulk density. In addition, about 500 g was sampled from the powder for tableting and the angle of repose was measured with an angle of repose measuring device.

(3) Locking A pestle was set in a locking machine (HT-P18A, Hata Iron Works) and locked at a locking pressure of 0.8 to 0.9 t. The pestle used was a circular pestle with a diameter of 6.0 mm and no score line on both sides, a 75 mg tablet with a circular pestle with a diameter of 6.5 mm and no score line on both sides, and a 150 mg tablet with a score line only on the upper pestle with a diameter of 8.0 mm. It was a circular pestle with.

The average tablet thickness was 2.140 mm for the 25 mg tablet, 2.631 mm for the 75 mg tablet, and 3.524 mm for the 150 mg tablet.

The size of the Lyrica capsule is as follows: the 25 mg capsule is 5.3 mm in diameter and 14.3 mm in length, and the 75 mg capsule is 5.3 mm in diameter and 14.3 mm in length, and the 150 mg capsule is 6.4 mm in length. Since it has a substantially cylindrical shape of 18.0 mm, it is smaller than a capsule, and since it is an uncoated tablet that is not made of gelatin like a capsule, it is clear that it does not easily adhere to the throat.

(4) Packaging As the packaging form, PTP packaging products and loose packaging products were produced. For PTP packages, each tablet was made into a PTP sheet using a polyvinyl chloride film having a thickness of 0.2 mm and aluminum foil, and placed in a paper box. For loosely packaged products, each tablet was placed directly in a polyethylene container, capped, and placed in a paper bag.

The 150mg tablet, and the amount of each additive in the process of the above (1) to (4) were changed as described in Table 14 A.
The 25mg tablets, the amount of each additive in the steps of (1) - (4) were changed as described in Table 14 A, the production of the post-addition mixture A, the sodium starch glycolate 300g In addition, 3770 g of D-mannitol for direct hitting was added.
For the 25 mg tablet, 70 g of calcium stearate was further added to the above-mentioned post-addition mixture A and mixed using a V-20 mixing device (Tokuju Kosakusho) to prepare a powder for tableting.

As the drug substance of the free form of pregabalin, the drug substance having a particle size of 0.1% impurities, 12.6 μm for D10, 64.8 μm for D50, and 218.3 μm for D90 was used.

The additives used were hydroxypropyl cellulose [HPC-L (trademark) normal particle type, Nippon Soda Co., Ltd.], reduced maltose starch syrup [Amalti MR100 (trademark), Mitsubishi Shoji Food Tech Co., Ltd.], and D-mannitol for direct hitting. [Partec M100 ™, Merck Millipore Corporation], sodium starch glycolate [Primogel ™, Matsutani Chemical Industry], calcium stearate [Taipei Chemical Industry Co., Ltd.].

(1) Presence or absence of defects in the granulation / drying process In the granulation / drying process, the flow of the powder could be maintained well, and no loss of pregabalin, which affects the content of the active ingredient in the tablets, was observed.

(2) Particle size distribution of dried granules after sizing As for the particle size distribution of dried granules after sizing, a good particle size distribution with a sharp peak at about 200 μm was obtained.

(3) Mixing uniformity after the post-additive For all of the 25 mg tablets, 75 mg tablets, and 150 mg tablets, the average value of the mixing homogeneity of the post-additive mixture A was within 97.5% to 102.5%, and each of them. It was confirmed that the content of the tablets was also in the range of 95% to 105%.

(4) Bulk density and angle of repose of the powder for tableting The loose bulk density of the powder for tableting of 25 mg tablets, 75 mg tablets, and 150 mg tablets are 0.56 g / mL, 0.42 g / mL, and 0.45 g, respectively. It was / mL.
The tap bulk densities of the 25 mg tablet, 75 mg tablet, and 150 mg tablet at the end of the lock were 0.62 g / mL, 0.49 g / mL, and 0.55 g / mL, respectively.
The angles of repose at the end of the 25 mg tablet, 75 mg tablet, and 150 mg tablet for tableting were 37 °, 37 °, and 39 °, respectively.

(5) Presence or absence of tableting disorder The 25 mg tablet was 100,000 tablets, capping was 0 tablets, sticking was 0 tablets, and lamination was 0 tablets.
The 75 mg tablets were 100,000 tablets, capping was 0 tablets, sticking was almost the total number of tablets, and lamination was 0 tablets. However, it was confirmed that sticking of the 75 mg tablet can be completely prevented by using a pestle whose surface is coated with chromium nitride.
The 150 mg tablets were 50,000 tablets, 0 tablets for capping, 2 tablets for sticking, and 0 tablets for lamination.

(6) Variation in mass of each tablet The powder flow was good, and the variation in mass of each tablet was within 2% of the coefficient of variation for all of the 25 mg, 75 mg, and 150 mg tablets, and no variation was observed. rice field.

(7) Elution to water The elution to water is good, and all of the 25 mg, 75 mg, and 150 mg tablets are stored at 40 ° C. and 75% relative humidity for 1 month and then for 3 months at the start of storage. At each time point after storage for 6 months, 85% or more was eluted after 15 minutes ( see Table 14B ).

実施例１４の最終処方の保存開始時、４０℃７５％相対湿度で１箇月保存後、４０℃７５％相対湿度で３箇月保存後、４０℃７５％相対湿度で６箇月保存後の、ラクタム体（％）、溶出試験結果（％）、及び錠剤硬度（Ｎ）。
（ラクタム体の定量は１回の試験結果である。溶出試験は１８ベッセルの試験結果（パドル法５０ｒ．ｐ．ｍ、水、１５分時点）である。錠剤硬度は１０錠の試験結果である。）

At the start of storage of the final formulation of Example 14, the lactam body was stored at 40 ° C. and 75% relative humidity for 1 month, then stored at 40 ° C. and 75% relative humidity for 3 months, and then stored at 40 ° C. and 75% relative humidity for 6 months. (%), Dissolution test result (%), and tablet hardness (N).
(The quantification of lactam is the result of one test. The dissolution test is the test result of 18 Vessel (Paddle method 50 rpm, water, at 15 minutes). The tablet hardness is the test result of 10 tablets. .)

(8) Elution to pH 1.2 elution test solution The elution property to pH 1.2 elution test solution is good, and 85% or more of all 25 mg tablets, 75 mg tablets, and 150 mg tablets are eluted after 15 minutes. rice field.

(9) Elution to pH 4.0 elution test solution The elution property to pH 4.0 elution test solution is good, and 85% or more of all 25 mg tablets, 75 mg tablets, and 150 mg tablets are eluted after 15 minutes. rice field.

(10) Elution to pH 6.8 elution test solution Elution to pH 4.0 elution test solution is good, and 85% or more of all 25 mg tablets, 75 mg tablets, and 150 mg tablets are eluted after 15 minutes. rice field.

(11) Changes in tablet hardness over time The tablet hardness is good, and the average tablet hardness immediately after tableting is 64.9 N for 25 mg tablets, 64.4 N for 75 mg tablets, and 70.0 N for 150 mg tablets. ( See Table 14B ).

The tablet hardness after being stored in a PTP sheet at 40 ° C. and 75% relative humidity for one month is also good, and the average tablet hardness is 30.0 N for 25 mg tablets, 34.6 N for 75 mg tablets, and 44 for 150 mg tablets. It was .6N ( see Table 14B ).

The tablet hardness after storage in a PTP sheet at 40 ° C. and 75% relative humidity for 3 months is also good, and the average tablet hardness is 34.2N for 25mg tablets, 39.4N for 75mg tablets, and 47 for 150mg tablets. It was .5N ( see Table 14B ).

The tablet hardness after storage in a PTP sheet at 40 ° C. and 75% relative humidity for 6 months is also good, and the average tablet hardness is 26.6N for 25mg tablets, 26.6N for 75mg tablets, and 44 for 150mg tablets. It was .3N ( see Table 14B ).

(12) Changes in lactam mass over time
The storage stability is also good, and the average value of the amount of lactam at the start of storage when wrapped in a PTP sheet made of polyvinyl chloride film and aluminum foil in a relative humidity of 40 ° C. and 75% is 25 mg. The tablets were 0.007%, 75 mg tablets were 0.005%, and 150 mg tablets were 0.005%, whereas the amount of lactam after 1 month of storage was 0.018% and 75 mg for 25 mg tablets. The tablets were 0.011% and the 150 mg tablets were 0.010% ( see Table 14B ).

Similarly, the average amount of lactams after packaging in a PTP sheet made of polyvinyl chloride film and aluminum foil at 40 ° C. and 75% relative humidity and storing for 3 months is 0.036% for 25 mg tablets. , 75 mg tablets were 0.022% and 150 mg tablets were 0.021% ( see Table 14B ).

Similarly, the average amount of lactams after packaging in a PTP sheet made of polyvinyl chloride film and aluminum foil at 40 ° C. and 75% relative humidity and storing for 6 months is 0.059% for 25 mg tablets. , 75 mg tablets were 0.036%, and 150 mg tablets were 0.027%.

(13) Bitterness masking
A bitterness evaluation test was conducted by 10 healthy volunteers for each of the pregabalin drug substance 150 mg and pregabalin 150 mg tablets. The reason for selecting the 150 mg tablet is that the content of the drug substance is the highest in the pregabalin tablet standard, and it is considered that the worst case can be assumed as an evaluation of bitterness.

Ten healthy volunteers evaluated their bitterness according to the following evaluation procedure.
(1) Rinse the mouth thoroughly with water.
(2) The total amount of pregabalin drug substance 150 mg is contained in the mouth.
(3) Evaluate the bitterness when 150 mg of pregabalin drug substance is contained in the mouth for 5 seconds (this time, the bitterness of the drug substance is evaluated as 5 out of 5).
(4) Rinse the mouth thoroughly with water (rinse until the aftertaste of the pregabalin drug substance disappears).
(5) Contains 1 pregabalin tablet 150 mg in the mouth.
(6) Evaluate the bitterness when one pregabalin tablet 150 mg is taken in the mouth for 5 seconds (when the bitterness of the drug substance is set to 5 out of 5 levels, the relative bitterness is evaluated).

The bitterness was evaluated in the following five stages.
1: No bitterness 2: Slightly weak bitterness 3: Feeling bitterness 4: Slightly strong bitterness 5: Strongly bitterness

As a result, the bitterness of 150 mg of pregabalin tablets was significantly suppressed as compared with the pregabalin drug substance (Table 14C ). On the other hand, with regard to the pregabalin drug substance, the spread of bitterness in the mouth or the discomfort of the aftertaste was remarkable due to the fineness of the drug substance (Table 14C ).
It is considered that the reason why the bitterness was suppressed was that the pregabalin drug substance was covered with HPC, reduced maltose starch syrup, and sodium starch glycolate, so that the bitterness was less likely to be felt.

苦み感応試験

Bitter sensitivity test

From the above experimental results, 25 mg tablet according to Table 14 A, 75 mg tablets, 150 mg tablets, either, it is possible to maintain the production of lactams below 1.0% throughout the period until the expiration date of three years, Sufficient hardness can be maintained throughout the period up to the expiration date of 3 years, sufficient elution is provided throughout the period up to the expiration date of 3 years, no tableting problems such as capping, sticking and lamination occur, and powder It was found that the flow was good, the yield was good without loss, stable production was possible, there was no variation in the mass of each tablet, and the content had good uniformity.

Moreover, Table 14 25 mg tablet according to A, 75 mg tablets, 150 mg tablets are both or split, or by crushing, the generation of any lactam body after the uncompressed state below 1.0% It was confirmed that it could be kept.

Further, 25 mg tablet according to Table 14 A, 75 mg tablets, 150 mg tablets, smaller than capsules, moreover, difficult to adhere to the throat, can be film-coated, were divided possible by putting secant ..

Further, 25 mg tablet according to Table 14 A, 75 mg tablets, 150 mg tablets, were confirmed to have sufficiently suppressed bitterness.

Prototype of orally disintegrating solid preparation
(Effect of dry coating of main drug nucleus granules with calcium stearate) ;
In Example 15, the main ingredient granules are steered as a means to prevent contact between a compound having a γ-aminobutyric acid structure and a pharmaceutically acceptable salt thereof and a cellulosic additive other than hydroxypropyl-substituted cellulose. By mixing with a powder of calcium phosphate, the surface of the main drug granules was coated with calcium stearate to delay the elution of the main drug, thereby trying to prevent the bitterness from spreading in the mouth after disintegrating in the oral cavity.

The additives used were hydroxypropyl cellulose [HPC-SL (trademark) ordinary particle type, hydroxypropyl cellulose [HPC-SSL (trademark) ordinary particle type, Nippon Soda Co., Ltd.], reduced malt sugar syrup [Amarti MR100 (trademark),). Mitsubishi Corporation Food Tech Co., Ltd.], Calcium stearate [Taipei Chemical Industry Co., Ltd.], Saccharin sodium hydrate [A-2, Yamato Kasei Co., Ltd.], Eudragit E [EVONIK], D-mannitol [Mannitol P (trademark) ), Mitsubishi Corporation Food Tech Co., Ltd.], D-mannitol [Pearitol 200SD ™, Roquette], Light anhydrous silicic acid [Adsolider 101 ™, Freund Sangyo Co., Ltd.], Crospovidone (Corridon CL-F, BASF) , Crystalline cellulose [Theoras KG-802 (trade), Asahi Kasei Co., Ltd.], Grapefruit oil [Saneigen FFI Co., Ltd.], Sclarose [Saneigen FFI Co., Ltd.].

Prototype tablets containing 75 mg of pregabalin were prepared using 5000 tablets of the active ingredient and additives according to Table 15. The outline of the production method was that pregabalin-containing main ingredient granules, shaped granules for imparting orally disintegrating properties, and post-additives were mixed and tableted so that the weight of one tablet was 190 mg.

In the production of the main ingredient granules, as described below, the main ingredient nuclear granules 1 containing pregavalin are granulated in the first step, and the nuclear granules are mixed with calcium stearate in the second step to produce the main ingredient nuclear granules 2. In the third step, the core granules 2 are coated with the coating liquid 1 using a fluidized bed granulation / drying / fine particle coating device to prepare the main agent coated granules 1, and in the fourth step, the fluidized bed granules / drying are performed. -Using a fine particle coating device, the coated granule 1 was coated with the coating liquid 2 to prepare the main agent granule (main agent coated granule 2).

In order to verify the effect of dry coating of the main drug nucleus granules with calcium stearate, in the second step, the amount of calcium stearate powder to be dry-mixed with the main drug granules was 7.5 mg per tablet (prototype tablet S-1). Three types of prototype tablets were prepared at 0 mg per tablet (prototype tablet S-2) and 2.5 mg per tablet (prototype tablet S-3).

In the first step, 37.5 g of hydroxypropyl cellulose (HPC-SL) (1 tablet formulation 7.5 mg) and 7.5 g of saccharin sodium hydrate (A-2) (1 tablet formulation 1.5 mg) were weighed. , 337.5 g (1 tablet formulation 67.5 mg) of purified water was dissolved to prepare a main drug granule granulation solution. Separately, 375 g of pregavalin (1 tablet formulation 75 mg), 18.75 g of powdered reduced maltose water candy (Amalti MR100) (1 tablet formulation 3.75 mg), and calcium stearate 7.5 g (1 tablet formulation 1.5 mg) are mixed to form a fluidized bed. 382.5 g of the main ingredient granulation liquid prepared for granulation in advance by putting it into a granulation / drying / coating device (FD-MP-01-SFP) at a speed of 12 grams per minute and an intake temperature of 80. Granulation was performed while spraying at ° C. and an exhaust temperature of 30 ° C. for about 35 minutes. The obtained granulated product was dried as it was at 80 ° C. using a fluidized bed, and the obtained granulated product was measured for water content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). It was dried to 1%. Then, the main drug nucleus granule 1 was prepared by sieving with a screen of mesh 30 (diameter 0.5 mm).

In the second step, for the prototype tablet S-1 in which the main drug nuclear granule 1 is dry-coated with 0.75 mg of calcium stearate in one tablet formulation, 446.25 g (89.25 mg in one tablet formulation) is dried and sized. The main drug nuclear granules 1 and 3.75 g of calcium stearate (1 tablet prescription 0.75 mg) were weighed and mixed in a plastic bag to produce the main drug nuclear granules 2 for the prototype tablet S-1. It was designated as the main drug nuclear granule 2 for -1.

In addition, the main ingredient nuclear granules 2 in which the main ingredient nuclear granules 1 were not dry-coated with calcium stearate and the main ingredient nuclear granules 2 in which the main ingredient nuclear granules 1 were dry-coated with half the standard amount of calcium stearate were prepared. "Main drug nuclear granules 2 for S-2" and "Main drug nuclear granules 2 for prototype tablet S-3". Regarding the "main agent nuclear granule 2 for the prototype tablet S-2", the main agent nuclear granule 1 not subjected to the second step was used as it was as the "main agent nuclear granule 2 for the prototype tablet S-2". Regarding "main ingredient nuclear granules 2 for trial tablet S-3", 446.25 g (1 tablet formulation 89.25 mg) of the main ingredient nuclear granules 1 after drying and sizing, and 1.25 g of calcium stearate (1 tablet formulation 0). .25 mg) was weighed and mixed in a plastic bag to produce the main ingredient nuclear granules 2 for the prototype tablet S-3, which were referred to as "the main ingredient nuclear granules 2 for the prototype tablet S-3".

In the third step, after mixing 840 g of absolute ethanol (168 mg of 1 tablet formulation) and 105 g of purified water (21 mg of 1 tablet formulation), 105 g of aminoalkyl methacrylate E (Eudragit E) (21 mg of 1 tablet formulation) is dissolved, and steer is added thereto. A coating liquid 1 was prepared by dispersing 9 g of calcium phosphate (1.8 mg of 1 tablet formulation).

Next, in order to prepare the main ingredient coated granule 1 for the prototype tablet S-1, 450 g of "the main ingredient nuclear granule 2 for the prototype tablet S-1" was weighed and the fluidized bed granulation / drying / coating apparatus (FD). -MP-01-SFP) and 1059 g of coating liquid 1 prepared in advance for granulation at a speed of 8 g / min at an intake temperature of 60 ° C. and an exhaust temperature of 30 ° C. for about 135 minutes. Granulation was performed while spraying. The obtained granulated product was dried as it was at 60 ° C. using a fluidized bed, and the obtained granulated product was measured for water content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). It was dried to 1%. Then, it was sieved with a screen of mesh 30 (diameter 0.5 mm) to prepare "Coated Granules 1 for Prototype Tablet S-1".

The production of "main agent-coated granules 1 for prototype tablet S-2" is the same as the production of "main agent-coated granules 1 for prototype tablet S-1" using "main agent nuclear granules 2 for prototype tablet S-2". It was made in the same way.
The production of "main agent-coated granules 1 for prototype tablet S-3" is the same as the production of "main agent-coated granules 1 for prototype tablet S-1" using "main agent nuclear granules 2 for prototype tablet S-3". It was made in the same way.

In the fourth step, 45 g (1 tablet formulation 9 mg) of D-mannitol (mannit P) was weighed and dissolved in 180 g of purified water (1 tablet formulation 36 mg) to prepare a coating solution 2.
Next, 564 g of "Coated Granules for Trial Tablets S-1" (1 tablet formulation 112. 8 mg) was weighed and charged into a fluidized layer granulation / drying / coating device (FD-MP-01-SFP), and 225 g (1 tablet formulation 45 mg) of coating liquid 2 prepared in advance for granulation. Was granulated at a speed of 6 grams per minute at an intake temperature of 80 ° C. and an exhaust temperature of 30 ° C. while spraying for about 40 minutes. The obtained granulated product was dried as it was at 80 ° C. using a fluidized bed, and the obtained granulated product was measured for water content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). It was dried to 1%. Then, the main ingredient coated granules 2 for the prototype tablet S-1 (the main ingredient granules for the prototype tablet S-1) were prepared by sieving with a screen of mesh 22 (diameter 0.7 mm).

"Main agent coated granule 2 for trial tablet S-2 (main agent granule for trial tablet S-2)" was prepared by using "main agent coated granule 1 for trial tablet S-2" and "trial tablet S-". It was prepared by the same method as the preparation of the main ingredient coated granule 2 for 1 (the main ingredient granule for the prototype tablet S-1).
"Main agent coated granule 2 for trial tablet S-3 (main agent granule for trial tablet S-2)" was prepared by using "main agent coated granule 1 for trial tablet S-3" and "trial tablet S-". It was prepared by the same method as the preparation of the main ingredient coated granule 2 for 1 (the main ingredient granule for the prototype tablet S-1).

To produce the excipient granules, first, 16 g (1 tablet formulation 0.4 mg) of hydroxypropyl cellulose (HPC-SSL) is dissolved in 304 g (1 tablet formulation 7.6 mg) of purified water to prepare an excipient granule granule. Made. Next, 1168 g of D-mannitol (1 tablet prescription 29.2 mg), 44 g of light anhydrous silicic acid (1 tablet prescription 1.1 mg), and crospovidone 292 g (1 tablet prescription 7.3 mg) were added to a high-speed mixer (Fukae Pautech EarthTechnica, Inc.). It was charged into FS-GS-10J), and 320 g of a shaped granulation granulating solution prepared in advance for granulation was added at a speed of 320 g / min for stirring and granulation. The obtained granulated product was put into a fluidized bed granulation / drying / coating device (Freund Sangyo, FLO-5) and dried at 80 ° C., and the obtained granulated product was used as a moisture meter (MOC-120H, Shimadzu Corporation). While measuring the water content using (manufactured by), the product was dried until the water content reached 1%. Then, the shaped granules were prepared by sieving with a screen of mesh 30 (diameter 0.5 mm).

After that, 609 g (1 tablet prescription 121.8 mg) of "main agent coated granules 2 for prototype tablet S-1 (main agent granules for prototype tablet S-1)", 190 g of excipient granules (1 tablet prescription 38 mg), and later As additives, crystalline cellulose (Theoras KG-802) 146.5 g (1 tablet formulation 29.3 mg), grapefruit oil 0.45 g (1 tablet formulation 0.09 mg), sclarose 0.9 g (1 tablet formulation 0.18 mg) and 4.5 g of calcium stearate (0.9 mg per tablet prescription) is mixed in a plastic bag, 190 mg per tablet is weighed, and the tableting pressure is 0 using a single tablet tableting machine (AUTOTAB-500, Ichihashi Seiki). Tableting was performed at .5 tons to obtain a prototype tablet S-1.

Regarding the prototype tablet S-2, a trial production was performed except that 605.25 g (1 tablet prescription 121.05 mg) of "main agent coated granule 2 for the prototype tablet S-2 (main agent granule for the prototype tablet S-2)" was used. A prototype tablet S-2 was prepared in the same manner as in the preparation of tablet S-1.
Regarding the prototype tablet S-3, a trial production was performed except that 606.5 g (1 tablet prescription 121.3 mg) of "main agent coated granule 2 for the prototype tablet S-3 (main agent granule for the prototype tablet S-3)" was used. A prototype tablet S-3 was prepared in the same manner as in the preparation of tablet S-1.

The composition of the prototype tablet S-1, the prototype tablet S-2, and the prototype tablet S-3 per tablet is as shown in Table 15A.

To verify whether the surface of the main ingredient granules could be coated with calcium stearate to delay the elution of the main ingredient by mixing the main ingredient granules with the powder of calcium stearate, the prototype tablets S-1, the prototype tablets S-2, and the prototype tablets S-2, and The elution rate of the prototype tablet S-3 with respect to purified water at 50 rpm was measured at 0 minutes (before the start), 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, and 15 minutes. The measurement results are shown in FIG. In FIG. 2, the prototype tablet described as "Ca 0.75 mg / tablet of stearate" is "prototype tablet S-1", and the prototype tablet described as "without Ca stearate" is "prototype". The prototype tablet described as "tablet S-2" and "Ca 0.25 mg / tablet of stearate" is "prototype tablet S-3".

As can be seen from FIG. 2, the elution of pregabalin could be delayed by dry-coating the main drug nucleus granules containing pregabalin with calcium stearate. However, the dissolution rate of pregabalin in purified water after 15 minutes was almost 100%, and it was considered that the same medicinal effect of pregabalin as 75 mg of Lyrica ™ capsules could be obtained.

A prototype tablet (prototype tablet) in which the content of the Lyrica (trademark) capsule 75 mg was directly tableted at a tableting pressure of 0.5 t for comparison with the drug product in which the content of the Lyrica (trademark) capsule 75 mg was tableted. L13994) was produced.
Table 15B shows the verification results including the dissolution rate of the pharmaceutical product obtained by tableting the contents of 75 mg of Lyrica ™ capsules. In Table 15B, the prototype tablet described as "Ca 0.75 mg / tablet of stearate" is "prototype tablet S-1", and the prototype tablet described as "without Ca stearate" is "prototype". The prototype tablet described as "tablet S-2" and "Ca 0.25 mg / tablet of stearate" is "trial tablet S-3", and the prototype tablet described as "initiative product 75 mg tablet" is It is a "tablet formulation of the contents of 75 mg of Lyrica (trademark) capsules".

表１５Ｂわかるとおり、１５分後のプレガバリンの精製水に対する溶出率は「リリカ（商標）カプセル７５ｍｇの内容物を錠剤化した製剤」と同等であり、リリカ（商標）カプセル７５ｍｇと同様のプレガバリンの薬効が得られると考えられた。

As can be seen in Table 15B, the dissolution rate of pregabalin in purified water after 15 minutes is equivalent to that of "a tableted product of the contents of 75 mg of Lyrica (trademark) capsules", and the same medicinal effect of pregabalin as 75 mg of Lyrica (trademark) capsules. Was thought to be obtained.

Next, by mixing the main drug granules containing pregavalin with the powder of calcium stearate, the surface of the main drug granules is coated with calcium stearate to delay the elution of the main drug, thereby causing a bitter taste in the mouth after disintegrating in the oral cavity. In order to verify whether or not the spread was suppressed, three subjects were given double-blind trial tablets S-1, trial tablets S-2, trial tablets S-3, and "Lyrica ™ Capsules 75 mg." The sensory evaluation of the bitterness of "a tableted formulation of the contents of" was performed. In the evaluation, each prototype tablet was held in the oral cavity for 1 minute, and when no bitterness was felt, it was evaluated as 0 bitterness, and depending on the degree of bitterness, it was evaluated as bitterness 5 when it felt strong bitterness, and the bitterness in between was evaluated. Was evaluated on a 6-point scale as bitterness 1 (slightly bitter), bitterness 2 (weak bitterness), bitterness 3 (moderate bitterness), and bitterness 4 (slightly strong bitterness). The results are shown in Table 15C.

As can be seen from Table 15C, the bitterness of the prototype tablet S-2, which is not dry-coated with calcium stearate, is a very strong bitterness with an average of 4.67. The bitterness was about the same.
On the other hand, the bitterness of the prototype tablet S-1, which was dry-coated with 0.75 mg of calcium stearate per tablet, was only 1.67.
Further, since the bitterness of the prototype tablet S-3 in which the main drug nuclei granules were dry-coated with 0.25 mg of calcium stearate per tablet was 2.67, the bitterness-suppressing effect of the main drug nuclei granules by calcium stearate was dry-coated. It was found that it depends on the amount of calcium stearate used in. The prototype tablet S-1 dry-coated with 0.75 mg of calcium stearate per tablet has the mildest bitterness, and is suppressed to a weak bitterness of bitterness 1 (slightly bitter) to bitterness 2 (weak bitterness). did it.

From the above results, by forming a hydrophobic film of calcium stearate on the surface of the main drug nucleus granules, the infiltration of saliva into the granules is suppressed during the disintegration in the oral cavity, and the dissolution of the main component is delayed. It turned out that the bitterness was less likely to be felt.

Prototype of orally disintegrating solid preparation
(Coating of the main drug nuclear granules with D-mannitol has the effect of improving oral disintegration and mouthfeel) ;
In the prototype tablet S-1 of Example 15, a means for preventing contact between a compound having a γ-aminobutyric acid structure and a pharmaceutically acceptable salt thereof and a cellulosic additive other than hydroxypropyl-substituted cellulose. In addition to the dry coating of the main drug nucleus granules with calcium stearate, the coating liquid 1 containing Eudragit E and calcium stearate was further coated with the coating liquid 2 containing D-mannitol.

Coating with Eudragit E masks the bitterness of pregabalin, in addition to the purpose of blocking contact between compounds having a γ-aminobutyric acid structure and their pharmaceutically acceptable salts with cellulosic additives other than hydroxypropyl-substituted cellulose. To do.
Similarly, dry coating of the active nucleus granules with calcium stearate is intended to block contact between compounds having a γ-aminobutyric acid structure and their pharmaceutically acceptable salts with cellulosic additives other than hydroxypropyl-substituted cellulose. And to further strengthen the purpose of masking the bitterness of pregabalin.

However, when a prototype tablet was prepared using the main ingredient granules, which was simply a dry coating of the main ingredient nuclear granules with calcium stearate and a wet coating with Eudragit E, the disintegration in the oral cavity was delayed, and when it was put in the mouth, it became "rough." It was found that an unpleasant oral tactile sensation (mouse feel) was generated.
Therefore, in the prototype tablet S-1, in addition to the dry coating with calcium stearate and the wet coating with Eudragit E, the main drug nucleus granules are further coated with D-mannitol on the outside.

Therefore, in Example 16, in addition to dry-coating the main drug nuclear granules with calcium stearate and wet-coating with Eudragit E, the outside thereof is further coated with D-mannitol without losing the bitterness-suppressing effect. It was confirmed whether or not the disintegration property in the oral cavity and the tactile sensation in the oral cavity (mouse feel) could be improved.

The additives used were hydroxypropyl cellulose [HPC-SL (trademark) ordinary particle type, hydroxypropyl cellulose [HPC-SSL (trademark) ordinary particle type, Nippon Soda Co., Ltd.], reduced malt sugar syrup [Amarti MR100 (trademark),). Mitsubishi Corporation Food Tech Co., Ltd.], Calcium stearate [Taipei Chemical Industry Co., Ltd.], Saccharin sodium hydrate [A-2, Yamato Kasei Co., Ltd.], Eudragit E [EVONIK], D-mannitol [Mannitol P (trademark) ), Mitsubishi Corporation Food Tech Co., Ltd.], D-mannitol [Pearitol 200SD ™, Roquette], Light anhydrous silicic acid [Adsolider 101 ™, Freund Sangyo Co., Ltd.], Crospovidone (Corridon CL-F, BASF) , Crystalline cellulose [Theoras KG-802 (trade), Asahi Kasei Co., Ltd.], Grapefruit oil [Saneigen FFI Co., Ltd.], Sclarose [Saneigen FFI Co., Ltd.].

Prototype tablets containing 75 mg of pregabalin were prepared using 5000 tablets of the active ingredient and additives according to Table 16A. As for the outline of the production method, as in Example 15, the prototype tablet S-1 is mixed with pregabalin-containing main ingredient granules, shaped granules for imparting orally disintegrating properties, and post-additives, and 1 The tablets were tableted so that the tablet weight was 190 mg.

In the production of the main ingredient granules, as described below, the main ingredient nuclear granules 1 containing pregavalin are granulated in the first step, and the nuclear granules are mixed with calcium stearate in the second step to produce the main ingredient nuclear granules 2. In the third step, the core granules 2 are coated with the coating liquid 1 using a fluidized bed granulation / drying / fine particle coating device to prepare the main agent coated granules 1, and in the fourth step, the fluidized bed granules / drying are performed. -Using a fine particle coating device, the coated granule 1 was coated with the coating liquid 2 to prepare the main agent granule (main agent coated granule 2).

In order to verify the effect of wet coating with D-mannitol, in the fourth step, the amount of D-mannitol to be wet-coated with respect to the main drug-coated granules 1 was 9 mg per tablet (prototype tablet S-1), 1 tablet. Three types of prototype tablets were prepared at 0 mg per tablet (prototype tablet T-1) and 12 mg per tablet (prototype tablet T-2).

The first step was carried out in the same manner as in Example 15.
That is, in the first step, 37.5 g of hydroxypropyl cellulose (HPC-SL) (1 tablet formulation 7.5 mg) and 7.5 g of saccharin sodium hydrate (A-2) (1 tablet formulation 1.5 mg) are weighed. It was taken and dissolved in 337.5 g (1 tablet formulation 67.5 mg) of purified water to prepare a main drug granule granulation solution. Separately, 375 g of pregavalin (1 tablet formulation 75 mg), 18.75 g of powdered reduced maltose water candy (Amalti MR100) (1 tablet formulation 3.75 mg), and calcium stearate 7.5 g (1 tablet formulation 1.5 mg) are mixed to form a fluidized bed. 382.5 g of the main ingredient granulation liquid prepared for granulation in advance by putting it into a granulation / drying / coating device (FD-MP-01-SFP) at a speed of 12 grams per minute and an intake temperature of 80. Granulation was performed while spraying at ° C. and an exhaust temperature of 30 ° C. for about 35 minutes. The obtained granulated product was dried as it was at 80 ° C. using a fluidized bed, and the obtained granulated product was measured for water content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). It was dried to 1%. Then, the main drug nucleus granule 1 was prepared by sieving with a screen of mesh 30 (diameter 0.5 mm).

The second step was also carried out in the same manner as in the preparation of the prototype tablet S-1 of Example 15.
That is, in the second step, in order to dry-coat the main drug nuclear granules 1 with 0.75 mg of calcium stearate, which is formulated as one tablet, for all of the trial tablet S-1, the trial tablet T-1, and the trial tablet T-2, 446. .25 g (1 tablet prescription 89.25 mg) of the main ingredient nuclear granules 1 after drying and sizing, and 3.75 g of calcium stearate (1 tablet prescription 0.75 mg) are weighed and mixed in a plastic bag, and the trial tablet The main drug nucleus granules 2 common to S-1, the prototype tablet T-1, and the prototype tablet T-2 were produced.

The third step was carried out in the same manner as in Example 15.
In the third step, after mixing 840 g of absolute ethanol (168 mg of 1 tablet formulation) and 105 g of purified water (21 mg of 1 tablet formulation), 105 g of aminoalkyl methacrylate E (Eudragit E) (21 mg of 1 tablet formulation) is dissolved, and steer is added thereto. A coating liquid 1 was prepared by dispersing 9 g of calcium phosphate (1.8 mg of 1 tablet formulation).

Next, for each of the trial tablet S-1, the trial tablet T-1, and the trial tablet T-2, 450 g of the main drug nucleus granules 2 were weighed and the fluidized bed granulation / drying / coating device (FD-MP-01-) was used. Granulation while spraying 1059 g of coating liquid 1 prepared for granulation in advance into SFP) at a speed of 8 g / min at an intake temperature of 60 ° C. and an exhaust temperature of 30 ° C. for about 135 minutes. bottom. The obtained granulated product was dried as it was at 60 ° C. using a fluidized bed, and the obtained granulated product was measured for water content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). It was dried to 1%. Then, it was sieved with a screen of mesh 30 (diameter 0.5 mm) to prepare "main agent coated granule 1" common to the prototype tablet S-1, the prototype tablet T-1, and the prototype tablet T-2.

In the fourth step, 45 g (1 tablet formulation 9 mg) of D-mannitol (mannit P) was weighed and dissolved in 180 g of purified water (1 tablet formulation 36 mg) to prepare a coating solution 2.
Next, 564 g of the main ingredient coated granule 1 (1 tablet formulation 112.8 mg) was weighed and fluidized in order to prepare the main ingredient coated granule 2 for the prototype tablet S-1 (the main ingredient granule for the prototype tablet S-1). 225 g (1 tablet formulation 45 mg) of coating liquid 2 prepared for granulation in advance by putting it into a layer granulation / drying / coating device (FD-MP-01-SFP) at a speed of 6 g / min. Granulation was performed while spraying at an intake temperature of 80 ° C. and an exhaust temperature of 30 ° C. for about 40 minutes. The obtained granulated product was dried as it was at 80 ° C. using a fluidized bed, and the obtained granulated product was measured for water content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). It was dried to 1%. Then, the main ingredient coated granules 2 for the prototype tablet S-1 (the main ingredient granules for the prototype tablet S-1) were prepared by sieving with a screen of mesh 22 (diameter 0.7 mm).

The main ingredient coated granule 2 for the prototype tablet T-1 (the main ingredient granule for the prototype tablet S-1) is the main ingredient coated granule 1 for the prototype tablet T-1 as it is, and the main ingredient coated granule 2 for the prototype tablet T-1 (for the prototype tablet S-1). Used as the main drug granule).

In order to prepare the main ingredient coated granules 2 for the prototype tablet T-2 (the main ingredient granules for the prototype tablet S-1), 564 g of the main ingredient coated granules 1 (1 tablet formulation 112.8 mg) were weighed and granulated into a fluid layer. -Put into a drying / coating device (FD-MP-01-SFP) and apply 300 g (1 tablet formulation 45 mg) of coating liquid 2 prepared in advance for granulation at a speed of 6 g / min and intake temperature. Granulation was performed while spraying at 80 ° C. and an exhaust temperature of 30 ° C. for about 53 minutes. The obtained granulated product was dried as it was at 80 ° C. using a fluidized bed, and the obtained granulated product was measured for water content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). It was dried to 1%. Then, the main ingredient coated granules 2 for the prototype tablet T-2 (the main ingredient granules for the prototype tablet T-2) were prepared by sieving with a screen of mesh 22 (diameter 0.7 mm).

The shaped granules were produced in the same manner as in Example 15.
That is, in the production of the excipient granules, first, 16 g (1 tablet formulation 0.4 mg) of hydroxypropyl cellulose (HPC-SSL) is dissolved in 304 g of purified water (1 tablet formulation 7.6 mg) to granulate the excipient granules. A liquid was prepared. Next, 1168 g of D-mannitol (1 tablet prescription 29.2 mg), 44 g of light anhydrous silicic acid (1 tablet prescription 1.1 mg), and crospovidone 292 g (1 tablet prescription 7.3 mg) were added to a high-speed mixer (Fukae Pautech EarthTechnica, Inc.). It was charged into FS-GS-10J), and 320 g of a shaped granulation granulating solution prepared in advance for granulation was added at a speed of 320 g / min for stirring and granulation. The obtained granulated product was put into a fluidized bed granulation / drying / coating device (Freund Sangyo, FLO-5) and dried at 80 ° C., and the obtained granulated product was used as a moisture meter (MOC-120H, Shimadzu Corporation). While measuring the water content using (manufactured by), the product was dried until the water content reached 1%. Then, the shaped granules were prepared by sieving with a screen of mesh 30 (diameter 0.5 mm).

After that, 609 g (1 tablet prescription 121.8 mg) of "main agent coated granules 2 for prototype tablet S-1 (main agent granules for prototype tablet S-1)", 190 g of excipient granules (1 tablet prescription 38 mg), and later As additives, crystalline cellulose (Theoras KG-802) 146.5 g (1 tablet formulation 29.3 mg), grapefruit oil 0.45 g (1 tablet formulation 0.09 mg), sclarose 0.9 g (1 tablet formulation 0.18 mg) and 4.5 g of calcium stearate (0.9 mg per tablet prescription) is mixed in a plastic bag, 190 mg per tablet is weighed, and the tableting pressure is 0 using a single tablet tableting machine (AUTOTAB-500, Ichihashi Seiki). Tableting was performed at .5 tons to obtain a prototype tablet S-1.

Regarding the prototype tablet S-2, the prototype tablet S was used except that 564 g (1 tablet prescription 112.8 mg) of "main agent coated granule 2 for the prototype tablet S-2 (main agent granule for the prototype tablet S-2)" was used. A prototype tablet S-2 was prepared in the same manner as in the preparation of -1.
Regarding the prototype tablet S-3, the prototype tablet S was used except that 624 g (1 tablet prescription 124.8 mg) of "main agent coated granule 2 for the prototype tablet S-3 (main agent granule for the prototype tablet S-3)" was used. A prototype tablet S-3 was prepared in the same manner as in the preparation of -1.

The composition of the prototype tablet S-1, the prototype tablet T-1, and the prototype tablet T-2 per tablet is as shown in Table 16A.

In addition to dry coating with calcium stearate and wet coating with Eudragit E, the main drug nucleus granules are further coated with D-mannitol on the outside, so that the effect of suppressing bitterness is not lost, and the oral disintegration and discomfort are achieved. Whether or not the tactile sensation (mouse feel) in the oral cavity could be improved was confirmed by the method of <> ....
In addition, a sensory test of bitterness evaluation was conducted on three subjects in a double-blind manner. In the evaluation, each prototype tablet was held in the oral cavity for 1 minute, and when no bitterness was felt, it was evaluated as 0 bitterness, and depending on the degree of bitterness, it was evaluated as bitterness 5 when it felt strong bitterness, and the bitterness in between was evaluated. Was evaluated on a 6-point scale as bitterness 1 (slightly bitter), bitterness 2 (weak bitterness), bitterness 3 (moderate bitterness), and bitterness 4 (slightly strong bitterness). The results are shown in Table 16B. The value of the evaluation of bitterness in Table 16B shows an average value.

As can be seen from Table 16B, the oral disintegration time of the prototype tablet T-1 without the main drug coating (2) with D-mannitol took 1 minute or more, whereas the main drug with 9 mg of D-mannitol per tablet. Since the orally disintegrating time of the prototype tablet S-1 coated (2) was 25 seconds, the orally disintegrating property is sufficient as an orally disintegrating tablet by applying the main drug coating (2) with D-mannitol. It was confirmed that the improvement was achieved to a certain level.
On the other hand, when the amount of the main drug coating (2) was increased to 12 mg of D-mannitol per tablet, the oral disintegration time was 24 seconds. Therefore, the amount of D-mannitol in the main drug coating (2). It was found that 9 mg per tablet was sufficient, and that even if the dose was increased to 12 mg, the improvement in oral disintegration was slight.
It was confirmed that the disintegration property in the oral cavity was improved and the unpleasant texture (mouth feel) in the oral cavity, which was "rough" and "motamota" when it was put in the mouth, was also reduced.
Regarding the evaluation of bitterness, since both the prototype tablet S-1 and the prototype tablet T-1 had a bitterness 2 (feeling a weak bitterness), the presence or absence of the main ingredient coating (2) did not affect the bitterness of the prototype tablet. all right.
On the other hand, the bitterness of the prototype tablet T-2, in which the amount of the main drug coating (2) was increased to 12 mg of D-mannitol per tablet, was bitterness 3 (a moderate bitterness was felt). It was found that when the amount of D-mannitol in the coating (2) was increased to 12 mg per tablet, the bitterness was slightly increased.

Furthermore, in order to obtain objective data on the unpleasant oral texture (mouse feel) that was "rough" and "motamota" when it was put in the mouth, the prototype tablet T-1 was dry-coated with calcium stearate. Scanning electron micrographs of the main drug nuclear granules 2, the main drug coated granules 1 after coating with Eudragit E, and the main drug coated granules 2 after coating with D-mannitol (2). It was taken (Fig. 3). In FIG. 3, "after granulation" means the main ingredient core granules 2 after dry coating with calcium stearate, and "after Eudracoat" means the main ingredient coated granules 1 after coating (1) with Eudragit E. , "After D-mannitol coating" means the main ingredient coated granules 2 after coating with D-mannitol (2).

As can be seen from FIG. 3, the surface of the main ingredient nuclei granules 2 after the coating (1) with Eudragit E was smoother than that of the main ingredient nuclei granules 2 after the dry coating with calcium stearate. The surface unevenness of the main ingredient coated granules 2 after the coating with D-mannitol (2) was increased as compared with the main ingredient nuclear granules 2 after the coating with Eudragit E (1). Coating with D-mannitol increases the unevenness of the surface, makes it easier for saliva to infiltrate through the gaps when tableted, and quickly disintegrates, making it "rough" and "motamota" when it is in the mouth, which is unpleasant. It was confirmed that the tactile sensation (mouth feel) in the oral cavity was improved.

From the above results, in addition to dry coating with calcium stearate and wet coating with Eudragit E, the core granules are further coated with D-mannitol on the outside, so that the bitterness-suppressing effect is not lost in the oral cavity. It was found that the disintegration property could be improved. It was also found that the amount of D-mannitol was 9 mg per tablet, which was suitable for both improvement of oral disintegration and suppression of bitterness.

Confirmation of storage stability of orally disintegrating solid preparation The storage stability of the tableting granules of the prototype tablet S-1 after 1 week and 2 weeks when stored at 60 ° C (glass bottle sealed) Evaluate the amount, and use this as the result of the combination test of pregabalin and crystalline cellulose (1: 1), the result of the combination test of pregabalin and light anhydrous silicic acid (1: 0.1), and the combination of pregabalin and crospovidone (1: 1). It was compared with the test result. The results are shown in Table 17.

As can be seen from Table 17, the prototype tablet S-1 is a crystalline cellulose (KG-802) and light anhydrous silicic acid (additiver) that promote the production of lactams over time and impair storage stability in a solid preparation containing pregabalin. Despite containing 101) and crospovidone (corridone CL-F), the production of lactams remained at a low level due to the blockage of contact between these additives and pregabalin.
In particular, when light silicic anhydride was added, the amount of lactams after storage at 60 ° C. (sealed in a glass bottle) for 2 weeks was 1.640%, whereas that of the prototype tablet S-1 was The fact that it remained at 0.067% was a surprising effect of improving storage stability over time.

In order to confirm the storage stability of the prototype tablet S-1 over time, the prototype tablet S-1, Lyrica ™ OD tablet 25 mg, Lyrica ™ OD tablet 75 mg, and Lyrica ™ OD tablet 150 mg were added to aluminum. It was sealed in a bag and stored under accelerated conditions of 40 ° C. and 75% relative humidity, and the formation of lactams over time was measured. The results are shown in FIG. In FIG. 4, the original 25 mg tablet means Lyrica ™ OD tablet 25 mg, the original 75 mg tablet means Lyrica ™ OD tablet 75 mg, and the original 150 mg tablet means Lyrica ™ OD tablet 150 mg. do. In FIG. 4, the prototype 75 mg tablet means the prototype tablet S-1.

As can be seen from FIG. 4, the amount of lactams after storage at 40 ° C. and 75% relative humidity for 1 month is only about 0.02%, and the estimated amount of lactams after storage for 6 months is 0. Since it is considered to be about .12%, the condition of 0.2% or less, which is the safety threshold, could be cleared with a margin.

In order to confirm the storage stability of the prototype tablet S-1 over time, the prototype tablet S-1 was sealed in an aluminum bag and stored under accelerated conditions of 40 ° C. and 75% relative humidity. The elution rate with respect to purified water after storage in May and after storage in January was measured. The test conditions were the paddle method and 50 rotations. The results are shown in FIG. The value indicates the average value of 3 vessels. In FIG. 5, the starting OD 75 mg means Lyrica ™ OD tablet 75 mg. Further, in FIG. 5, lines other than the starting OD 75 mg mean the prototype tablet S-1. “At the start of the starting OD 75 mg” is a measurement of the elution rate of Lyrica ™ OD tablet 75 mg not stored under acceleration conditions as a control group. "At the start", "4075-0.5M", and "4075-1M" are each before starting storage under the acceleration condition of 40 ° C. and 75% relative humidity by sealing the prototype tablet S-1 in an aluminum bag. , 0.5 months storage, and January storage elution rate was measured.

As can be seen from FIG. 5, even after storage for one month under the acceleration condition of 40 ° C. and 75% relative humidity, no elution delay was observed and good storage stability was shown.

From the above results, it was found that the bitterness of the main component was masked by Eudragit E, but it was not 100% suppressed in the oral cavity. Therefore, as a result of various studies on fragrances that reduce the bitterness of pregabalin, by adding a small amount of citrus fragrance, not only the bitterness of pregabalin is subjectively reduced, but also a refreshing feeling can be obtained. I found that. Among them, grapefruit flavor, lemon flavor and orange flavor reduced the bitterness of pregabalin and brought a refreshing feeling. In particular, the grapefruit flavor had the best pregabalin bitterness-reducing effect and a refreshing feeling of administration.

Summary of Examples:
As described above, in the pharmaceutical preparation of the present application containing a γ-aminobutyric acid derivative or a pharmaceutically acceptable salt thereof, the lactam form increases over time by adding a cellulosic additive and tableting. I understood.

However, HPC and L-HPC are allowed to be added to pharmaceutical preparations containing a γ-aminobutyric acid derivative or a pharmaceutically acceptable salt thereof because the formation of lactams generated over time is very small. I was able to.

Therefore, it was found that by not adding a cellulosic additive other than hydroxypropyl-substituted cellulose, it is possible to produce a storage-stable compressed solid preparation that does not produce lactams over time due to tableting.

In addition, the pharmaceutical preparation containing the γ-aminobutyric acid derivative of the present application or a pharmaceutically acceptable salt thereof does not contain any of pregelatinized starch, sucrose, gum arabic, gelatin, and D-sorbitol, so that the expiration date is reached. It was found that the tablet hardness of 20 N or more can be maintained through the above.

In addition, pharmaceutical preparations containing the γ-aminobutyric acid derivative of the present application or a pharmaceutically acceptable salt thereof contain sugar alcohols such as mannitol, reduced maltose starch syrup, maltitol, hydroxypropyl starch, or sodium starch glycolate. Therefore, it was found that the formation of lactams over time after tableting can be remarkably suppressed.

Further, the pharmaceutical preparation containing the γ-aminobutyric acid derivative of the present application or a pharmaceutically acceptable salt thereof is stored in an airtight blister package obtained by crimping an aluminum sheet with polyvinyl chloride, polypropylene, polyethylene or the like. It was found that this suppresses the production of lactams over time after tableting.

In addition, the pharmaceutical preparation containing the γ-aminobutyric acid derivative of the present application or a pharmaceutically acceptable salt thereof maintains the tablet hardness by containing an appropriate amount of sodium starch glycolate, and after tableting. It was found that it has good dissolution property while preventing the formation of lactam form over time.

Further, in the pharmaceutical preparation containing the γ-aminobutyric acid derivative of the present application or a pharmaceutically acceptable salt thereof, the powder before compression has good fluidity, good content uniformity, and capping. It was found that there is no tableting disorder such as sticking and lamination, there is no variation in the mass of each tablet, and stable production is possible with good yield without loss.

It was also found that a pharmaceutical preparation containing the γ-aminobutyric acid derivative of the present application or a pharmaceutically acceptable salt thereof can mask the bitterness of pregabalin.

Claims (6)

Contains one or more active ingredients selected from the group consisting of pregabalin and its pharmaceutically acceptable salt.
Granules in which the active ingredient is coated with one or more ingredients selected from the group consisting of a cellulose coating base, a water-soluble film coating base, an enteric film coating base, D-mannitol, and calcium stearate. The granules contain one or more optional additives, and the granules and the coating in contact with the granules do not contain cellulosic additives other than hydroxypropyl-substituted cellulose).
The active ingredient has a pharmaceutical structure that does not come into contact with a cellulosic additive other than hydroxypropyl-substituted cellulose (however, hydroxypropyl-substituted cellulose may be present outside the granules) existing outside the granules. ,
An instantly release orally disintegrating tablet in which the formation of lactams over time is suppressed, which is produced by tableting in a state where a cellulosic additive other than hydroxypropyl-substituted cellulose is in contact with the active ingredient.
Claimed to contain one or more components selected from the group consisting of carboxymethyl group modified starch or pharmaceutically acceptable salts thereof, sugar alcohols, calcium stearate, lactose hydrate, and hydroxypropyl substituted cellulose. Item 2. The tablet according to item 1.
The tablet according to claim 1 or 2 , which contains one or more sugar alcohols selected from the group consisting of erythritol, mannitol, isomalt, reduced starch syrup, reduced maltose starch syrup, maltitol, and sorbitol.
One or more active ingredients selected from the group consisting of pregavalin and its pharmaceutically acceptable salt are magnesium aluminometasilicate, light anhydrous silicic acid, hydrous silicon dioxide, talc, titanium oxide, povidone, crospovidone, macro. Any of claims 1 to 3 , which has a pharmaceutical structure that does not come into contact with one or more components selected from the group consisting of goal, sucrose fatty acid ester, hypromerose, gelatin, starch, partially pregelatinized starch, and calcium dihydrogen phosphate. The tablet according to paragraph 1.
The tablet according to any one of claims 1 to 4 , which does not contain 1.7% or more of the tablet weight of one or more components selected from the group consisting of pregelatinized starch, sucrose, gum arabic, and gelatin.
The method for producing an orally disintegrating tablet according to any one of claims 1 to 5 , which comprises the following steps:
(1) One or more active ingredients selected from the group consisting of pregavalin and a pharmaceutically acceptable salt thereof, and one or more arbitrary additives (provided that the additives are cellulosic other than hydroxypropyl-substituted cellulose). The process of mixing with (without additives),
(2) A step of spraying a hydroxypropyl-substituted cellulose solution onto the above mixture to granulate the mixture.
(3) The granulated product contains one or more components selected from the group consisting of a cellulose coating base, a water-soluble film coating base, an enteric film coating base, D-mannitol, and calcium stearate. A step of coating with a coating material (however, the coating material does not contain a cellulosic additive other than hydroxypropyl-substituted cellulose) .
(4) a pre-Symbol coating granulated material, a step of tableting are mixed with additives or granules containing hydroxypropyl-substituted cellulose than the cellulose-based additive of the one or more.

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