JP2018118966A - COMPRESSED SOLID PHARMACEUTICAL COMPOSITION CONTAINING γ-AMINOBUTYRIC ACID DERIVATIVE SUBSTITUTED AT POSITION 3 - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide compression solid formulations containing a γ-aminobutyric acid derivative, the formulations having preservation stability to be able to maintain 1.0% or less of generation of γ-aminobutyric acid derivative lactam within the expiration date, having sufficient hardness, good dissolution properties, and good content uniformity, causing no tablet disorder such as capping, sticking, and lamination, being able to be stably produced with good yield, further having masked bitterness of γ-aminobutyric acid derivative, being smaller than capsules, being hard to adhere to the throat, being easy to take in, and being easy to divide.SOLUTION: The present invention provides a compression solid formulation which does not contain a cellulose additive except hydroxypropylcellulose.SELECTED DRAWING: Figure 1

Description

The present invention relates to 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 the compressed solid pharmaceutical composition.
The present invention relates to a solid pharmaceutical composition or a compressed solid pharmaceutical composition that stably holds a derivative of γ-aminobutyric acid (GABA), preferably a compressed solid pharmaceutical that stably holds a γ-aminobutyric acid derivative substituted at the 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 feel the bitterness of a derivative of γ-aminobutyric acid (GABA), preferably a γ-aminobutyric acid derivative substituted at the 3-position, is excellent in the dissolution property of the derivative, maintains sufficient hardness, and molded. A solid pharmaceutical composition or a compressed solid pharmaceutical composition capable of producing a high-quality pharmaceutical preparation, which has excellent properties, low adhesion, good powder flow, and the derivative has sufficient storage stability. The present invention relates to a method for producing a solid pharmaceutical composition or a compressed solid pharmaceutical composition.

Pregabalin, gabapentin, and baclofen are known as typical pharmaceuticals of γ-aminobutyric acid derivatives. The structures of pregabalin, gabapentin, and baclofen are as shown in the following formulas I to III, respectively.

Formula I Pregabalin Structural Formula

Formula II Structural formula of gabapentin

Formula III Structural formula of baclofen

Pregabalin is marketed in Japan as a hard capsule under the brand name “Lilica” from Pfizer for the treatment of neuropathic pain and pain associated with fibromyalgia. According to Lyrica's interview form, the expiration date is three years.
In Japan, gabapentin is marketed as a tablet and syrup under the trade name “Gabapen” by Pfizer for the treatment of hemorrhoids. According to the “Gabapen” interview form, the expiration dates for Gabapen tablets and syrups are both three years.

  Baclofen is sold as a tablet in Japan for the treatment of spastic paralysis under the brand name “Liolesal” from Novartis and under the brand name “Gabalon” from Daiichi Sankyo. Baclofen is sold as a solution for intrathecal injection by Daiichi Sankyo Co., Ltd. for the treatment of severe spastic paralysis resulting from cerebrospinal disease. According to the interview form, the expiration date for Liolesar tablets is 3 years, the expiration date for Gabalon's intrathecal injection is 3 years, and the expiration date for Gabalon tablets is 5 years.

Pregabalin and gabapentin are GABA derivatives that increase the fat solubility of γ-aminobutyric acid (GABA) and pass through the blood-brain barrier. Pregabalin and gabapentin have a structure similar to γ-aminobutyric acid (GABA), but binding to the GABA (GABA _A , GABA _B , benzodiazepine) receptor, inhibitory action on GABA metabolism and reuptake are Not allowed. In addition, there are no actions such as voltage-dependent sodium channel blockade, opioid receptor activation, NMDA receptor blockade, cyclooxygenase inhibition, monoamine reuptake inhibition, etc., which are the action mechanisms of existing analgesics.

Voltage-dependent calcium channels are classified into P-type, Q-type, N-type, L-type, R-type, and T-type based on electrophysiological differences. These are all 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 bind to α2δ subunit, an auxiliary subunit of N-type calcium channel, reduce calcium influx into nerve endings, and excitatory neurotransmitters depend on increased intracellular calcium ion concentration The release of.

  On the other hand, since calcium inhibitors used mainly as antihypertensive drugs act on L-type calcium channels and exert their effects, pregabalin and gabapentin, which antagonize only N-type calcium channels, are effective in blood pressure and cardiac function. It does not affect.

  Pregabalin and gabapentin are both first-line drugs for neuropathic pain. Pregabalin and gabapentin are N-type voltage-dependent when the painful primary neurons such as C fibers and Aδ fibers that transmit pain sensations in the skin project onto the collagen of the dorsal horn of the spinal cord to form synapses with secondary neurons. It binds to the α2δ subunit of the calcium channel and inhibits the influx of calcium into the nerve endings to suppress the release of excitatory neurotransmitters, thereby producing an analgesic action against neuropathic pain. Pregabalin has been found to have a statistically significant analgesic effect in clinical trials for patients with postherpetic neuralgia and painful diabetic neuropathy.

  The analgesic potency of gabapentin and pregabalin is 1: 5, and gabapentin needs to be taken 5-6 times the amount of pregabalin. Both pregabalin and gabapentin have side effects such as drowsiness, lightheadedness, falls, peripheral edema, and weight gain, so fine-tuning of the dose is necessary.

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 inhibits nervous system overactivity by activating GABA transporter at the nerve endings of GABAergic nervous system widely distributed in the central nervous system to maintain and enhance the function of GABAergic nervous system So it can be used to treat hemorrhoids.

Baclofen acts as an agonist of GABA _B receptor and has a muscle relaxing action, and thus 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, and gabapentin is absorbed by the L-amino acid transporter, but pregabalin is absorbed by both the D- and L-amino acid transporters. Therefore, when gabapentin is used at high doses, bioavailability decreases and it is difficult to predict blood levels. However, pregabalin has a bioavailability of 90% or more and exhibits dose-dependent pharmacokinetics. It is easy to predict. In addition, pregabalin reaches its peak in about 1 hour compared with the case where gabapentin reaches its peak in about 3 hours after taking it, so that the effect can be obtained quickly.

  In terms of excretion, pregabalin does not bind to plasma proteins and does not undergo metabolism in the liver and therefore is less likely to cause drug interactions. In addition, 99% of urinary excretion of pregabalin is unchanged. The plasma half-life of pregabalin and gabapentin is approximately 6 hours regardless of dose escalation or repeated administration. Absorption of pregabalin and gabapentin is a drug with very little drug interaction because it is hardly affected by diet and is not metabolized in the liver, and does not increase or inhibit liver enzymes. The systemic clearance of pregabalin in healthy adults is 60-100 mL / min, the average value of systemic clearance of gabapentin is 116 mL / min, both of which are consistent with the glomerular filtration rate, and the unchanged urinary excretion rate is There are reports that it was almost 100%.

  The most common side effects of pregabalin and gabapentin are sleepiness and wandering. The frequency increases with increasing dose and with age. The frequency of side effects of pregabalin is around 20% in domestic studies up to approval. Pregabalin also has reports of sudden loss of consciousness. About 15% of other side effects of pregabalin have been reported.

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%), double vision (about 5%), and fatigue (about 4%).
The frequency of side effects of baclofen is about 37% in domestic studies up to approval. The main side effects were sleepiness (about 10%), nausea (about 5%), loss of appetite (about 3%), weakness (about 7%), wandering (3%) and the like.

  Pregabalin and gabapentin are unlikely to cause harmful interactions with other drugs, but there are reports that the combined use of pregabalin and opioids has enhanced respiration suppression by opioids, and caution is required.

  These γ-aminobutyric acid derivatives have common characteristics based on a common structure, and even when formulated, have 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 very bitter drugs and have extremely poor compression moldability and fluidity. ing. Patent Document 1 discloses that the allowable amount of lactam during the expiration date is 1.0% or less from the viewpoint of safety, and that many assistants react with gabapentin, pregabalin or baclofen over time. To form a lactam (an intramolecular dehydration condensation product of an amino group and a carboxyl group present in the molecule of a compound having a γ-aminobutyric acid structure), and the dehydration condensation reaction is accelerated as the compaction state is reached. Further acceleration is described by the use of water or organic solvents in the conversion. The structures of pregabalin lactam body, gabapentin lactam body, and baclofen lactam body are as shown in the following formulas IV to VI, respectively.

Formula IV Structural formula of lactam form of pregabalin

Formula V Structural formula of the gammapentin lactam body

Formula VI Structural formula of the lactam body of baclofen

And as a solution to the above-mentioned problem, Patent Document 1 blends γ-aminobutyric acid derivative with ethylene glycol, propylene glycol, butylene glycol, sorbitol, glycerin and their fatty acid esters as water retention agents as stabilizers. Thus, a stabilized solid composition of a γ-aminobutyric acid derivative is proposed.
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 have the same description.

  Japanese Patent Application Laid-Open No. 2000-034226 (Patent Document 4) describes the same problems as in Patent Documents 1 to 3, and as a solution thereof, γ-aminobutyric acid is obtained by adding an amino acid to a 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 an aqueous solution state and a solid state.

  JP-T 2009-514847 (Patent Document 5) also describes that a pregabalin preparation may form a lactam body by dehydration condensation of an amino group and a carboxyl group present in the molecule of pregabalin. Patent Document 5 discloses that pregabalin is absorbed in the small intestine and ascending colon and is difficult to absorb beyond the right colonic curve. Therefore, in a sustained-release preparation that simply releases the active ingredient over 6 hours, It is described that it cannot be a sustained-release preparation taken once a day because it moves beyond the right colonic curve and becomes difficult to be absorbed.

  As a solution to this problem, Patent Document 5 contains pregabalin, polyvinyl acetate, povidone, and cross-linked povidone, so that it stays in the stomach for a long period of time and releases pregabalin continuously while staying in the stomach. Proposed sustained-release pharmaceutical preparations for once-daily use.

  Japanese Patent Application Laid-Open No. 2014-521639 (Patent Document 6) also describes that the average absorption window of pregabalin is 6 hours or less. As a solution, pregabalin is contained by including “pregabalin or a salt thereof and hydroxypropylmethylcellulose”. The first release control phase for the purpose of controlling the release and improving the floatability of the resin and the second release control phase having both the swellability and the floatability by “including polyethylene oxide as the swellable polymer” are uniform. Proposed sustained, sustained release tablets.

  In JP-T-2003-504324 (Patent Document 7), as means for solving the problem of producing a coated granule whose taste is masked and immediately releases an active ingredient, first, sodium carboxymethylcellulose (carmellose sodium), cloth Disintegrants such as povidone and carboxymethyl starch are first dry mixed with the active ingredient powder, wet granulated with a binder, and then a film disintegrant such as sodium carboxymethylcellulose, crospovidone, carboxymethyl starch and a coating agent are added. It is proposed to dry after spraying with the suspension containing.

In Example 3 of Patent Document 7, granules containing pregabalin, crospovidone, acesulfame potassium, precipitated silica, ethylcellulose and crospovidone are mixed with mannitol, crospovidone, aspartame, fragrance, magnesium stearate and compressed into tablets. Quick-disintegrating tablets are described.
In Example 3 of Patent Document 7, there is a description that taste masking and elution characteristics have been confirmed, but there is no description about storage stability.

  WO2015 / 007890 (Patent Document 8) proposes a capsule containing pregabalin and vitamin B12 in order to prevent the occurrence of vitamin B deficiency resulting in nerve damage and anemia when pregabalin is taken.

WO2015 / 114656 (Patent Document 9) describes that pregabalin is absorbed only in the upper digestive 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 a mucoadhesive additive in the direct compression formulation of Example 1 of Patent Document 9 Is described.
However, in Patent Document 9, there is no description that these preparations were actually produced, and there is no description that any test was performed.

WO2015 / 114655 (Patent Document 10) describes that pregabalin is absorbed only in the upper digestive tract.
Therefore, as a solution to the problem of producing a once-daily sustained-release preparation of pregabalin, Patent Document 10 discloses that a tablet is fragmented during the period of staying in the stomach by adding an additive having a low density. Proposal of a tablet that maintains the "physical unity" that keeps the original shape, and maintains a "hydraulic equilibrium" where the tablet floats in the gastric juice without sinking or passing through the pylorus . The direct compression formulation of Example 1 of Patent Document 10 describes various film-coated tablets containing pregabalin, microcrystalline cellulose, colloidal silicon dioxide, and ethyl cellulose.
However, in Patent Document 10, there is no description that these preparations were actually produced, and there is no description that any test was performed.

EP243055 (Patent Document 11) describes pregabalin or a pharmaceutically acceptable salt thereof, colloidal silicon dioxide, phosphoric acid as a solution to the problem of producing a stable preparation containing pregabalin, particularly a stable capsule. A solid preparation containing calcium hydride and corn starch is proposed. The capsule of Example 1 of Patent Document 11 is composed of these components, and describes that the elution and stability were good even after 6 months had passed under the condition of 40 ° C. and 75% relative humidity. Has been.
However, Patent Document 11 does not describe that a compressed solid preparation has been produced.

JP 2011-173881 (Patent Document 12) shows that dogs have stronger stomach muscle strength than humans, and that the length of the gastrointestinal tract is only about half that of humans. It is described that it is difficult to produce a releasable tablet.
Patent Document 12 uses a high molecular weight or high viscosity polymer sufficient to withstand the muscle strength of the dog's gastrointestinal tract as a solution, and the tablet settles at the bottom of the dog's stomach and rapidly hydrates. And the tablet which accumulates in the stomach for a long time is proposed.

  Claims 1 to 19 of Patent Document 12 are not an invention for specifying 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 a tablet containing pregabalin and polyethylene oxide WSR N-60K NF as a high molecular weight or high viscosity polymer.

And in FIG. 3 of patent document 12, the sustained release elution profile of the pregabalin tablet of Example 3 and Example 4 is described. Furthermore, FIG. 8 of Patent Document 12 shows the time course of plasma pregabalin concentration when the pregabalin tablets and release capsules of Example 3 and Example 4 were administered to a dog once.
However, Patent Document 12 does not describe any storage stability of the compressed solid preparation containing pregabalin.

  JP 2008-528494 (Patent Document 13) discloses (a) gabapentin or pregabalin coated with a pH-independent soluble polymer, and (b) pH-independent to form a sustained-release preparation of gabapentin or pregabalin. A composition comprising gabapentin or pregabalin coated with a soluble insoluble polymer and (c) gabapentin or pregabalin coated with a pH-dependent soluble polymer is proposed.

  JP 2013-535477 (Patent Document 14) describes that pregabalin is absorbed only in the upper intestine, and in order to prepare pregabalin as a sustained-release preparation, a matrix-forming agent, a swelling agent, and buoyancy By containing pregabalin in a matrix containing an agent or a precipitating agent, it is proposed not only to swell in the stomach, but also to float or settle in the stomach and stay in the stomach .

  JP-T-2010-524991 (Patent Document 15) discloses a pregabalin preparation that can be taken even by a lactose intolerant patient who is unable to decompose saccharides such as lactose due to lack of lactose-degrading enzyme or the like and becomes diarrhea when lactose is ingested. The present invention proposes a pregabalin-containing pharmaceutical composition that does not require an amino acid other than pregabalin for the stabilization of pregabalin and is essentially free of sugars such as lactose.

  In JP-T-2002-522375 (Patent Document 16), gabapentin and pregabalin tend to decompose in an aqueous solution to form a lactam body by intramolecular cyclization, and that gabapentin and pregabalin have bitterness. Have been described.

  Patent Document 16 discloses, as a solution, a polymer such as Eudragit E, aminoethyl methacrylate copolymer, ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, cellulose acetophthalate, etc., dissolved in an organic solvent such as acetone, ethanol, isopropanol. Thus, it has been proposed to prepare coated particles by spraying onto the particle surface of gabapentin or pregabalin, and to mix with other additives as necessary to make tablets.

  In WO2011 / 107812 (Patent Document 17), as a solution to the fact that GABA derivatives such as pregabalin tend to form a lactam body by intramolecular dehydration condensation of an amino group and a carboxyl group, a preparation of a GABA derivative of pregabalin is proposed. Disaccharides such as isomalt, isomalt, hydrogenated maltulose, lactitol, maltitol, isomaltitol, maltotriitol, maltotritriol, Toll (maltotetraitol), a hydrogenated polysaccharide obtained by hydrolysis of starch and subsequent hydrogenation, cellobiitol Cellotriitol, xylobiitol, xylobitriol, inulotriitol, cellulose, xylans, hydrolyzed fructans And the addition of hydrogenated polysaccharides obtained by subsequent hydrogenation.

However, Examples 1 to 5 of Patent Document 17 are examples of a mixed state (Example 1) and capsules (Examples 2 to 5), and actually lactam bodies in Examples 1 to 3. The only additives measured for the production of are lactose hydrate, talc, silicon dioxide (Aerosil 200P), isomalt (galen IQ960), partially pregelatinized starch, and corn starch.
There is no description in Patent Document 17 that a compressed solid preparation has been produced, and of course the storage stability in the state of a compressed solid preparation is not examined. Patent Document 17 does not examine the effects of D-sorbitol and D-mannitol on the storage stability of pregabalin compressed solid preparations.

Huda & Toshiniwa (Non-Patent Document 1) describes that pregabalin is a severely bitter drug.
Non-Patent Document 1 proposes to formulate a complex of weak cation exchange resin Kyron T134 and pregabalin in order to mask the bitter taste of pregabalin in pregabalin orally disintegrating tablets.
Non-Patent Document 1 does not describe any storage stability of pregabalin.

JP 2000-034227 A JP 2003-055211 A JP 2004-043506 A JP 2000-034226 A Special table 2009-514847 gazette Special table 2014-521639 gazette Special table 2003-504324 gazette WO2015 / 007890 pamphlet WO2015 / 114656 pamphlet WO2015 / 114655 pamphlet EP243055 JP 2011-173881 A JP 2008-528494 A Special table 2013-535477 gazette Special table 2010-524991 gazette Japanese translation of PCT publication No. 2002-522375 WO2011 / 107812 pamphlet

Huda & Toshinival, International Journal of Drug Delivery, Vol. 5, 2013, pp. 56-62, Formation test masked orodable table of preregalin.

  However, in any of the above-mentioned known documents, a cellulose additive other than hydroxypropyl-substituted cellulose is a lactam body over time in a solid preparation or a compressed solid preparation containing a γ-aminobutyric acid derivative such as gabapentin, pregabalin, baclofen, etc. It is not described that the formation of is impaired to impair storage stability. In addition, in any of the above-mentioned known documents, magnesium aluminate metasilicate, light silicic anhydride, hydrous silicon dioxide, titanium oxide, povidone, crospovidone, macrogol, sucrose fatty acid ester, stearic acid, gelatin starch partially alphalated It is described that starch and calcium dihydrogen phosphate impair the storage stability by accelerating the formation of lactam over time in solid preparations or compressed solid preparations containing γ-aminobutyric acid derivatives such as gabapentin, pregabalin, baclofen, etc. It has not been.

  Moreover, 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. by alpha starch, sucrose, gum arabic, gelatin, D-sorbitol It is not described that it is damaged.

  Further, in any of the above-mentioned known documents, the lactam body is produced over time in a compressed solid preparation containing a gamma-aminobutyric acid derivative such as gabapentin, pregabalin, baclofen, etc., not only by the compacted state but by the impact of tableting. It is not described that the formation of lactam body over time is still promoted even after crushing and releasing the compacted state after it is accelerated and storage stability is impaired.

  In addition, none of the above-mentioned documents describes that a lactam body is produced to the same extent even if the strength of tableting pressure is changed, and contains a cellulose-based additive other than hydroxypropyl-substituted cellulose. It is not described that, in a compressed solid preparation containing a γ-aminobutyric acid derivative, the production of lactam does not “accelerate” as “consolidation occurs”.

  In addition, in any of the above-mentioned known documents, sugar alcohols such as erythritol, mannitol, xylitol, isomalt, reduced starch syrup, reduced palatinose, reduced maltose water candy, maltitol, carboxymethyl groups such as hydroxypropyl starch, sodium starch glycolate, etc. Alternatively, starch modified with hydroxypropoxyl group improves storage stability by suppressing the formation of lactam over time in solid or compressed solid formulations containing γ-aminobutyric acid derivatives such as gabapentin, pregabalin, baclofen, etc. It is not described to do.

  In any of the above-mentioned known documents, the lactam body over time in a solid preparation or a compressed solid preparation containing a γ-aminobutyric acid derivative such as gabapentin, pregabalin, baclofen, etc. is stored in an aluminum laminate bag in a sealed manner. It is not described that the production is promoted and the storage stability is impaired. A solid preparation or a compressed solid preparation containing a γ-aminobutyric acid derivative is bonded with polyvinyl chloride, polypropylene, polyethylene, etc. and an aluminum sheet. It is not described that the production of lactam bodies over time is suppressed by storing in the resulting airtight blister pack.

  In any of the above-mentioned known documents, when a tableting granule for a compressed solid preparation containing a γ-aminobutyric acid derivative such as gabapentin, pregabalin, baclofen or the like is produced by stirring granulation, the compressed solid preparation When the hardness is lost over time, and when granules for tableting for compressed solid preparations containing γ-aminobutyric acid derivatives such as gabapentin, pregabalin and baclofen are produced by fluidized bed granulation, the compression It is not described that the hardness of the solid preparation is not impaired over time.

In addition, none of the above-mentioned known documents describes that the dissolution property of a solid preparation or a compressed solid preparation containing a γ-aminobutyric acid derivative such as gabapentin, pregabalin, or baclofen is not good.
In addition, none of the above-mentioned known documents describes that γ-aminobutyric acid derivatives such as gabapentin, pregabalin and baclofen have high adhesion and a high friction coefficient.

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

  In addition, in any of the above-mentioned known documents, the compression moldability of compressed solid preparations containing γ-aminobutyric acid derivatives such as gabapentin, pregabalin and baclofen is poor, and tableting troubles such as capping, sticking and lamination are likely to occur. Is not listed.

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

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

  The 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 and the like, which has good storage stability.

  Another object of the present invention is to provide a gabapentin that is hard to lose the hardness of a compressed solid preparation containing a γ-aminobutyric acid derivative such as gabapentin, pregabalin, baclofen, etc., and maintains a sufficient hardness throughout the period until the expiration date. It is to provide a compressed solid preparation containing a γ-aminobutyric acid derivative such as pregabalin and baclofen.

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

  The object of the present invention is to provide a solid preparation or a compressed solid preparation that disintegrates rapidly and has a good dissolution property 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. Is to provide.

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

The 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 and the like having a good content uniformity.
Another object of the present invention is to provide a solid preparation or a compressed solid preparation containing a γ-aminobutyric acid derivative that can simultaneously solve one, two, three, or four or more of the above-mentioned problems. It is.

As a result of earnest research to provide a solid pharmaceutical composition or a compressed solid pharmaceutical composition containing a γ-aminobutyric acid derivative such as pregabalin, gabapentin, baclofen, etc., the present inventor has found that the above problem exists for the first time. Recognized and repeated trial and error to solve this problem, and based on the insight, found out its solution and completed the present invention.
The present invention is specifically as follows.

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

[2]
containing at least one active ingredient selected from the group consisting of a compound having a γ-aminobutyric acid structure and a pharmaceutically acceptable salt thereof, crystalline cellulose, cellulose acetate, carmellose, carmellose calcium, carmellose sodium, carme Loose potassium, croscarmellose sodium, croscarmellose calcium, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hypromellose acetate succinate, cellulose acetate, cellulose acetate phthalate, hypromellose phthalate, carboxymethylethylcellulose, 1, 2, or selected from the group consisting of methylcellulose, ethylcellulose, microcrystalline cellulose, powdered cellulose, lactose / crystalline cellulose spherical granules, 3 or more or not containing a cellulose-based additive, or, with a formulation structure active ingredient is not in contact with the cellulose-based additive, solid preparation, or compressed solid preparation according to [1].

[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, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hypromellose acetate succinate, cellulose acetate, cellulose acetate phthalate, hypromellose phthalate, carboxymethylethylcellulose, methylcellulose, Selected from the group consisting of ethyl cellulose, microcrystalline cellulose, powdered cellulose, lactose / crystalline cellulose spherical granules The solid preparation according to [1] or [2], which does not contain 1, 2, or 3 or more cellulosic additives, or has a preparation structure in which the active ingredient does not contact the cellulosic additives Compressed solid formulation.

[4]
Magnesium metasilicate alumina, 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 One or more activities selected from the group consisting of compounds having no γ-aminobutyric acid structure and pharmaceutically acceptable salts thereof, which do not contain one, two, three or more additives selected from the group The solid preparation or compressed solid preparation according to any one of [1] to [3], wherein the ingredient has a preparation structure that does not come into contact with the additive.

[5]
The solid preparation or compressed solid preparation according to any one of [1] to [4], which does not contain one, two, or three 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], comprising 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 A solid preparation or a compressed solid preparation according to Item.

[8]
The solid preparation or compressed product according to any one of [1] to [7], comprising starch or a pharmaceutically acceptable salt thereof modified with a carboxymethyl group or a hydroxypropoxyl group, 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]
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, sorbitol, [1] to [9 ] The solid formulation or compressed solid formulation as described in any one of.

[11]
The solid preparation or compressed solid preparation according to any one of [1] to [10], which is immediate release.
[12]
The solid preparation or compressed solid preparation according to any one of [1] to [11], which is not sealed and 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 the compressed solid preparation according to any one of [1] to [13], which is airtightly packaged using blister packaging 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], having 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 2 to 400 mPa · s measured at 20 ° C.

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

[20]
The amount ratio of hydroxypropyl-substituted cellulose and starch modified with carboxymethyl group or hydroxypropoxyl group is 0.1-10 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]
A 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 an optional additive The solid preparation or compressed solid preparation according to any one of [1] to [20], comprising:

[22]
Fluidized bed 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 an optional additive The solid preparation or compressed solid preparation according to any one of [1] to [21], comprising a product.

[23]
[1] A method for producing a solid preparation or a compressed solid preparation according to any one of [22], comprising the following steps:
(1) A step of mixing one or more active ingredients selected from a compound having a γ-aminobutyric acid structure or a pharmaceutically acceptable salt thereof together with an optional additive,
(2) A step of granulating the mixture by spraying a hydroxypropyl-substituted cellulose solution;
(3) Optionally, mixing the granulated product with one or more optional additives or granulated products.

[24]
[1] A method for producing a solid preparation or a compressed solid preparation according to any one of [23], comprising the following steps.
(1) A step of mixing one or more active ingredients selected from a compound having a γ-aminobutyric acid structure or a pharmaceutically acceptable salt thereof together with an optional additive,
(2) A step of granulating the mixture by spraying a hydroxypropyl-substituted cellulose solution;
(3) Optionally mixing the granulation with one or more optional additives or granules containing starch modified with carboxymethyl groups.
[25]
It is a manufacturing method of the solid formulation or compressed solid formulation as described in any one of [1]-[24], Comprising: The method including the following processes.
(1) One or more active ingredients selected from a compound having a γ-aminobutyric acid structure or a pharmaceutically acceptable salt thereof are magnesium aluminate metasilicate, light anhydrous silicic acid, hydrous silicon dioxide, titanium oxide, 1 selected from the group consisting of povidone, crospovidone, macrogol, sucrose fatty acid ester, stearic acid, gelatin, starch, partially pregelatinized starch, calcium dihydrogen phosphate, and cellulosic additives other than hydroxypropyl substituted cellulose Mixing with any additive that does not contain 2, or 3 or more additives,
(2) A step of granulating the mixture by spraying a hydroxypropyl-substituted cellulose solution;
(3) Optionally, mixing the granulated product with one or more optional additives or granulated products.
[26]
[23] A solid preparation or a compressed solid preparation produced by the production method according to any one of [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, production of a lactam body over time caused by the impact of tableting There is almost no. The solid preparation or the compressed solid preparation of the present invention can maintain the production of lactam body 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 through storage. In addition, the compressed solid preparation of the present invention can maintain the production of lactam body at 1.0% or less even after it is divided or crushed to make it into 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. There is little production of typical lactam bodies. According to the packaging form of the solid preparation or the compressed solid preparation of the present invention, it is stable during the period until the expiration date of 3 years, and the production of the lactam body can be kept at 1.0% or less.

The compressed solid preparation of the present invention hardly causes a decrease in hardness over 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 the compressed solid preparation of the present invention does not cause a decrease in dissolution properties over time. Sufficient dissolution can be maintained throughout the period from manufacture to the expiration date of 3 years. In addition, the compressed solid preparation of the present invention rapidly disintegrates.

The γ-aminobutyric acid derivative has high adhesion, a large friction coefficient, a bulky property, and despite its 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, and does not easily cause tableting troubles such as capping, sticking, and lamination, and can be stably manufactured with high 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 capsules having the same active ingredient content, and is difficult to adhere to the throat and is easy to drink.
The compressed solid preparation of the present invention can be film-coated and 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 properties.
When the solid preparation or compressed solid preparation of the present invention is an orally disintegrating tablet, it has good disintegration property in the oral cavity and tactile sensation (mouth feel) in the oral cavity.
The solid preparation or the compressed solid preparation of the present invention has a refreshing feeling.
The solid preparation or the compressed solid preparation of the present invention can simultaneously exhibit one, two, three, or four or more of the above effects.

It is a figure which shows the example of the manufacturing flow of this invention. (Example 14) (Example 15) which is a figure of the elution rate with respect to the purified water of the trial tablet which carried out the dry coating of the main ingredient granule with the calcium stearate. It is each scanning electron micrograph after having performed the coating (1) by Eudragit E after performing dry coating by calcium stearate about trial manufacture tablet T-1, and performing coating (2) by D-mannitol (Implementation) Example 17). The result of measuring the production of lactam body over time is shown in prototype tablet S-1 (“prototype 75 mg tablet” in the figure) sealed in an aluminum bag and stored under accelerated conditions of 40 ° C. and 75% relative humidity. (Example 18) which is a figure. In order to confirm the storage stability of the trial tablet S-1 over time, the trial tablet S-1 was 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) ”At the start”), 0.5 month after storage (“4075-0.5M” in the figure), and one month after storage (“4075-1M” in the figure), the elution rate with respect to purified water was measured. It is a figure which shows a result (Example 19).

  In the present invention, the solid preparation refers to a solid preparation such as a powder, a granule, a fine granule, a dry syrup, a capsule filled with granules, a wet tablet, and a heat-melt extruded product in addition to a compressed solid preparation. Say. Solid formulation is a superordinate concept of compressed solid formulation.

  In the present invention, the formulation structure in which the active ingredient is not in contact with the additive refers to a physical or chemical formulation structure in which the active ingredient and the additive are not in contact with each other to cause a chemical change. The formulation structure in which the active ingredient is not in contact with the additive contains, for example, a granule or the like containing the active ingredient and an additive in a formulation containing a plurality of granules or granules (hereinafter referred to as “granules etc.”). Either or both of the granules and the like are coated with a coating agent, so that the active ingredient and the additive are in contact with each other and do not cause a chemical change, thereby forming a physical or chemical formulation structure. Examples of preparations containing a plurality of granules, etc. include tablets containing a plurality of granules, capsules containing a plurality of granules, powders containing a plurality of granules, granules containing a plurality of granules, etc. And dry syrup containing a plurality of granules and the like. In addition, for example, a pharmaceutical structure in which an active ingredient is present in either the inner core or outer shell of a dry-coated tablet and an additive is present in the other is also a pharmaceutical structure in which the active ingredient is not in contact with the additive. Similarly, a pharmaceutical structure in which an active ingredient is present in one of the bilayer tablets and an additive is present in the other is also a pharmaceutical structure in which the active ingredient is not in 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. is there. The formulation structure in which the active ingredient is not in contact with the cellulosic additive is, for example, in addition to the physical or chemical formulation structure in which the active ingredient is in contact with the cellulosic additive and does not 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 by not containing the product. Similarly, the active ingredient is magnesium aluminate metasilicate, light anhydrous silicic acid, hydrous silicon dioxide, titanium oxide, povidone, crospovidone, macrogol, sucrose fatty acid ester, stearic acid, gelatin, starch, partially pregelatinized starch, Formulation structures that do not come into contact with additives selected from the group consisting of calcium dihydrogen phosphate include physical or chemical formulation structures that do not cause chemical changes when these additives come into contact with the active ingredient. Furthermore, there is a structure in which these additives and active ingredients do not come into contact with each other by not containing these additives.

The solid preparation or compressed solid preparation of the present invention is a solid preparation or compressed solid preparation containing a γ-aminobutyric acid derivative or a pharmaceutically acceptable salt thereof and containing no cellulose-based additive other than hydroxypropyl-substituted cellulose. is there.
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 desirably a γ-aminobutyric acid derivative in which the 3-position of γ-aminobutyric acid is substituted, and pregabalin, gabapentin, or baclofen is more desirable.

  The γ-aminobutyric acid derivative has a common characteristic that both the amino group and carboxyl group in the molecule are likely to form a lactam body by dehydration condensation due to its structural characteristics. There is 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. Is.

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 represented by the following formula VII are connected.

Formula VII Cellulose skeleton

Hydroxypropyl cellulose (hereinafter also referred to as “HPC”) is cellulose in which a part of alcohol of the glucose residue of cellulose is substituted with a hydroxypropoxyl group (—OC ₃ H ₆ OH), and in dry weight Of which 53.4% to 77.5% is a hydroxypropoxyl group. HPC is obtained by etherifying the hydroxyl group 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 used as a binder for tablets and granules.

For example, various grades of HPC 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 with a 50% particle diameter (D50) of 85 to 185 μm and an ultrafine particle type with a 50% particle diameter (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 with a 50% particle size (D50) of 85 to 185 μm and a fine particle type with 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. HPC-L is commercially available in two types: a normal particle type with a 50% particle size (D50) of 85 to 185 μm and a fine particle type with a 50% particle size (D50) of 80 to 110 μm.

  HPC-M is a grade for granulation / binding and sustained-release preparations. 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 with a 50% particle size (D50) of 85 to 185 μm and a fine particle type with a 50% particle size (D50) of 80 to 110 μm.

  HPC-H is a grade for sustained-release preparations. 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 diameter (D50) of 85 to 185 μm and an ultrafine particle type having a 50% particle diameter (D50) of 20 μm.

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

Structure of Formula VIII Hydroxypropyl Cellulose

Low-substituted hydroxypropylcellulose (hereinafter also referred to as “L-HPC”) is a cellulose in which a part of the alcohol of the glucose residue of cellulose is substituted with a hydroxypropoxyl group (—OC ₃ H ₆ OH). Thus, it is a cellulose containing a hydroxypropoxyl group (—OC ₃ H ₆ OH) of 5.0% to 16.0% by dry weight. L-HPC contains from 0.1 to 0.4 hydroxypropyl groups per unit of glucose of cellulose. HPC and L-HPC are different in substitution rate with a hydroxypropoxyl group, but are otherwise common. As a difference in properties between HPC and L-HPC, HPC is water-soluble, whereas L-HPC is insoluble in water, but absorbs water and swells. Utilizing this property, L-HPC can be used as a disintegrant for oral solid pharmaceutical preparations. Moreover, since L-HPC is fibrous, it has the effect | action which raises the hardness of a tablet, and since the kneaded material with water has bondability, it can be used also as a binder.

In the present specification, cellulose substituted with a hydroxypropoxyl group (—OC ₃ H ₆ OH) is referred to as hydroxypropyl-substituted cellulose (hereinafter also referred to as “HP-substituted cellulose”) regardless of the ratio of substitution. Call. In the present specification, HPC and L-HPC are distinguished from each other and treated as different things, and the term hydroxypropyl-substituted cellulose (or “HP-substituted cellulose”) is used as a general concept including both HPC and L-HPC.
The dry weight% of 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%, Preferably it is 53.0%-81.0%, More preferably, it is 53.4%-77.5%, Most preferably, it is 50.0%-75.0%.

  Cellulose-based additives other than hydroxypropyl-substituted cellulose promote the production of lactam bodies over time in a solid preparation or a compressed solid preparation containing a compound having a γ-aminobutyric acid structure, and impair its storage stability. Therefore, in the solid preparation or compressed solid preparation of the present invention, the compound having a γ-aminobutyric acid structure is selected from 1, 2, or 3 or more cellulosic additives selected from cellulosic additives other than hydroxypropyl-substituted cellulose. It is characterized by not touching.

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

  The solid preparation or compressed solid preparation of the present invention preferably contains no, or no, one, two, or three or more cellulosic additives selected from cellulosic additives other than hydroxypropyl-substituted cellulose. Further, when the solid preparation or compressed solid preparation of the present invention contains a cellulose-based additive other than hydroxypropyl-substituted cellulose, a compound having a γ-aminobutyric acid structure and a cellulose-based additive other than hydroxypropyl-substituted cellulose; However, it is preferable that the structure does not contact. Specific examples of structures in which a compound having a γ-aminobutyric acid structure and a cellulose-based additive other than hydroxypropyl-substituted cellulose do not 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, specific examples of structures in which a compound having a γ-aminobutyric acid structure and a cellulose-based additive other than hydroxypropyl-substituted cellulose are not in contact include cellulose-based additives other than hydroxypropyl-substituted cellulose or celluloses 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 cellulose-based additive other than hydroxypropyl-substituted cellulose or a cellulose-based additive other than hydroxypropyl-substituted cellulose It is further preferable to coat. As a specific example of a structure in which a compound having a γ-aminobutyric acid structure and a cellulose-based additive other than hydroxypropyl-substituted cellulose are not in contact with each other, a compound having a γ-aminobutyric acid structure is contained in the inner core, and hydroxypropyl-substituted cellulose Nucleated tablets containing other cellulose-based additives in the outer core, or those containing a compound having a γ-aminobutyric acid structure in the outer core and containing cellulose-based additives other than hydroxypropyl-substituted cellulose in the inner core Tablets are preferred.

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

  Therefore, the solid preparation or compressed solid preparation of the present invention is crystalline cellulose, cellulose acetate, carmellose, carmellose calcium, carmellose sodium, carmellose potassium, croscarmellose sodium, croscarmellose calcium, hydroxyethyl cellulose, hydroxyethyl methylcellulose, Group consisting of hydroxypropylmethylcellulose, hypromellose acetate succinate, cellulose acetate, cellulose acetate phthalate, hypromellose phthalate, carboxymethylethylcellulose, methylcellulose, ethylcellulose, microcrystalline cellulose, powdered cellulose, lactose / crystalline cellulose spherical granules 1, 2, or 3 or more cellulosic additives selected from the group having a γ-aminobutyric acid structure Characterized in that it does not contact the object.

  Therefore, the solid preparation or compressed solid preparation of the present invention is crystalline cellulose, cellulose acetate, carmellose, carmellose calcium, carmellose sodium, carmellose potassium, croscarmellose sodium, croscarmellose calcium, hydroxyethyl cellulose, hydroxyethyl methylcellulose, Group consisting of hydroxypropylmethylcellulose, hypromellose acetate succinate, cellulose acetate, cellulose acetate phthalate, hypromellose phthalate, carboxymethylethylcellulose, methylcellulose, ethylcellulose, microcrystalline cellulose, powdered cellulose, lactose / crystalline cellulose spherical granules It is characterized by not containing 1, 2, or 3 or more cellulosic additives.

  The solid preparation or compressed solid preparation of the present invention comprises crystalline cellulose, cellulose acetate, carmellose, carmellose calcium, carmellose sodium, carmellose potassium, croscarmellose sodium, croscarmellose calcium, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl Select from the group consisting of methylcellulose, hypromellose acetate succinate, cellulose acetate, cellulose acetate phthalate, hypromellose phthalate, carboxymethylethylcellulose, methylcellulose, ethylcellulose, microcrystalline cellulose, powdered cellulose, lactose / crystalline cellulose spherical granules It is particularly preferred not to contain any of the cellulosic additives that are made.

  Most preferably, the solid preparation or compressed solid preparation of the present invention is characterized in that it contains no cellulosic additives other than hydroxypropyl-substituted cellulose.

  Magnesium aluminate metasilicate, 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 production of lactam bodies over time is promoted, and the storage stability is impaired. Therefore, the solid preparation or compressed solid preparation of the present invention is characterized by not containing one, two, or three or more additives selected from these additives.

  In addition, magnesium metasilicate aluminate is marketed with the brand name of Neusilin (trademark, Fuji Chemical Industry Co., Ltd.).

Simply adding a small amount (eg 1.7%) of pregelatinized starch, sucrose, gum arabic, and gelatin to a compressed solid preparation containing a γ-aminobutyric acid derivative, the compressed solid preparation can be obtained at 7% at 40 ° C. and 75% relative humidity. The tablet hardness after storage for 0 days becomes zero.
Accordingly, the compressed solid preparation of the present invention is characterized by not containing 1.7% or more of one, two, or three or more additives selected from the group consisting of pregelatinized starch, sucrose, gum arabic, and gelatin. To do. More preferably, the compressed solid preparation of the present invention is characterized by not containing any 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 not containing any 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 preferably used as a granulating liquid for the main drug granules. The granulating liquid containing hydroxypropyl-substituted cellulose is desirably used as an aqueous solution, an ethanol solution, or a mixed solvent solution thereof.

  The gamma-aminobutyric acid derivative or pharmaceutically acceptable salt thereof, which is an active ingredient of the solid preparation or compressed solid preparation of the present invention, is desirably wet granulated while spraying a hydroxypropyl-substituted cellulose solution. Here, the hydroxypropyl-substituted cellulose is preferably HPC or L-HPC, and more preferably HPC.

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

  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. Moreover, the solid formulation or compressed solid formulation of the present invention can maintain good dissolution properties by adding L-HPC. However, if the amount of hydroxypropyl-substituted cellulose is too large, the amount of lactam increases with time. Therefore, the amount of hydroxypropyl-substituted cellulose in the solid preparation or compressed solid preparation of the present invention is desirably 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), more preferably 1. 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 mass% (about 2 to about 4 mass%), Most preferably, it is 4.2-4.6 mass%.
Here, as the hydroxypropyl-substituted cellulose, HPC is more preferable, and the content of HPC per one 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%), more preferably 1.5 to 5.9 mass% (about 2 to about 6 mass%). More preferably, it is 1.9 to 4.4% by mass (about 2 to about 4% by mass), and most preferably 4.2 to 4.6% by mass.

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

  The solid preparation or the compressed solid preparation of the present invention contains starch modified with a carboxymethyl group or a hydroxypropoxyl group, thereby suppressing the formation of lactam bodies over time. The preferred modified starch for inhibiting the formation of lactam over time is hydroxypropyl starch or starch modified with carboxymethyl group, and starch modified with carboxymethyl group is sodium carboxymethyl starch. A salt (hereinafter sometimes referred to as “CMS • Na”) is preferred. The sodium salt of carboxymethyl starch is also known as sodium starch glycolate and is sold under the trade name Primogel ™, for example.

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

  Examples of preferred 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 a more preferable sugar alcohol used in the solid preparation or compressed solid preparation of the present invention, sorbitol, isomalt, D-mannitol, reduced maltose starch syrup, and maltitol are more preferred, and reduced maltose starch syrup or D-mannitol is particularly preferred.

  Here, isomalt means α-D-glucopyranose-1,6-sorbitol (a disaccharide in which glucose and sorbitol are combined) and α-D-glucopyranoside-1,6-mannitol (a disaccharide in which glucose and mannitol are combined). ) Is an equimolar mixture mixed in a 1 to 1 ratio. Isomalt includes sugar coating type (for example, BALEO-Palatinit's galen IQ980), direct hitting type (for example, the company's galen IQ720), troche type (for example, the company's galen IQ990), capsule filling type (for example, the company's galen IQ960), There are various types such as a wet granulation type (for example, the company's galen IQ800), 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 hydroxypropoxyl group, and a sugar alcohol. By this, the production | generation of the lactam body with time after compression can be suppressed. 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 carboxymethyl group or hydroxypropoxyl group and sugar alcohol may be added to the main drug granule, You may add in a post-additive. When added to the main drug granule, wet granulation is preferred with the binding gamma-aminobutyric acid derivative of the main drug granule or a pharmaceutically acceptable salt thereof, and fluidized bed granulation is more preferred. When added in the post-additive, it can be used in the form of a powder and mixed 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 as desired. Here, the optional additive that may be contained is not particularly limited as long as it is an additive other than the unfavorable additives listed below. Cellulose additives other than hydroxypropyl-substituted cellulose, magnesium aluminate metasilicate, light anhydrous silicic acid, hydrous silicon dioxide, titanium oxide, povidone, crospovidone, macrogol, sucrose fatty acid ester, stearic acid, gelatin, starch , Partly pregelatinized starch, calcium dihydrogen phosphate, sucrose, or additives other than gum arabic are not particularly limited, excipients, disintegrants, binders, lubricants, colorants, pH adjusters, Surfactants, stabilizers, flavoring agents, fragrances, fluidizing agents, coating bases, coating additives and the like can be mentioned. These additives are used in conventional amounts in the pharmaceutical field unless otherwise specified.

  Examples of excipients include lactose, mannitol, xylitol, erythritol, sorbitol, maltitol, fructose, lactose, dextrose, dextrin / dextrate, maltodextrin and carbohydrates for compression; calcium citrate, calcium phosphate, calcium carbonate And inorganic salts such as dicalcium phosphate and calcium sulfate.

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

  A preferred example of the binder is hydroxypropylcellulose.

  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.

  Suitable examples of colorants include carotenoids, iron oxide, chlorophyll, and colorants. Examples of coloring agents include food dye red Nos. 2 and 3, food dye yellow Nos. 4 and 5, food dye green No. 3, food dye blue Nos. 1 and 2, and these Examples of the food dye include aluminum lake, iron sesquioxide, and yellow iron sesquioxide.

  Suitable examples of the pH adjuster 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 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 corrigent 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 fragrances include menthol, mint oil, orange oil and lemon oil.

  Preferable examples of the fluidizing agent include talc.

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

  As the sugar coating base, for example, a sugar alcohol such as erythritol is used, and one or more kinds 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; polysaccharides such as pullulan.

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

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

  Preferable examples of the coating additive include a fluidizing agent such as talc and / or a colorant such as iron sesquioxide and yellow iron sesquioxide; a plasticizer such as propylene glycol, triethyl citrate, castor oil, and polysorbates; Examples thereof include organic acids such as citric acid, tartaric acid, malic acid and ascorbic acid.

  Two or more of the above-mentioned additives may be mixed and used at an appropriate ratio.

  When the solid preparation or compressed solid preparation of the present invention contains starch modified with carboxymethyl group or hydroxypropoxyl group, by adding more starch modified with carboxymethyl group or hydroxypropoxyl group The production of lactam bodies can be suppressed, and good elution can be obtained. On the other hand, the tendency for hardness to fall over time is recognized by adding more starch modified with a carboxymethyl group or a hydroxypropoxyl group.

  Therefore, when the solid preparation or compressed solid preparation of the present invention contains starch modified with carboxymethyl group or hydroxypropoxyl group, the amount of starch modified with carboxymethyl group or hydroxypropoxyl group is determined as follows. It is preferable to be within the range. More preferably, the amount of starch modified with carboxymethyl groups is preferably within a predetermined range, more preferably the amount of carboxymethyl starch is more preferably within a predetermined range, even more preferably The amount of CMS · Na is particularly preferably within a predetermined range.

  The amount of starch modified with a carboxymethyl group or hydroxypropoxyl group per solid preparation or compressed solid preparation of the present invention is preferably 2.2% to 4.6% by mass, more preferably 3%. It is 0.3 mass%-4.5 mass%, More preferably, it is 4.2 mass%-4.6 mass%.

By adding more HPC in the solid preparation or 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 lactam over time by tableting, there is little HPC.
When the solid preparation or compressed solid preparation of the present invention contains hydroxypropyl-substituted cellulose and starch modified with carboxymethyl group or hydroxypropoxyl group, hydroxypropyl-substituted cellulose and carboxymethyl group or hydroxypropoxyl It is desirable that the weight ratio of starch modified with groups is within a predetermined range.

  When the HP-substituted cellulose and the starch modified with a carboxymethyl group or a hydroxypropoxyl group are included in the solid preparation or the compressed solid preparation of the present invention, the hydroxypropyl-substituted cellulose and the carboxymethyl group or hydroxypropoxyl group The amount ratio of starch modified with is preferably starch modified with 0.1 to 10 parts by weight of carboxymethyl group or hydroxypropoxyl group, respectively, with respect to 1 part by weight of hydroxypropyl-substituted cellulose, More preferably, the starch is modified with 0.25 to 4.0 parts by mass of carboxymethyl group or hydroxypropoxyl group, and more preferably, 0.25 to 2.3 parts by mass of carboxymethyl group or hydroxypropoxyl. Starch modified with a group, even more preferred Or starch modified with 0.75 to 2.3 parts by mass of carboxymethyl group or hydroxypropoxyl group, and still more preferably 0.25 to 1.3 parts by mass of carboxymethyl group or hydroxypropoxyl group And most preferably starch modified with 0.75 to 1.3 parts by weight of carboxymethyl group or hydroxypropoxyl group.

  Here, as the hydroxypropyl-substituted cellulose, HPC is more preferable. When the starch modified with carboxymethyl group or hydroxypropoxyl group is contained in the solid preparation or compressed solid preparation of the present invention, HPC and carboxymethyl group or The amount ratio of starch modified with hydroxypropoxyl group is preferably starch modified with 0.1 to 10 parts by mass of carboxymethyl group or hydroxypropoxyl group, respectively, with respect to 1 part by mass of HPC. More preferably, the starch is modified with 0.25 to 4.0 parts by mass of carboxymethyl group or hydroxypropoxyl group, and more preferably 0.25 to 2.3 parts by mass of carboxymethyl group or hydroxypropoxy group. Starch modified with an alkyl group, more preferably 0 75-2.3 parts by weight starch modified with carboxymethyl group or hydroxypropoxyl group, more preferably modified with 0.25-1.3 parts by weight carboxymethyl group or hydroxypropoxyl group Starch, most preferably starch modified with 0.75 to 1.3 parts by weight of carboxymethyl group or hydroxypropoxyl group.

  Here, the starch modified with a carboxymethyl group or a hydroxypropoxyl group is preferably a starch modified with a carboxymethyl group, more preferably CMS or CMS • Na, and particularly preferably CMS • Na. 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, respectively, with respect to 1 part by mass of HPC. 0.1 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, and still more preferably 0.25 to 2.3 parts by mass. CMS or CMS · Na, more preferably 0.75 to 2.3 parts by mass of CMS or CMS · Na, still more preferably 0.25 to 1.3 parts by mass of CMS or CMS · Na. Yes, most preferably 0.75 to 1.3 parts by mass of CMS or CMS · Na.

  The solid preparation or compressed solid preparation of the present invention preferably contains both starch modified with a carboxymethyl group or a hydroxypropoxyl group, and a sugar alcohol.

  Pregabalin is immediately absorbed and acts quickly, and is rapidly excreted without being metabolized. Therefore, the solid preparation or compressed solid preparation of the present invention may be an immediate release solid preparation or compressed solid preparation. Desirably, an immediate release tablet is more desirable. Here, the immediate release solid preparation or the compressed solid preparation means 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 Japanese Pharmacopoeia test solution used for confirming the dissolution property of the present invention includes a dissolution test first solution (pH 1.2), an acetic acid / sodium acetate buffer solution (pH 4.0), and a dissolution test second solution (pH 6.8). ) And water dissolution test solutions. 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, granules or powders before compression may be used as they are instead of the compressed solid preparation of the present invention.
The solid preparation or compressed solid preparation of the present invention is stable over the period until the expiration date, and the amount of lactam generated within the expiration date is 1.0% or less, preferably 0.5% or less.
The expiration date of the solid preparation or compressed solid preparation 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 hermetically packaged using a hermetically sealed material (for example, an aluminum laminated bag) using a gas-impermeable material, but is made of polyvinyl chloride, polypropylene, polyethylene, etc. Formation of lactam bodies can be suppressed by airtight packaging in a container using a gas permeable material. For example, the solid preparation or the compressed solid preparation of the present invention can be kept more stable by hermetically packaging a material such as polyvinyl chloride, polypropylene, polyethylene, etc. and PTP packaging (blister packaging) in which an aluminum sheet is crimped. it can. In addition, polyvinylidene chloride can also be used as a packaging material for hermetic packaging. In this case, since it is less gas permeable than polyvinyl chloride, polypropylene, and polyethylene, the storage stability of the γ-aminobutyric acid derivative is maintained. Therefore, it is more disadvantageous than polyvinyl chloride, polypropylene, and polyethylene, but 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 hermetic packaging means a packaging in which solid foreign matters are not mixed in a normal handling, transportation or storage state. Paper bags, boxes, etc. are sealed packaging.
In the present invention, the airtight package means a package in which solid or liquid foreign matters do not enter but gas cannot pass through in normal handling, transportation or storage. Most plastic packaging belongs to airtight packaging.

In the present invention, the sealed packaging means a package that does not allow gas to enter during normal handling, transportation or storage. Ampoules, vials, and aluminum laminated bags are hermetically sealed packages.
In the present invention, hermetic packaging, hermetic packaging, and hermetic packaging are concepts that do not overlap each other, and hermetic packaging and hermetic packaging are excluded from hermetic packaging.

  The hermetic packaging used in the present invention is preferably an airtight packaging that is not gas permeable. For example, gas permeable materials such as cyclic olefin polymers and cyclic olefin copolymers are not preferred as the packaging material of the present invention. The material for hermetic packaging used for packaging of the solid preparation or 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, even more preferably 35 N or more, and most preferably 40 N or more during the expiration date.

The preferable manufacturing method of the solid formulation or compressed solid formulation 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 optional additives,
(2) A step of granulating the mixture by spraying a hydroxypropyl-substituted cellulose solution;
(3) optionally mixing the granulated product with starch modified with at least carboxymethyl groups,
(4) A step of optionally compressing the mixture obtained in (3) to produce a solid preparation.

  Here, the optional additives in the step (1) are cellulose-based additives (however, hydroxypropyl-substituted cellulose may be used), magnesium aluminate metasilicate, light anhydrous silicic acid, hydrous silicon dioxide, titanium oxide. , Crospovidone, povidone, gum arabic, macrogol, sucrose fatty acid ester, stearic acid, gelatin, calcium dihydrogen phosphate, starch, pregelatinized starch, partially pregelatinized starch, sucrose It is preferred not to use additives. The optional additive in step (1) is preferably a sugar alcohol. Examples of particularly preferred sugar alcohols include mannitol, sorbitol, erythritol, xylitol, oligosaccharide alcohol, reduced starch syrup, reduced palatinose, reduced maltose syrup and One or more sugar alcohols selected from the group consisting of Tol, more preferably one or more sugar alcohols selected from the group consisting of mannitol, oligosaccharide alcohol, reduced maltose starch syrup and maltitol More preferably, it is reduced maltose starch syrup. In addition, in order to prevent nerve damage due to vitamin B deficiency, vitamin Bs, particularly vitamin B12, may be included as optional additives, but even when vitamin B is used in combination, nerve damage due to vitamin B deficiency Therefore, it can also be set as the formulation which does not add vitamin B class (especially vitamin B12).

  Moreover, the step of spraying and granulating the hydroxypropyl-substituted cellulose solution in the step (2) is preferably fluidized bed granulation. By spraying a hydroxypropyl-substituted cellulose solution onto its acceptable salt, the physical properties of the drug substance can be canceled out and good tableting properties (moldability, adhesion) can be ensured. Therefore, the step (2) is preferably “a step of spraying the mixture with a hydroxypropyl-substituted cellulose solution to perform fluidized bed granulation”.

  In addition, the hydroxypropyl-substituted cellulose in the step (2) is more preferably hydroxypropylcellulose from the viewpoint of suppressing the formation of lactam bodies 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 hydroxypropylcellulose solution to perform fluidized bed granulation”.

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

In all of the following examples, the drug substance of pregabalin has an impurity of 0.1%, D10 (particle size of 10% cumulative) is 2.2 μm, D50 (also 50% particle size) is 13.1 μm, D90 (also A free drug substance having a particle size of 90. 4% (89.4 μm) was used.
The angle of repose of pregabalin drug substance was 50 ° to 55 °, and it was observed that the coefficient of friction was large.

It was also found that pregabalin drug substance is attached in a large amount to the polyethylene bag packaging the drug substance and has high adhesion.
The pregabalin drug substance was bulky because it had a loose bulk density of 0.2 g / mL.

Formulation change test ;
A pre-gabalin drug substance and additive composition change test was conducted.
After pregabalin drug substance and additive were mixed at a mass ratio of 1: 1, stored at 30 ° C 75% relative humidity, 40 ° C 75% relative humidity, 60 ° C without humidity control, at the start of storage, and The mass ratio (%) of the mass of the lactam body after storage for 2 weeks to the mass of the initial pregabalin drug substance was measured (Table 1). The measurement was performed in 1 or 2 series.

  The lactam body was quantified by high performance liquid chromatography 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. The mobile phase is a mixed solvent (*) of mobile phase A and mobile phase B, detected at an OD of 210 nm at a flow rate of 1 mL / min, confirmed the relative retention time with a pregabalin lactam standard, and pregabalin as an internal standard. The peak with a relative retention time of 2.7 when used as a substance was identified as a lactam body. The quantification of the lactam body was calculated by the area under the peak with a relative retention time of 2.7, based on the area under the peak of 0.15 g pregabalin. Hereinafter, the lactam form was quantified by the same method in all tests.

* Mixed solvent:
Mobile phase A: A solution obtained by dissolving 5.28 g of diammonium hydrogen phosphate in 1000 mL of water, adjusting the pH to 6.5 by adding phosphoric acid, and adding 200 mL of methanol to 800 mL of this solution.
Mobile phase B: acetonitrile / methanol mixture (9: 1)
Mixing ratio: 0 to 10 minutes (A: B = 98: 2), 10 to 21 minutes (linear concentration gradient changing from A: B = 98: 2 to 80:20), 21 to 45 minutes (A: B = 80:20)

  Additives that were the subject of the compounding change test were lactose hydrate [Pharmacatase (trademark) 200M, DFE Pharma Co., Ltd.], corn starch (sun eclipse cornstarch (trademark), Nippon Shokuhin Kako Co., Ltd.), D-mannitol (Mannit) P (trademark), Mitsubishi Corporation Foodtech Co., Ltd.], crystalline cellulose [Theolas PH-101 (trademark), Asahi Kasei Co., Ltd.], crystalline cellulose [Theolas KG-802 (trademark), Asahi Kasei Corporation], isomalt [galen IQ800 (trademark) ), BENEO-Palatinit GmbH], crospovidone [Kollidon CL-F (trademark), BASF Japan Ltd.], crospovidone (Polyplasmone Ultra-10 (trademark), Ashland Inc. ], Light anhydrous silicic acid [Adsolider 101 (trademark), Freund Sangyo Co., Ltd.], hydroxypropylcellulose [HPC-L (trademark) normal particle type, Nippon Soda Co., Ltd.], povidone [K30, BASF Japan Ltd.], stearin Magnesium oxide [Taihei Chemical Industry Co., Ltd.], calcium stearate [Taihei Chemical Industry Co., Ltd.], sucrose fatty acid ester [San-Eigen FFI Co., Ltd.], talc [Lisplan (TM), Saneigen F.F. Co., Ltd.], hypromellose [TC-5R, Shin-Etsu Chemical Co., Ltd.], Macrogol 6000 [Sanyo Chemical Industries Co., Ltd.], titanium oxide [A-HR, Freund Sangyo Co., Ltd.], hydrous silicon dioxide type B [Freund Sangyo Co., Ltd.] Company] was used.

* Isomalt is a mixture in which 6-O-α-D-glucopyranosyl-D-sorbitol and 1-O-α-D-glucopyranosyl-D-mannitol dihydrate are mixed at a ratio of 1: 1.

  As can be seen from Table 1, it was confirmed that the powder of pregabalin drug substance was mixed with either hydrous silicon dioxide or light anhydrous silicic acid and placed in a dry condition at 60 ° C. for 2 weeks to form a very significant amount of lactam. Regarding titanium oxide, crystalline cellulose, hypromellose, and crospovidone, it was confirmed that a significant amount of lactam was formed by mixing any of these and pregabalin drug substance under dry conditions at 60 ° C. for 2 weeks. About crystalline cellulose, the production | generation of a fixed amount of lactam body was confirmed similarly after each storage condition of 30 degreeC75% relative humidity and 40 degreeC75% relative humidity.

  For povidone, macrogol 6000, and sucrose fatty acid ester, when any of these and pregabalin drug substance were mixed and placed in a dry condition at 60 ° C. for 2 weeks, a moderate amount of lactam was formed (after 2 weeks). At that 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, mix any of these with pregabalin drug substance and place in 60 ° C dry conditions for 2 weeks. The formation of lactam bodies was confirmed (at 2 weeks later, the talc group was 0.215%, the corn starch group was 0.222%, and the isomalt group was 0.234%).

  On the other hand, even when the powder of pregabalin drug substance alone was placed under dry conditions at 60 ° C. for 2 weeks, almost no lactam body was produced. Regarding magnesium stearate, calcium stearate, hydroxypropyl cellulose, lactose hydrate, D-mannitol, even if any of these and pregabalin drug substance are mixed and placed in dry condition at 60 ° C for 2 weeks, the lactam body is almost It was not produced or the amount of lactam produced was negligible.

  In the production of a significant amount of lactam by blending cellulose-based additives such as crystalline cellulose and hypromellose with pregabalin, only a very small amount of lactam is produced in hydroxypropyl cellulose. It was amazing.

Mixing change test (when kneaded) ;
A pre-gabalin drug substance and additive composition change test was conducted.
The powder of each additive was added to 75 parts by mass of the pregabalin drug substance so as to have a mass ratio of 1.125 parts by mass of the additive, and kneaded with water in a mortar. Sample No. FHB-10-1) was dried at 60 ° C. for 1 hour, and the whole amount was sieved with No. 30 mesh as a sample (sample name: W4 to W13). The fluidity of these specimens is confirmed by visual and repose angle measurement methods, and evaluated in five levels: very good (◎), good (○), slightly bad (△ +), bad (△), and very bad (×). did. The same granule was stored under the condition of 60 ° C. without humidity control, and the mass ratio (%) of the mass of the lactam body at the start of storage and after storage for 3 days to the mass of the initial pregabalin drug substance was measured. (Table 2). Measurement was performed in a single series.

In addition, pregabalin drug substance (sample name: W1), sample obtained by kneading only pregabalin drug substance with purified water (sample name: W2), and sample obtained by kneading only pregabalin drug substance with absolute ethanol (sample name: W3) While producing and confirming fluidity | liquidity, mass ratio (%) with respect to the mass of the initial pregabalin drug substance of the mass of the lactam body after storage for 3 days on the conditions of the start of storage and 60 degreeC humidity control was measured ( Table 2). Measurement was performed in a single series.
In addition, the contents of 75 mg of Lyrica (trademark) capsules were confirmed for its fluidity, and the sample (sample name: L13994) obtained by compressing it as it was was stored for 3 days under the conditions of 60 ° C. and no humidity control. The mass ratio (%) of the mass of the lactam body after storage to the mass of the initial pregabalin drug substance was measured (Table 2). Measurement was performed in a single series.

  Additives that were subjected to the compounding change test were hydroxypropyl cellulose [HPC-L (trademark) normal particle type, Nippon Soda Co., Ltd.], D-mannitol (Mannit P (trademark), Mitsubishi Corporation Foodtech Co., Ltd.), Isomalt [galen IQ800 (trademark), BENEO-Palatinit GmbH], D-sorbitol [Merck Co., Ltd.], concentrated glycerin [Merck Co., Ltd.], propylene glycol [BASF Japan K.K.], Macrogol 400 [Sanyo Chemical Industries, Ltd.] They were reduced maltose starch syrup [Amalty MR100 (trademark), Mitsubishi Corporation Foodtech Co., Ltd.], xylitol [San-Eigen FFI Co., Ltd.], and erythritol [San-Eigen FFI Co., Ltd.].

As can be seen from Table 2, the fluidity of the obtained granules is obtained by kneading, drying and sieving the powder of 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 ™ capsules 75 mg itself was “very bad (x)”.
Granules obtained by kneading, drying and sieving without adding the powder of pregabalin drug substance, granules obtained by kneading, drying and sieving with purified water, kneading with anhydrous ethanol, drying and sieving The granules thus obtained were all “bad” (Δ).

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

  The fluidity of the granules obtained by kneading the pregabalin drug substance with an aqueous solution of hydroxypropylcellulose, D-mannitol or reduced maltose starch syrup, drying, and sieving was “very good (◎)”. It was.

  For the production of lactam, the powder of pregabalin drug substance is kneaded with hydroxypropylcellulose aqueous solution, dried and sieved, and the granules obtained are placed under 60 ° C. dry conditions for 3 days, and the powder of pregabalin drug substance Obtained by mixing with D-mannitol, isomalt, D-sorbitol, concentrated glycerin, propylene glycol, macrogol 400, reduced maltose starch syrup, xylitol, erythritol, adding water, kneading, drying, and sieving. When the obtained granule was placed under dry conditions at 60 ° C. for 3 days, little or no lactam was produced.

  On the other hand, the production of a significant amount of a lactam body was confirmed by placing a trial tablet, in which the contents of 75 mg of Lyrica (trademark) capsules were compressed as it was by hand press, under dry conditions at 60 ° C. for 3 days or 2 weeks. Kneading, drying and sieving only the powder of pregabalin drug substance, almost no lactam is produced. Granules obtained by kneading, drying and sieving the powder of pregabalin drug substance with purified water or absolute ethanol When placed in a dry condition at 60 ° C. for 3 days, almost no lactam is produced, and in the state of 75 mg of Lyrica ™ capsules, the lactam during storage should be within an acceptable range. In consideration of the above, it can be understood that the impact of tableting significantly increased the production of lactams when placed in dry conditions at 60 ° C. for 3 days or 2 weeks (Table 2).

Trial production of compressed solid preparations ;
A prototype of a compressed solid preparation containing pregabalin was made.

  The additive used was hydroxypropylcellulose [HPC-L (trademark) normal particle type, Nippon Soda Co., Ltd.], low-substituted hydroxypropylcellulose [LH-11 (trademark), Shin-Etsu Chemical Co., Ltd.], aluminum silicate Magnesium oxide [Neucillin (trademark), Fuji Chemical Industry Co., Ltd.], crystalline cellulose [Theolas KG-802 (trademark), Asahi Kasei Corporation], carmellose calcium [ECG-505 (trademark), Gotoku Pharmaceutical Co., Ltd.], croscarme Loin sodium [Ac-Di-Sol (trademark), Wilber Ellis Co., Ltd.], Partially pregelatinized starch [PCS (trademark), Asahi Kasei Co., Ltd.], Corn starch [Niskan Cornstarch (trademark), Nippon Food Chemical Co., Ltd.] , Calcium dihydrogen phosphate [Taihei Chemical Industry Co., Ltd.], D-mannito [Mannit® P (trademark), Mitsubishi Corporation Foodtech Co., Ltd.], D-mannitol (Pertech M100 (trademark), Merck Millipore Corporation), D-sorbitol [Merck Co., Ltd.], granulated lactose hydrate for direct hitting [Dilactoise S (trademark), Freund Sangyo Co., Ltd.], isomalt (galen IQ800 (trademark), BENEO-Palatinit GmbH), calcium stearate (Taihei Chemical Industrial Co., Ltd.), and magnesium stearate (Taihei Chemical Sangyo Co., Ltd.).

Prototype tablets were prepared using 8000 tablets of the main drug and additives according to Table 3. Specifically, 600 g of pregabalin drug substance and “additive in granulation liquid” described in Table 3 were weighed 8000 times the amount of powder per tablet, and fluidized bed (FD-MP-01 type). And granulated while spraying 800 g of purified water at a speed of 12 g per minute at an intake temperature of 80 ° C. and an exhaust temperature of 30 ° C. for about 67 minutes. For example, when 4 mg of D-mannitol was added per tablet, 32 g of D-mannitol was added. However, when adding 4 mg of hydroxypropylcellulose per tablet without adding it as a powder for hydroxypropylcellulose, an 800 g 4 mass% HPC aqueous solution prepared in advance at a speed of 12 g per minute, 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 adding 2 mg of hydroxypropylcellulose per tablet, 400 grams of 4% by weight aqueous HPC solution is sprayed at a speed of 12 g / min at an intake temperature of 80 ° C. and an exhaust temperature of 30 ° C. for about 33 minutes. And then adding 8 mg of hydroxypropylcellulose per tablet, 1600 grams of 4% by weight aqueous HPC solution 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 directly dried using a fluidized bed at 80 ° C. for 5 minutes, and sieved with a mesh 30 filter. The post-additives listed in Table 3 are added to the granulated product after drying and sieving in an amount of 8000 times the amount per tablet, mixed, and punched using a single tableting machine (AUTOTAB-500, Ichihashi Seiki). Tableting was performed at a tableting pressure of 0.8 t. The resulting mass per tablet was as shown in Table 3.

Hardness of the prototype solid preparation:
The hardness immediately after the trial production of the prototype solid preparation was measured using a hardness measuring machine (KHT-20N, Fujiwara Seisakusho). The measurement results were as shown in Table 3.
As shown in Table 3, with respect to the hardness of the tablet, after adding D-sorbitol to the main drug granule part and granulating with a granulating liquid not containing hydroxypropyl cellulose (namely, water), crystalline cellulose and L- When HPC and calcium stearate are added (specimen name: MP5-1-1), and after granulating the main drug granule part with an HPC aqueous solution, partially pregelatinized starch, L-HPC and calcium stearate are added as post-additives (Specimen 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 granule part with an aqueous HPC solution (Specimen name: MP2- In 7-1), the hardness was less than 30N. However, all other specimens were able to obtain a sufficient hardness of 30 N or more.

Storage stability of the prototype compressed solid preparation:
Each compressed solid formulation was stored at 40 ° C. and 75% relative humidity for 1 week, 2 weeks, or 4 weeks. However, the contents of Lyrica (trademark) capsules 75 mg were stored as they were at 40 ° C. and 75% relative humidity without compression. Similarly, a part of the pregabalin drug substance was stored as it was at 40 ° C. and 75% relative humidity without compression.

  When only the drug substance is tableted (specimen name: drug substance +0.4 t, drug substance +0.8 t, drug substance +1.2 t), no lactam occurs at the start of storage, regardless of the strength of tableting pressure, Even after one week of storage, the lactam form did not increase at all. From this, it was found that the lactam body increased with time not only by tableting but only when tableting with a specific additive.

  Similarly, when the contents of 75 mg of Lyrica (trademark) capsules were stored at 40 ° C. and 75% relative humidity without compression (specimen name: Lyrica (trademark)), the amount of lactam at the start of storage was 0. Despite the presence of .342%, the lactam form after 2 weeks of storage and after 4 weeks of storage did not increase at all. On the other hand, in Example 2, when the contents of 75 mg of Lyrica (trademark) capsules were tableted as they were and stored under dry conditions at 60 ° C. for 3 days and 14 days (specimen name: L13994), Lactose hydration contained in the contents of 75 mg of Lyrica (trademark) capsules, when combined with the fact that a significant increase in lactam was observed despite the fact that the amount of lactam was about the same. It was found that tableting pregabalin together with food, corn starch and talc was the cause of lactam formation over time by tableting.

  As an additive that triggers the formation of a lactam body over time by being present at the time of tableting, the addition of magnesium aluminate metasilicate (neucillin) as a post-additive, the amount of lactam body at the start of storage is 0.066% Compared to the above, after storing for 1 week at 40 ° C. and 75% relative humidity, production of a lactam body having a remarkable amount of 1.270% was confirmed (specimen name MP2-2-1). The amount of lactam produced when magnesium metasilicate aluminate (neucillin) is added as a post-additive is the same amount of partially pregelatinized starch (specimen name MP2-9-1), phosphorus instead of magnesium aluminate metasilicate. Calcium dihydrogen oxide (sample name MP2-6-1), corn starch (sample name MP2-8-1), D-mannitol for direct hitting (sample name MP2-4-1), granulated lactose hydrate (sample) Name MP2-7-1), isomalt (specimen name MP2-3-1), D-sorbitol (specimen name MP2-5-1) was added, and the amount of lactam was much higher than that when added. .

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

  Even among the group to which 41 mg of crystalline cellulose per tablet was added as a post-additive, the greater the amount of hydroxypropylcellulose added to the main drug granule, the more the lactam after storage for 2 weeks at 40 ° C. and 75% relative humidity (Specimen names 75-M1, 75-M2, 75-M3) increased.

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

  However, even when 10.5 mg of crystalline cellulose per tablet is added as a post-additive, D-mannitol (specimen name MP3-1-1 (lactam body increased by 0.089%)) in the main drug granule Or D-sorbitol (specimen name: MP4-1-1 (increased lactam form: 0.018%), MP5-1-1 (increased lactam form: 0.039%), MP6-1-1 (lactam form: 0.1%) 02% increase)) was added, the lactam body increased after storage for 1 week under the conditions of 40 ° C. and 75% relative humidity when the sample was not added (specimen name MP2-1-1 (lactam). The body was suppressed compared to 0.12% increase)).

  Similarly, even when both crystalline cellulose and croscarmellose sodium are added as a post-additive, D-sorbitol (specimen name MP2-1-3-5-3 (lactam form is 0.1%) in 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 -2 (lactam body increased by 0.024%) and MP2-1-3-5-4 (lactam body increased by 0.011%)) were added at 40 ° C. and 75% relative humidity. The increase in lactam form after storage for 1 week was suppressed as compared with the case where these were not added (specimen name MP2-1-3 (lactam form increased by 0.087%)).

  Partially pregelatinized starch (sample name MP2-9-1 (lactam body increased by 0.088%)), granulated corn starch (sample name MP2-8-1 (lactam body increased by 0.080%)) as post-additive Or calcium dihydrogen phosphate (specimen name MP2-6-1 (increased by 0.085% lactam)) under the conditions of 40 ° C. and 75% relative humidity compared to the start of storage. The lactam body clearly increased after storage for 1 week.

  On the other hand, when only the HPC is added to the main drug granule and no cellulosic additive other than L-HPC is added as a post-additive, partially pregelatinized starch (specimen name MP2-9- 1) Except for the case where granular corn starch (specimen name MP2-8-1) or calcium dihydrogen phosphate (specimen name MP2-6-1) is added, one week under conditions of 40 ° C. and 75% relative humidity No increase in lactam form due to storage was observed (specimen name MP2-5-1 (apparently lactam form decreased by 0.019%)) or very slight (specimen name MP2-3-1). (Lactam form is increased by 0.030%), MP2-7-1 (lactam form is increased by 0.042%), MP2-4-1 (lactam form is increased by 0.050%)). Sample names MP2-5-1, MP2-3-1, MP2-7-1, and MP2-4-1 are sample names MP2-5-1 as post-additives 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. If no cellulose-based additives other than L-HPC are added, the formation of a lactam body over time does not occur even when tableted, and HPC, L-HPC, D-sorbitol, D-mannitol, lactose water It was found that the addition of a Japanese product and isomalt did not produce lactam bodies over time due to tableting.

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

Sample name MP-2-2-1:
After granulating 75 mg pregabalin per tablet using 4% HPC aqueous solution (4 mg HPC per tablet), 10.5 mg magnesium aluminate metasilicate (neucillin) per tablet was added to this. The disintegration time was 12 minutes when 10 mg of L-HPC and 0.5 mg of calcium stearate per tablet were added and mixed and tableted at a pressure of 0.8 t.

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

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

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

Sample name MP4-1-1:
After mixing 75 mg pregabalin per tablet and 4 mg D-sorbitol per tablet and spraying it with 4% HPC aqueous solution to give 4 mg HPC per tablet, The 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 and mixed and compressed at a pressure of 0.8 t. Met.

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

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

Trial production of compressed solid preparations ;
Only a granulated product containing pregabalin was tableted to produce a compressed solid preparation.

  Additives used were hydroxypropylcellulose [HPC-L (trademark) normal particle type, Nippon Soda Co., Ltd.], D-mannitol (Mannit P (trademark), Mitsubishi Corporation Foodtech Co., Ltd.), D-sorbitol [Merck Ltd.].

  In accordance with Table 4, trial tablets were prepared using the main drug and additives in an amount of 8000 tablets. Specifically, for samples with sample names starting with 75-MP, pregabalin drug substance 600 g and “additives in granulation liquid” (D-mannitol or D-sorbitol; HPC 8,000 times the amount per tablet of (added into the granulation liquid) and weighed into a fluidized bed (FD-MP-01 type, Paulek), and 800 g of a 4% by weight hydroxypropylcellulose 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. 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 directly dried using a fluidized bed at 80 ° C. for 5 minutes, and sieved with a mesh 30 filter. The granulated product after drying and sieving was tableted with the tableting pressure shown in Table 4 using a single tableting machine (AUTOTAB-500, Ichihashi Seiki). The resulting mass per tablet was as shown in Table 4. In addition, when “−” is displayed in the punching pressure column, it indicates that tableting is not performed.

  Since the sample name: 75-M3 contains 8 mg of hydroxypropylcellulose per tablet, 1600 grams of a 4% by weight hydroxypropylcellulose aqueous solution at a speed of 12 grams per minute, an intake temperature of 80 ° C., and exhaust gas Granulation was performed while spraying at a temperature of 30 ° C. for about 133 minutes. Otherwise, a trial tablet was produced in the same manner as described above.

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

  The content of 75 mg of Lyrica ™ capsules contained 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 contents of 75 mg of Lyrica (trademark) capsules were tableted as they were and stored under dry conditions at 60 ° C. for 3 days and 14 days (specimen name: L13994), Combined with the fact that a significant increase in lactam was observed in spite of the same amount of lactam, the increase in lactam was due to the contents of 75 mg of Lyrica ™ capsules. It was understood that it progressed over time triggered by the impact of tableting together with lactose hydrate, corn starch and talc contained in.

  For the pregabalin granulated product containing HPC, D-mannitol and D-sorbitol, no increase in lactam form was observed after storage at 40 ° C. and 75% relative humidity for 7 days unless tableting. That is, granulated 75 mg of pregabalin using 4% HPC aqueous solution (4 mg of HPC per tablet) and dried (specimen name: 75-MP2-40, 75-MP2-45), 4% HPC And D-mannitol aqueous solution (HPC and D-mannitol per tablet are 4 mg each), granulated 75 mg of pregabalin (sample names: 75-MP3-40, 75-MP3-45), Granulated 75 mg of pregabalin using 4% HPC and D-sorbitol aqueous solution (4 mg each for HPC and D-sorbitol) (Specimen name: 75-MP4-40, 75-MP4) -45), the increase in lactam form after storage for 7 days at 40 ° C. and 75% relative humidity is 0.012% or less, and the increase in lactam form is completely It is did not. Also from this, it was understood that the increase in the lactam body progressed over time triggered by the impact of tableting together with a predetermined additive.

  When the granulated pregabalin containing HPC, D-mannitol and D-sorbitol was tableted, the amount of lactam at the start of storage was slightly increased compared to the case of not tableting. The increase in lactam form after storage for 7 days at 40 ° C. and 75% relative humidity was negligible. That is, 75 mg of pregabalin was granulated using a 4% HPC aqueous solution (4 mg of HPC per tablet), dried, and then tableted at 0.4 t, 0.8 t, and 1.2 t (specimen name 75- MP2-04, 75-MP2-08, 75-MP2-12) Granulate 75 mg of pregabalin using 4% HPC and D-mannitol (4 mg each for HPC and D-mannitol per tablet) And then tableted at 0.4t, 0.8t, and 1.2t (sample names 75-MP3-04, 75-MP3-08, 75-MP3-12), and 4% HPC and D- 75 mg of pregabalin is granulated using sorbitol (HPC and D-sorbitol per tablet is 4 mg each), dried and then tableted at 0.4 t, 0.8 t and 1.2 t (specimen name 75-MP -04, 75-MP4-08, 75-MP4-12) all have an increase in lactam form of 0.026% or less due to storage for 7 days at 40 ° C. and 75% relative humidity. The body gain was negligible. In addition, no clear relationship was found between the striking pressure and the increased amount of lactam.

  Therefore, even when HPC is added to a compressed solid preparation containing a γ-aminobutyric acid derivative or a pharmaceutically acceptable salt thereof, almost no lactam body is produced over time due to the impact of tableting. I found that there was no.

  In addition, 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 body over time produced by the impact of tableting It has been found that little production occurs.

Trial production of compressed solid preparations ;
A prototype of a compressed solid preparation containing pregabalin was made.

  The additive used was hydroxypropylcellulose [HPC-L (trademark) normal particle type, Nippon Soda Co., Ltd.], low-substituted hydroxypropylcellulose [LH-11 (trademark), Shin-Etsu Chemical Co., Ltd.], reduced maltose starch syrup [Amarti MR100 (trademark), Mitsubishi Corporation Foodtech Co., Ltd.], crystalline cellulose [Theolas KG-802 (trademark), Asahi Kasei Corporation], croscarmellose sodium [Ac-Di-Sol (trademark), Wilber Ellis Co., Ltd. ], D-mannitol [Pertech M200 (trademark), Merck Millipore Corporation], D-sorbitol [Merck Co., Ltd.], granulated lactose hydrate [Dilactos S (trademark) Freund Sangyo Co., Ltd.), Erythritol [Sanei] Gen-F.F.I Co., Ltd. Company], calcium stearate [Taihei Chemical Industry Co., Ltd.].

  In accordance with Table 5, trial tablets were prepared using the main drug and additives in an amount of 8000 tablets. Specifically, 600 g of pregabalin drug substance and 8000 times the amount of “granulated portion additive (powder)” shown in Table 5 per tablet were weighed to obtain a fluidized bed (FD-MP-01 type). And granulated while spraying a 4 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. When adding 4 mg of D-sorbitol per tablet, add 32 g of D-sorbitol as a powder, and add 7 mg of reduced maltose starch syrup per tablet. In some cases, 56 g of reduced maltose starch syrup was added as a powder, and when 7 mg of erythritol was added per tablet, 56 g of erythritol was added as a powder. Spray amount and spraying time of aqueous HPC solution, when adding 4 mg of HPC per tablet, granulate while spraying 800 grams of 4 wt% HPC aqueous solution for about 67 minutes and add 6 mg of HPC per tablet In some cases, granulate while spraying 1200 grams of 4 wt% HPC aqueous solution for about 100 minutes, and when adding 8 mg HPC per tablet, spray 1600 grams of 4 wt% HPC aqueous solution over about 133 minutes. While granulating. The obtained granulated product was directly dried using a fluidized bed at 80 ° C. for 5 minutes, and sieved with a mesh 30 filter. The post-additives listed in Table 5 are added to the granulated product after drying and sieving in an amount of 8000 times the amount per tablet, mixed, and punched using a single tableting machine (AUTOTAB-500, Ichihashi Seiki). Tableting was performed at a tableting pressure of 0.8 t. The mass per tablet obtained as a result was as shown in Table 5.

  As shown in Table 5, the granulation liquid used was a 4% HPC solution with a content of 4 mg, 6 mg, or 8 mg per tablet, and D-sorbitol, reduced as an additive for the granulated part containing pregabalin. We examined maltose syrup and erythritol. In addition, as a cellulosic additive in the post-additives, all specimens contained 2 mg of croscarmellose sodium per tablet. In addition, the specimen names: MP7-1 (1), MP7-2 (1), MP7-3 (1), and MP8-2 (1) each further contained 10 mg of crystalline cellulose per tablet. .

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

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

Storage stability of the prototype compressed solid preparation:
Each compressed solid formulation was stored for 7 days at 40 ° C. and 75% relative humidity.
In the trial tablet using D-sorbitol as an additive for the granulation part, the amount of lactam increased approximately twice or more by storage for 7 days at 40 ° C. and 75% relative humidity. The amount of lactam increased by storage for 7 days at 40 ° C. and 75% relative humidity 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 croscarmellose sodium was included in the post-additive, the increase in lactam body could be sufficiently suppressed if D-sorbitol was included in the granulated portion. .

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

Disintegration of the prototype compressed solid preparation:
Sample names: MP7-1 (1), MP7-2 (1), MP7-3 (1), and MP8-2 (2) only in the form of paddles according to the dissolution test method prescribed in the Japanese Pharmacopoeia Using the method, the disintegration time for water in the vessel was measured under the condition of 50 revolutions per minute.
As a result, as described below, it was found that the disintegration within 30 minutes required for the uncoated tablets in the Japanese Pharmacopoeia was achieved for all the specimens, and the disintegration was sufficiently fast.

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

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

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

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

Summary of Example 5:
As described above, in the preparation containing crystalline cellulose and / or croscarmellose sodium in the post-additive, the disintegration time was sufficiently fast. However, the trial 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 after storage for 3 days was significantly reduced. The trial tablet using reduced maltose starch syrup or erythritol as an additive for the granulation part has 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.

Trial production of compressed solid preparations ;
Using a main drug granule containing 1%, 2%, or 3% water, trial production of a compressed solid preparation containing pregabalin was performed.

  Additives used were hydroxypropylcellulose [HPC-L (trademark) normal particle type, Nippon Soda Co., Ltd.], reduced maltose starch syrup (Amalty MR100 (trademark), Mitsubishi Corporation Foodtech Co., Ltd.), crystalline cellulose [Seolus KG- 802 (trademark), Asahi Kasei Corporation], croscarmellose sodium [Ac-Di-Sol (trademark), Wilber Ellis Co., Ltd.], calcium stearate [Taihei Chemical Sangyo Co., Ltd.].

  In accordance with Table 6, trial tablets were prepared using the main drug and additives in an amount of 8000 tablets. Specifically, 600 g of pregabalin drug substance and 56 g of reduced maltose starch syrup are weighed and put into a fluidized bed (FD-MP-01 type, Paulek), and 800 g of a 4% hydroxypropylcellulose aqueous solution at a speed of 12 grams per minute, 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 moisture content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). Dried to 1%, 2%, or 3%. Thereafter, the mixture was sieved with a mesh 30 filter. The post-additives listed in Table 6 are added to the granulated product after drying and sieving in an amount of 8000 times the amount per tablet, mixed, and punched using a single tableting machine (AUTOTAB-500, Ichihashi Seiki). Tableting was performed at a tableting 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 preparation:
Storage stability of the active ingredient granule itself, using the active ingredient granule containing 1%, 2%, or 3% water, preservation of tableting granule mixed with the active ingredient granule together with crystalline cellulose, croscarmellose sodium, calcium stearate Each of the trial tablets obtained by compressing the stability and tableting granules at 0.8 t was 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 increase in lactam body due to storage for 7 days at 40 ° C. and 75% relative humidity is 0 when the tablet is not compressed. .014%, 0.015%, and 0.015% compared to 0.035%, 0.042%, and 0.035% when tableting, so the water content Regardless, it was reconfirmed that the lactam body increased with time due to the impact of tableting. On the other hand, the increase in lactam body over time in the main drug granules, tableting granules, and prototyped compressed solid preparations did not change depending on the water content of the main drug granules.

Trial production of compressed solid preparations ;
A pregabalin preparation that can maintain the hardness of a tablet even after storage under accelerated conditions was examined.

  Additives used were hydroxypropylcellulose [HPC-L (trademark) normal particle type, Nippon Soda Co., Ltd.], reduced maltose syrup (Amalty MR100 (trademark), Mitsubishi Corporation Foodtech Co., Ltd.), pregelatinized starch (Nissho) Chemical Co., Ltd.], white sugar [Merck Co., Ltd.], gum arabic [San-Ei Gen F.F.I. Ltd.], gelatin [San-Ei Gen F.F.I. Ltd.], stearic acid [Taihei Chemical Industrial Co., Ltd.], starch They were sodium glycolate [Primogell (trademark), DFE Pharma Co., Ltd.], croscarmellose sodium [Ac-Di-Sol (trademark), Wilber Ellis Co., Ltd.], and calcium stearate (Taihei Chemical Industry Co., Ltd.).

  According to Table 7, trial tablets for 200 tablets were prepared using a mortar. Specifically, 15 g of pregabalin and 1.4 g of reduced maltose starch syrup are mixed in a mortar, and each granulating aqueous solution (0.3 g HPC, 0.3 g pregelatinized starch, 0.3 g sucrose, 0.3 g 6g aqueous solution containing gum arabic or 0.3g gelatin), granulated in a mortar and dried with an 80 ° C dryer (electric constant temperature dryer, Higaki Medical Science Co., Ltd.) 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). Thereafter, the mixture was sieved with a mesh 30 filter. 100 tablets of the granulated product after drying and sieving are weighed, the post-additives listed in Table 7 are added in an amount 100 times the amount per tablet, and mixed, and the single tableting machine (AUTOTAB-500, Tableting was performed at a tableting pressure of 0.8 t using Ichibashi Seiki). The mass per tablet obtained as a result was as shown in Table 7.

  In addition, for the trial tablet containing stearic acid, 15 g of pregabalin and 1.4 g of reduced maltose starch syrup are mixed in a mortar, 1.6 g of stearic acid powder is added, and an 80 ° C. dryer (electric constant temperature dryer, Higaki) is added. It was granulated while being heated and melted by Medical Science Co., Ltd. Thereafter, the mixture was sieved with a mesh 30 filter. The post-additives listed in Table 7 are added to the granulated product after sieving in an amount 100 times the amount per tablet and mixed, and the tableting pressure is determined using a single tableting machine (AUTOTAB-500, Ichihashi Seiki). Tableting was performed at 0.8 t. The mass per tablet obtained as a result was as shown in Table 7.

  As shown in Table 7, for each of the test tablets of specimen names: N3-4 to N3-8, the type and amount of post-additives were fixed to 2 mg croscarmellose sodium per tablet and 1 mg calcium stearate per tablet. After fixing the amount of reduced maltose starch syrup added to the granulated granule to 7 mg per tablet, the additive added by dissolving in the granulation liquid was changed in various ways at 40 ° C and 75% relative humidity. The increase of tablet hardness and lactam body after storage with was examined.

  Specimen name: For only one group of N3-9, 7 mg of reduced maltose starch syrup is added as a powder into granulated granules, and 1.5 mg of HPC per tablet is dissolved in the granulation liquid and granulated. Spray and granulate with liquid, add 2 mg sodium starch glycolate per tablet and 1 mg calcium stearate per tablet as post-additives, mix and tablet to make prototype tablets. Sample name: Contrast with trial tablet of N3-4.

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

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

  When 1.5 mg of pregelatinized starch is added per tablet together with 7 mg of reduced maltose starch syrup as an additive in the granulated part (sample name N3-5), 1.5 mg of sucrose per tablet is also used. (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 tablet hardness after 7 days storage at 40 ° C. and 75% relative humidity decreased to 0 (zero) N. From this, it was found that at least when the 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 are used as additives in the granulation liquid (sample names N3-4 and N3-9), 40 ° C. and 75% relative The hardness of the tablet after storing for 7 days at humidity was maintained at about 10 N, and it was found that the hardness of the pregabalin tablet during the period of use could be maintained by adding HPC to the granulated part.

  In addition, when granulation is performed using 8 mg of stearic acid per tablet and 7 mg of reduced maltose starch syrup as an additive in the granulation liquid (sample name N4-1), 25N tablets at the start of storage The hardness of the pregabalin preparation was increased by melt granulation in which stearic acid was added to the granulated portion, since the hardness was 17 N even after being stored at 40 ° C. and 75% relative humidity for 7 days. It was found that it is difficult to reduce tablet hardness during storage.

Storage stability of the prototype compressed solid preparation:
Each compressed solid preparation was stored at 40 ° C. and 75% relative humidity, and after 7 days in a high performance 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. And the lactam body after 14 days was quantified.

  When the granulated portion is melt granulated by adding 8 mg of stearic acid per tablet together with 7 mg of reduced maltose starch syrup per tablet (sample name N4-1), the lactam content at the start of storage is 0 Compared to 0.064%, the lactam content after 14 days storage at 40 ° C. and 75% relative humidity has increased to 0.437%. An increase in lactam form was observed.

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

  When adding 1.5 mg of HPC per tablet together with 7 mg of reduced maltose starch syrup as an additive for the granulation part (sample name N3-4), add 1.5 mg of pregelatinized starch per tablet. (Sample name N3-5), when 1.5 mg of sucrose is added per tablet (sample name N3-6), and when 1.5 mg of gum arabic is added per tablet (sample name N3-6) 7), the lactam content after storage for 14 days at 40 ° C. and 75% relative humidity is between 0.103% and 0.124%, and it is stored for 14 days at 40 ° C. and 75% relative humidity. Since the increased amount of the lactam body was also 0.042% to 0.067%, a slight increase in the lactam body over time was observed.

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

Trial production of compressed solid preparations ;
The storage stability of the prototype compressed solid preparation was examined.

  Additives used were hydroxypropylcellulose [HPC-L (TM) normal particle type, Nippon Soda Co., Ltd.], D-sorbitol [Merck Co., Ltd.], reduced maltose syrup (Amalty MR100 (TM), Mitsubishi Corporation Foodtech Co., Ltd.) Company], erythritol [San-Ei Gen FFI Co., Ltd.], crystalline cellulose [Theorus KG-802 (trademark), Asahi Kasei Co., Ltd.], croscarmellose sodium [Ac-Di-Sol (trademark), Wilber Ellis Ltd. Company], calcium stearate [Taihei Chemical Industrial Co., Ltd.], magnesium stearate [Taihei Chemical Industrial Co., Ltd.], low-substituted hydroxypropylcellulose [LH-11 (trademark), Shin-Etsu Chemical Co., Ltd.].

  Prototype tablets were prepared according to Table 8 using the main drug and additives in an amount of 8000 tablets. Specifically, 600 g of pregabalin drug substance and 8000 times the amount per tablet of “additive to be added to granulated granule” described in Table 8 were weighed to obtain a fluidized bed (FD-MP-01 And then granulated while spraying a 4% by mass HPC aqueous solution prepared for granulation at a speed of 12 grams per minute at an intake air temperature of 80 ° C. and an exhaust gas temperature of 30 ° C. . When adding 4 mg of HPC per tablet, the spraying amount and spraying time of the HPC aqueous solution are granulated while spraying 800 g of 4% by weight of HPC aqueous solution over about 67 minutes and adding 6 mg of HPC per tablet. Was granulated while spraying 1200 g of a 4% by weight aqueous HPC solution for about 100 minutes, and when adding 8 mg of HPC per tablet, it was granulated while spraying 1600 g of the 4% by weight aqueous HPC solution for about 133 minutes. The amount of “additive added as a powder in the granulated granule” is as follows. When 1 mg of D-sorbitol is added per tablet, 8 g of D-sorbitol is added as a powder, and 4 mg of D-sorbitol is added per tablet. When adding, 32 g of D-sorbitol was added as a powder, and when adding 7 mg of D-sorbitol per tablet, 56 g of D-sorbitol was added as a powder. Similarly, reduced maltose starch syrup and erythritol were 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 moisture content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). Dried to 1%. Thereafter, the mixture was sieved with a mesh 30 filter. The post-additives listed in Table 8 are added to the granulated product after drying and sieving in an amount of 8000 times the amount per tablet, mixed, and punched using a single tableting machine (AUTOTAB-500, Ichihashi Seiki). Tableting was performed at a tableting 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 trial tablet whose sample name starts with N, 4% HPC solution was used as the granulation solution so that the HPC content was 4 mg per tablet, and the addition of the granulated portion containing pregabalin As a product, 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 was a composition containing 10 mg crystalline cellulose per tablet, 2 mg croscarmellose sodium per tablet, and 1 mg calcium stearate per tablet.

  In the trial tablet whose sample name starts with M, 4% HPC solution is used as a granulation solution so that the HPC content per tablet is 4 mg, and D-sorbitol is used as an additive for the granulation part containing pregabalin. The powder was added to give 4 mg per tablet.

  As shown in Table 8, the post-additives were prepared by fixing the amount of crystalline cellulose and calcium stearate per tablet and changing the amount of L-HPC to 10 mg or 2 mg per tablet (specimen name MP4-1- 1 and MP4-1-2).

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

  Furthermore, in the trial tablet whose sample name starts with 75, the post-additive was fixed to 41 mg crystalline cellulose per tablet, 10 mg L-HPC per tablet, and 1.5 mg magnesium stearate per tablet, The granulation liquid used for the production of the granulated product containing pregabalin was granulated by increasing / decreasing the liquid volume of the 4% HPC solution so that the HPC content was 2 mg, 4 mg or 8 mg per tablet (specimen name MP75 -M1, 75-M2, and 75-M3).

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

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

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

  On the other hand, when 1 mg, 4 mg, or 7 mg of erythritol is added per tablet as an additive in the granulation part in addition to 4 mg of HPC per tablet, it is stored at 40 ° C. and 75% relative humidity for 2 weeks. Although the time-dependent increase in lactam in the experimental tablet 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 is added in addition to 4 mg of HPC per tablet as an additive in the granulation part, the time-dependent increase in lactam in the trial tablet is added The amount of reduced maltose starch syrup increased as the amount of reduced maltose starch syrup increased, and the amount of lactam body in the trial tablet that was stored for 2 weeks at 40 ° C and 75% relative humidity was increased over time when 1 mg of reduced maltose starch syrup was added per tablet. 0.202% when 4 mg of reduced maltose starch syrup was added to 1 tablet, 0.139% 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, it was possible to maintain a smaller amount of lactam 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 is added per tablet as an additive in the granulation part in addition to 4 mg HPC per tablet, the increase in lactam in the trial tablet over time is As the amount of D-sorbitol was increased, the amount of lactam body in the trial tablet was increased when stored at 40 ° C. and 75% relative humidity for 2 weeks. When 1 mg of D-sorbitol was added per tablet 0.178% and 4 mg D-sorbitol per tablet was 0.103%. When 7 mg of D-sorbitol was added per tablet, the absolute amount of lactam after storage for 2 weeks at 40 ° C. and 75% relative humidity was only 0.137% (because there is no data at the start of storage). The amount of lactam over time is unknown). Thus, in the sample added with 1 mg, 4 mg, or 7 mg of D-sorbitol per tablet, the amount of lactam body could be maintained even smaller than when the same amount of reduced maltose starch syrup was added ( Sample name: N2-1, N2-2, N2-3).

  4 mg HPC per tablet and 4 mg D-sorbitol per tablet as additives for the granulation part, 10 mg crystalline cellulose per tablet, 1 mg calcium stearate per tablet, and 1 tablet as a post-additive When 2 mg of L-HPC was added (specimen name: MP4-1-2), the time-dependent increase in lactam in the trial tablet due to storage at 40 ° C. and 75% relative humidity for 2 weeks was 0.076. %, The amount of lactam in the trial tablet increased with time when stored at 40 ° C. and 75% relative humidity for 2 weeks when the L-HPC amount of the sample was changed to the same amount of croscarmellose sodium. Even when compared with 103% (specimen name: N2-2), it was possible to maintain the production amount of lactam body with time even smaller. From this, it was found that croscarmellose sodium is not preferable and L-HPC is preferable for suppressing the increase of lactam over time triggered by the impact of tableting.

  Moreover, even when the amount of L-HPC in 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). From this, it was found that L-HPC does not significantly affect the increase in lactam body over time.

  4 mg HPC per tablet and 4 mg D-sorbitol per tablet as additives in the granulation part, 10 mg crystalline cellulose per tablet, 2 mg croscarmellose sodium per tablet, and 1 Post-addition compared to the amount of lactam (0.158%) after a sample (sample name: MP4-2-2) added with 1 mg of calcium stearate per tablet was stored at 40 ° C. and 75% relative humidity for 2 weeks The amount of lactam after a sample (sample name 4-2-1), in which the amount of crystalline cellulose in the product was reduced to 5 mg per tablet, was stored at 40 ° C. and 75% relative humidity for 2 weeks, decreased to 0.150%. The amount of lactam after a sample (sample name 4-2-3) in which the amount of post-additive crystalline cellulose was increased to 20 mg per tablet was stored at 40 ° C. and 75% relative humidity for 2 weeks was 0.132 It was increased to. From this, it was found that by compressing pregabalin together with crystalline cellulose, the amount of lactam body increased over time, and the amount of lactam body produced over time increased as the amount of crystalline cellulose added increased. .

  Only 2 mg, 4 mg or 8 mg HPC per tablet is added as an additive in the granulation part, 41 mg crystalline cellulose per tablet, 10 mg L-HPC per tablet, and 1.5 mg per tablet as a post-additive The amount of lactam produced by storing the samples (sample names 75-M1, 75-M2, and 75-M3) to which magnesium stearate was added at 40 ° C. and 75% relative humidity for 2 weeks was 2 mg HPC per tablet 0.337% by addition, 0.387% by addition of HPC at 4 mg per tablet, and 0.428% by addition of HPC at 8 mg per tablet, both of which produced too much lactam over time The preparation was far from practical use. From this, it was found that when 41 mg of crystalline cellulose was added per tablet, basically, the production of lactam body over time was too much. In addition, since the amount of lactam produced over time tended to increase slightly when the amount of added HPC was large, the amount of lactam produced over time can be tolerated with a certain amount of HPC. Even within the range, it was found that a smaller amount of HPC is preferable in order to suppress the formation of lactam over time.

Disintegration of the prototype compressed solid preparation:
For the compressed solid preparation of specimen name MP4-1-1 only, the disintegration time for water in the vessel was measured using the paddle method according to the dissolution test method prescribed in the Japanese Pharmacopoeia, under the condition of 50 revolutions per minute. did.
As a result, as shown below, the sample with the sample name: MP4-1-1 has achieved disintegration within 30 minutes, which is required for uncoated tablets in the Japanese Pharmacopoeia, and has sufficiently fast disintegration. all right.

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

Trial production of compressed solid preparations ;
In order to establish prescriptions for pregabalin preparations that can maintain hardness when stored at 40 ° C. and 75% relative humidity, the hardness of various prototype tablets and the amount of lactam were examined. In the trial production of Example 9, crystalline cellulose was not used because it caused the lactam body to increase over time.

  Additives used were hydroxypropylcellulose [HPC-L (trademark) normal particle type, Nippon Soda Co., Ltd.], D-mannitol (Mannit P (trademark), Mitsubishi Corporation Foodtech Co., Ltd.), D-sorbitol [Merck Co., Ltd.], reduced maltose starch syrup [Amarti MR100 (trademark), Mitsubishi Corporation Foodtech Co., Ltd.], erythritol [Saneigen FFI Co., Ltd.], isomalt [galen IQ800 (trademark), BENEO-Palatinit GmbH], croscarme It was roast sodium [Ac-Di-Sol (trademark), Wilber Ellis Co., Ltd.], calcium stearate [Taihei Chemical Industry Co., Ltd.].

  In accordance with Table 9, trial tablets were prepared using the main drug and additives in an amount of 8000 tablets. Specifically, 600 g of pregabalin drug substance and 8000 times the amount of “additive added as a powder in granulated granule” described in Table 9 per tablet are weighed and powdered in a fluidized bed (FD-MP -01 type, Paulek), and sprayed with 4% HPC aqueous solution prepared for granulation at a speed of 12 grams per minute at an intake temperature of 80 ° C and an exhaust temperature of 30 ° C. Grained. When adding 4 mg of HPC per tablet, the spray amount and spraying time of the HPC aqueous solution are those when granulating while spraying 800 g of 4% by weight of HPC aqueous solution for about 67 minutes and adding 8 mg of HPC per tablet. Was granulated while spraying 1600 g of a 4% by weight aqueous HPC solution over about 133 minutes. The amount of “additive added as a powder in the granulated granule” is such that when 4 mg of D-sorbitol is added per tablet, 32 g of D-sorbitol is added as a powder, and 4 mg of D-mannitol is added per tablet. When adding 32 g of D-mannitol as a powder, when adding 7 mg of reduced maltose starch syrup, add 56 g of reduced maltose starch syrup, and when adding 7 mg of erythritol per tablet 56 g erythritol was added as a powder. The obtained granulated product was dried as it was at 80 ° C. using a fluidized bed, and the obtained granulated product was measured for moisture content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). Dried to 1%. Thereafter, the mixture was sieved with a mesh 30 filter. The post-additives listed in Table 9 are added to the granulated product after drying and sieving in an amount of 8000 times the amount per tablet, mixed, and punched using a single tableting machine (AUTOTAB-500, Ichihashi Seiki). Tableting was performed at a tableting 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 trial tablet, only 4% HPC solution is used as a granulating solution so that the HPC content per tablet is 4 mg, and only 1 mg calcium stearate per tablet is used as a post-additive. Added. Specimen name: In the MP2-A trial tablet, 2 mg of croscarmellose sodium per tablet was added as a post-additive to the MP2-B trial tablet.

Specimen name: For MP5 prototype tablet, instead of granulating with HPC solution used for specimen name: MP2-A prototype tablet, 4 mg of D-sorbitol powder is added per tablet and sprayed with water. And granulated.
In the sample tablet of specimen name: MP3, 4 mg of D-mannitol was added in powder form as an additive to the granulated portion containing pregabalin of the specimen tablet of specimen name: MP2-A.

  In the prototype tablet of specimen name: MP4, 4 mg of D-sorbitol was added in powder form as an additive to the granulated portion containing pregabalin of the prototype tablet of specimen name: MP2-A.

  Specimen name: MP7-1, MP7-3, MP8-1, MP8-3, MP9-1, MP9-3 In the trial tablets, 2 mg of croscarmellose sodium per tablet and 1 mg per tablet 4 mg of D-sorbitol (specimen name: MP7-1, MP7-3) per tablet as an additive of granulated portion fixed to calcium stearate and 7 g of reduced maltose starch syrup (1 tablet) Specimen name: MP8-1, MP8-3) or 7 mg erythritol (sample name: MP9-1, MP9-3) per tablet is added, and in each of these, the amount of HPC used for granulation is 1 4 mg (sample name: MP7-1, MP8-1, MP9-1) or 8 mg (sample name: MP7-3, MP8-3, MP9-3) per tablet.

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

  Specimen name: MP8-1-1 trial tablet is a trial tablet in which 7 mg of reduced maltose starch syrup is added as a powder to the granulated product of specimen name: MP2-A-1. That is, in the trial tablet of MP8-1-1, a mixture of 75 mg pregabalin per tablet and 7 mg reduced maltose starch syrup in each tablet is mixed with 4% HPC solution so that the HPC content is 4 mg per tablet. As a post-additive, 2 mg of croscarmellose sodium per tablet, 1 mg of calcium stearate per tablet, and 10 mg of isomalt per tablet were added as a post-additive.

  The sample name: MP8-3-1 prototype tablet is a prototype tablet in which the HPC content in the granulated product of the 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 pregabalin per tablet and 7 mg reduced maltose starch syrup in each tablet has a 4% HPC solution so that the content of HPC is 8 mg per tablet. As a post-additive, 2 mg of croscarmellose sodium per tablet, 1 mg of calcium stearate per tablet, and 10 mg of isomalt per tablet were added as a post-additive.

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

  Furthermore, the prototype tablet of specimen name MP8-3-2 was a trial tablet in which the HPC amount of the prototype tablet of specimen name: MP8-1-2 was increased to 8 mg per tablet. That is, in the trial tablet of MP8-3-2, a mixture of 75 mg pregabalin per tablet and 7 mg reduced maltose starch syrup in each tablet is mixed with 4% HPC solution so that the HPC content per tablet is 8 mg. As a post-additive, 2 mg of croscarmellose sodium per tablet, 1 mg of calcium stearate per tablet, and 10 mg of D-sorbitol per tablet were added as a post-additive.

Hardness of the prototype solid preparation:
The hardness immediately after the trial production of the prototype solid preparation was measured using a hardness measuring machine (KHT-20N, Fujiwara Seisakusho). The measurement results were 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 as post-additives to pregabalin-containing granules granulated using only D-sorbitol without using HPC A prototype tablet (specimen name: MP5) tableted with 0.8t tableting pressure after addition and mixing was manufactured using other HPC aqueous solution except that the hardness at the start of storage was only 22N. Each 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 a sufficient hardness.

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

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

  Only 4% HPC solution was used as a granulating solution so that the HPC content was 4 mg per tablet, and 10 mg isomalt per tablet, 2 mg croscarmellose sodium per tablet, and 1 tablet as a post-additive. The tablet hardness of the trial tablet (sample name: MP2-A-1) to which 1 mg of calcium stearate is added has a tablet hardness of 36.5 N at the start of storage and is 40 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 is added per tablet as an additive in the granulated product of the prototype tablet of specimen name: MP2-A-1, the tablet hardness was 60.5 N at the start of storage, After 7 days of storage at 40 ° C. and 75% relative humidity, the tablet hardness decreased to only 8.0 N (specimen name: MP8-1-1). When the HPC content in the granulated product of the test sample name: MP8-1-1 was increased to 8 mg per tablet, it was 20.0 N even after 7 days storage at 40 ° C. and 75% relative humidity. However, the tablet hardness was still not satisfactory (specimen name: MP8-3-1).

  In contrast, a 4% HPC solution was used as a granulation solution so that the HPC content was 4 mg per tablet, and 1 mg calcium stearate per tablet was added as a post-additive (sample name) : MP2-B), a prototype tablet obtained by adding 2 mg of croscarmellose sodium as a post-additive to the MP2-B prototype tablet, and MP2-A prototype tablet In the trial tablet (specimen name: MP3) to which 4 mg of D-mannitol was added per tablet as an additive for the granulated part containing pregabalin, it 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, granulate containing 4 mg or 8 mg of HPC per tablet, 7 mg of reduced maltose starch syrup and 75 mg of pregabalin per tablet in a fluidized bed, and 2 mg of croscarmellose sodium per tablet 1 mg of calcium stearate per tablet was added, mixed, and tableted (sample names: MP8-1, MP8-3) after storage for 7 days at 40 ° C. and 75% relative humidity. An extremely good tablet hardness of 50 N or more was maintained.

  Similarly, granulate containing 4 mg or 8 mg HPC per tablet, 7 mg erythritol per tablet and 75 mg pregabalin per tablet in a fluidized bed, 2 mg croscarmellose sodium per tablet and 1 tablet 1 mg of calcium stearate per post-added, mixed, and tableted (sample name: MP9-1, MP9-3) was 44.0 N even after 7 days storage at 40 ° C. and 75% relative humidity. The above good tablet hardness was maintained.

  From these experimental results, when D-sorbitol is added, the tablet hardness after storage under accelerated conditions is significantly reduced, and when reduced maltose starch syrup and isomalt are used in combination, the tablet hardness after storage under accelerated conditions is reduced. It turned out that it falls remarkably. In addition, erythritol was preserved under accelerated conditions by not reducing tablet hardness after storage under accelerated conditions and by adding reduced maltose starch syrup to the active ingredient granulation unless used in combination with isomalt or D-sorbitol Later tablet hardness was found to be significantly improved.

Storage stability of the prototype compressed solid preparation:
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 a granulation liquid so that the HPC content per tablet was 4 mg, and only 1 mg calcium stearate per tablet was added and mixed as a post-additive. In the prototype tablet (specimen name: MP2-B) which was tableted with a tableting pressure of 0.8 t later, the amount of lactam hardly increased even after being stored 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 lactam body over time after tableting was observed.

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

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

And, when 4 mg of HPC per tablet is excluded from the granulated product of the sample name: MP2-A prototype tablet, the increase in lactam body over time is further suppressed (sample name: MP5). When the amount of HPC was increased to 8 mg per tablet, the degree of inhibition of the increase in lactam over time decreased (sample name: MP7-3).
From this fact, HPC essentially does not promote the formation of lactam body over time after tableting, but depending on the amount added, it may slightly produce lactam body over time after tableting. all right.

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

Furthermore, even in the trial tablet (sample name: MP8-1-2) in which 7 mg of reduced maltose starch syrup is added to the granulated product of the specimen name: MP2-A-2, the specimen name: MP2 The increase in lactam over time was substantially suppressed to the same extent as in the trial tablet of -A-2.
From this, it was found that even when 7 mg of reduced maltose starch syrup was added per tablet, the production of lactam bodies over time after tableting was not promoted.

And the significant suppression of the increase in the lactam body with time in the sample name: MP8-1-2 prototype tablet was achieved by increasing the amount of HPC in the granulated product to 8 mg per tablet (sample name: MP8). -2) also remained suppressed to the same extent.
This also indicates that HPC essentially does not promote the formation of lactam bodies over time after tableting.

Only 4% HPC solution was used as a granulation solution so that the content of HPC was 4 mg per tablet, and 2 mg croscarmellose sodium per tablet and 1 mg calcium stearate per tablet were added as post-additives. And then mixing 4 mg of D-mannitol per tablet into the granulated product of the trial tablet, which was tableted with a tableting pressure of 0.8 t after mixing. In the tablet (specimen name: MP3), the increase in lactam body over time was not suppressed at all.
From this, it was found that 4 mg of D-mannitol per tablet neither promotes nor inhibits the production of lactam body over time after tableting.

Similarly, only 4% HPC solution was used as a granulation solution so that the content of HPC was 4 mg per tablet, 2 mg croscarmellose sodium per tablet as a post-additive, and 1 mg calcium stearate per tablet Was added to and mixed, and then 10 mg isomalt per tablet was added as a post-additive to the prototype tablet (specimen name: MP2-A) that was tableted with a tableting pressure of 0.8 t. In the tablet (specimen name: MP2-A-1), the increase in lactam body over time was only slightly suppressed.
From this, it was found that 10 mg of isomalt per tablet slightly suppressed the formation of lactam body over time after tableting.

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

In addition, the lactam over time was also obtained in the trial tablet (specimen name: MP8-3-1) in which the amount of HPC in the granulated product of the specimen name: MP8-1-1 was increased to 8 mg per tablet. The increase in body remained largely suppressed.
This also indicates that HPC essentially does not promote the formation of lactam bodies over time after tableting.

Only 4% HPC solution was used as a granulation solution so that the content of HPC was 4 mg per tablet, and 2 mg croscarmellose sodium per tablet and 1 mg calcium stearate per tablet were added as post-additives. A test tablet (specimen name: MP2-A) tableted with a tableting pressure of 0.8 t and mixed with 7 mg of reduced maltose starch syrup into the granulated product of this test tablet (specimen) Name: MP8-1), although it was not a significant suppression of the increase in lactam body over time as the prototype tablet (sample name: MP4, MP7-1) added with 4 mg of D-sorbitol, the lactam body over time The increase of was suppressed to some extent.
From this, it was found that the addition of 7 mg of reduced maltose starch syrup per tablet can suppress the production of lactam body over time after tableting.

Specimen name: Even in the trial tablet (specimen name: MP8-3) in which the amount of HPC in the granulated product of the trial tablet of MP8-1 was increased to 8 mg per tablet, the sample name was the same as the prototype tablet of MP8-1. Although the suppression of the increase in lactam body over time was observed, the amount of lactam body produced over time was slightly increased by increasing the amount of HPC in the granulated product.
From this fact, HPC essentially does not promote the formation of lactam body over time after tableting, but depending on the amount added, it may slightly produce lactam body over time after tableting. all right.

Only 4% HPC solution was used as a granulation solution so that the content of HPC was 4 mg per tablet, and 2 mg croscarmellose sodium per tablet and 1 mg calcium stearate per tablet were added as post-additives. In contrast to the experimental tablet (sample name: MP2-A), which was compressed with a tableting pressure of 0.8 t after mixing, the experimental tablet in which 7 mg of erythritol was added to each granulated product of this experimental tablet ( Specimen name: MP9-1) was not as much suppression of the increase in lactam body over time as the prototype tablet (sample name: MP4, MP7-1) added with 4 mg of D-sorbitol, but the lactam over time The increase in body was suppressed to some extent.
From this, it was found that the addition of 7 mg of erythritol per tablet can suppress the production of lactam body over time after tableting 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 was increased to 8 mg per tablet was the same as the specimen name: MP9-1. Although the suppression of the increase in lactam body over time was observed, the amount of lactam body produced over time was slightly increased by increasing the amount of HPC in the granulated product.
From this fact, HPC essentially does not promote the formation of lactam body over time after tableting, but depending on the amount added, it may slightly produce lactam body over time after tableting. all right.

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

  The increase in lactam body over time is slightly increased by increasing the amount of HPC in the granulated product, while there is no change in the amount of lactam body even when D-mannitol is added to the granulated product. It was found that by adding reduced maltose starch syrup or erythritol in the granulated product, it was moderately suppressed. Further, the increase in lactam body over time is greatly suppressed by adding D-sorbitol to the granulated product, and also by adding isomalt and / or D-sorbitol as a post-additive. It was found to be greatly suppressed.

However, the tablet hardness after 7 days storage at 40 ° C. and 75% relative humidity 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 can't keep it. The tablet hardness after storage for 7 days at 40 ° C. and 75% relative humidity is the same even if the granulated product contains pregabalin drug substance, HPC, and reduced maltose starch syrup, and isomalt is added as a post-additive. It was found that the hardness could not be maintained.
Therefore, in the trial tablet shown in Table 9, only 4% HPC solution was used as a granulation liquid so that the HPC content per tablet was 4 mg, and only 1 mg calcium stearate per tablet was added as a post-additive. Except for the prototype tablet (specimen name: MP2-B), maintenance of tablet hardness during the expiration date and storage stability could not be achieved at the same time.

Trial production of compressed solid preparations ;
In order to establish the prescription of pregabalin preparations that can maintain hardness when stored at 40 ° C and 75% relative humidity, and to establish prescriptions for pregabalin preparations that are stable in storage, various trial tablets were prepared. The amount was verified.

  Additives used were hydroxypropylcellulose [HPC-L (trademark) normal particle type, Nippon Soda Co., Ltd.], reduced maltose starch syrup (Amalty MR100 (trademark), Mitsubishi Corporation Foodtech Co., Ltd.), sodium starch glycolate [primo Gel (trademark), Matsutani Chemical Industry], hydroxypropyl starch (HPS-101 (trademark), Freund Sangyo Co., Ltd.), corn starch (sun eclipse cornstarch (trademark), Nippon Shokuhin Kako Co., Ltd.), partially pregelatinized starch (PCS) (Trademark), Asahi Kasei Co., Ltd.], pregelatinized starch [Amicol (trademark), Nissho Chemical], low-substituted hydroxypropylcellulose [LH-11 (trademark), Shin-Etsu Chemical Co., Ltd.], D-mannitol for direct hitting [Partec M100 (trademark), Merck Millipore Co poration], croscarmellose sodium [Ac-Di-Sol (TM), Wilbur Ellis Co.], it was calcium stearate [Taihei Chemical Industry Co., Ltd.].

In accordance with Table 10, trial tablets were prepared using the main drug and additives in an amount of 8000 tablets. Specifically, 600 grams of pregabalin drug substance and reduced maltose starch syrup powder are weighed and put into a fluidized bed (FD-MP-01 type, Paulek), and 4% by mass prepared in advance for granulation. The aqueous HPC 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. When adding 4 mg of HPC per tablet, spraying amount of HPC aqueous solution is granulated while spraying 800 g of 4% by weight of HPC aqueous solution over about 67 minutes, and then adding 1.3 mg of HPC per tablet In some cases, it was granulated while spraying 260 g of a 4% by weight aqueous HPC solution for about 22 minutes. 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 as a powder. The obtained granulated product was dried as it was at 80 ° C. using a fluidized bed, and the obtained granulated product was measured for moisture content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). Dried to 1%. Thereafter, the mixture was sieved with a mesh 30 filter. The post-additives listed in Table 10 are added to the granulated product after drying and sieving in an amount of 8000 times the amount per tablet, mixed, and punched using a single tableting machine (AUTOTAB-500, Ichihashi Seiki). Tableting was performed at a tableting pressure of 0.8 t. The mass per tablet obtained as a result was as shown in Table 10.

  Of the prototype tablets listed in Table 10, all of the samples whose sample names begin with MP10 are granulated containing 4 mg of HPC per tablet, 7 mg of reduced maltose starch syrup and 75 mg of pregabalin per tablet. After the product is granulated in a fluidized bed and dried, in addition to 1 mg of calcium stearate per tablet, the additives listed in Table 10 are added so as to have the added amount per tablet listed in Table 10, By mixing and tableting with a tableting pressure of 0.8 t, a trial tablet capable of maintaining both tablet hardness and preventing the lactam body from increasing with time was investigated.

  Among the prototype tablets shown in Table 10, for samples whose sample name begins with MP11, a granulated product containing 1.3 mg of HPC per tablet, 20 mg of reduced maltose starch syrup and 75 mg of pregabalin per tablet In addition to 0.7 mg calcium stearate per tablet and 3 mg sodium starch glycolate per tablet, 20 mg or 40 mg D-mannitol for direct compression is added per tablet. Then, by mixing and tableting with a tableting pressure of 0.6 t, a trial tablet capable of maintaining both tablet hardness and preventing the lactam body from increasing with time was investigated.

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

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

  Specimen name: In the prototype tablet of MP10-1, specimen name: MP10-8 prototype tablet, except that 4 mg sodium starch glycolate per tablet was added later instead of 2 mg croscarmellose sodium per tablet Produced similarly.

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

  Specimen name: In the trial tablet of MP10-3, except that 4 mg of hydroxypripyr starch per tablet was added later instead of 2 mg of croscarmellose sodium per tablet, specimen name: Produced similarly.

  Specimen name: Manufactured in the same manner as the prototype tablet of MP10-8, except that MP10-4 prototype tablet was added with 4 mg corn starch per tablet instead of 2 mg croscarmellose sodium per tablet. did.

  Specimen name: In the prototype tablet of MP10-5, except that 4 mg of partially pregelatinized starch was added per tablet instead of 2 mg of croscarmellose sodium per tablet, the specimen name was: Produced similarly.

  Specimen name: For MP10-6 prototype tablet, specimen name: MP10-8, similar to the prototype tablet, except that 4 mg pregelatinized starch was added after each tablet instead of 2 mg croscarmellose sodium per tablet. Manufactured.

  Specimen name: MP10-7 prototype tablet Specimen name: MP10-8 prototype, except that 4 mg of low-substituted hydroxypropylcellulose per tablet was added later instead of 2 mg of croscarmellose sodium per tablet Produced in the same way as tablets.

  Specimen name: In the prototype tablet of MP10-10, in addition to 2 mg of croscarmellose sodium per tablet and 3 mg of sodium starch glycolate after tablet addition, the specimen name: MP10-8 Produced similarly.

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

  Specimen name: In the trial tablet of MP11-1, a granulated product containing 1.3 mg of HPC per tablet, 20 mg of reduced maltose starch syrup and 75 mg of pregabalin per tablet is fluidized and granulated. 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 compression per tablet were added, mixed, and compressed with a tableting pressure of 0.8 t. did.

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

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

  Granules containing 4 mg of HPC per tablet, 7 mg of reduced maltose starch syrup and 75 mg of pregabalin per tablet are fluid bed granulated, dried and then dried with 2 mg of croscarmellose sodium and 1 A trial tablet (specimen name: MP10-8) obtained by adding 1 mg of calcium stearate per tablet and mixing and compressing at a tableting pressure of 0.8 t was stored at 40 ° C. and 75% relative humidity for 7 days. The tablet hardness of 0.5 N was maintained, and the amount of lactam increased over time was small. This result generally coincided with the fact that the hardness of the tablet of Example 9 (Table 9), which was the same prescription: MP8-1, was maintained, and the lactam body increase was moderate over time.

  From this, the production of lactam 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 in the main drug granule. It turned out that it can suppress to some extent.

Similarly, in the prototype tablet (sample name: MP10-9) in which the addition amount of croscarmellose sodium was reduced to 1 mg per tablet in the prototype tablet of the specimen name: MP10-8, 40 ° C. and 75% relative humidity. After 7 days of storage, the tablet hardness was maintained, and the amount of lactam increased over time was still smaller.
From this, it was found that the smaller the amount of croscarmellose sodium added, the less the lactam body produced over time after tableting.

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

Specimen name: Prototype tablet (sample name: MP10-2) in which 4 mg of sodium starch glycolate was reduced to 3 mg per tablet of the MP10-1 prototype tablet was stored for 7 days at 40 ° C. and 75% relative humidity. As a result, no increase in lactam over time was observed, but the tablet hardness decreased to 20.0 N.
This shows that sodium starch glycolate does not promote the formation of lactam over time after tableting, and that it decreases tablet hardness over time according to the amount of sodium starch glycolate added. It was.

Specimen name: Prototype tablet (sample name: MP10-3), in which 4 mg of hydroxypripyr starch was added after 1 tablet instead of 2 mg of croscarmellose sodium per tablet in the prototype tablet of MP10-8, 1 Prototype tablet (sample name: MP10-4) after addition of 4 mg corn starch per tablet, prototype tablet (sample name: MP10-5) after addition of 4 mg partially pregelatinized starch per tablet, 4 mg α per tablet Each of the trial tablets (sample name: MP10-7) to which 4 mg of L-HPC was added after the addition of the modified starch (sample name: MP10-6) was added at 40 ° C. and 75% relative humidity. Even after being stored for 7 days, the tablet hardness was maintained at about 38 N or more, and the amount of lactam increased over time was small.
Therefore, these formulations were found to be compatible with maintaining the tablet hardness during the expiration date and suppressing the generation of lactam body over time after tableting.

In the prototype tablet of the sample name: MP10-8, a prototype tablet (sample name: MP10-10) to which 3 mg of sodium starch glycolate was further added per tablet was stored for 7 days at 40 ° C. and 75% relative humidity. Later, the amount of lactam increased over time was very small, but the tablet hardness decreased to 23.8N.
From this, it was found that sodium starch glycolate did not promote the formation of lactam body over time after tableting, but at the same time, it was found that the tablet hardness was lowered over time.

In the trial tablet of the above-mentioned sample name MP10-8, instead of 2 mg of croscarmellose sodium per tablet, 7 mg of sodium starch glycolate and 60 mg of mannitol for direct compression per tablet were post-added. In (Specimen name: MP10-11), the amount of lactam increased with time after being stored at 40 ° C. and 75% relative humidity for 7 days remained small, but the tablet hardness decreased to 20.5 N.
From this, it was found that sodium starch glycolate did not promote the production of lactam body over time after tableting, but at the same time, it was found that the tablet hardness was lowered over time.

Granules containing 1.3 g of HPC per tablet, 20 mg of reduced maltose starch syrup and 75 mg of pregabalin per tablet by adjusting the amount of additive in the test sample name: MP10-11 After the product is granulated and dried, 3 mg of sodium starch glycolate per tablet, 20 mg of D-mannitol for direct compression and 1 mg of calcium stearate per tablet are added and mixed. Although the trial tablet (specimen name: MP11-1) which was tableted with the tableting pressure of 5%, the increase in lactam body over time after storage for 7 days at 40 ° C. and 75% relative humidity was small, but the tablet hardness Dropped to 15.0 N.
From this, it was found that sodium starch glycolate did not promote the production of lactam body over time after tableting, but at the same time, it was found that the tablet hardness was lowered over time.

The above-mentioned sample name: the prototype tablet (sample name: MP11-2) in which the amount of D-mannitol for direct compression in the prototype tablet of MP11-1 was increased to 40 mg per tablet was stored at 40 ° C. and 75% relative humidity for 7 days. After that, the amount of lactam increased over time further increased slightly, and the tablet hardness decreased to 13.5N.
From this, it was found that sodium starch glycolate did not promote the production of lactam body over time after tableting, but at the same time, it was found that the tablet hardness was lowered over time. In addition, it was found that D-mannitol for direct compression does not promote the formation of a lactam body over time after tableting, but at the same time, it was found that the tablet hardness was decreased over time depending on the amount added.

  From the above experimental results, a granulated product containing 4 mg of HPC per tablet, 7 mg of reduced maltose starch syrup and 75 mg of pregabalin per tablet was fluid bed granulated, dried, and 1 mg per tablet. Post-additives added with calcium stearate include 4 mg hydroxypropyl starch (sample name: MP10-3) per tablet, 4 mg corn starch (sample name: MP10-4) per tablet, 4 mg of partial α per tablet Modified starch (specimen name: MP10-5), 4 mg of α-modified starch (sample name: MP10-6) per tablet, 4 mg of L-HPC (sample name: MP10-7) per tablet is 40% 75% Even after storage for 7 days at relative humidity, the tablet hardness is maintained at about 38 N or more, and the increase in lactam body over time is only a small amount. Therefore, it was most suitable for both maintaining tablet hardness and preventing lactam body formation over time.

  Also, granulate containing 4mg HPC per tablet, 7mg reduced maltose starch syrup and 75mg pregabalin per tablet is fluid bed granulated and dried, then added with 1mg calcium stearate per tablet When 4 mg sodium starch glycolate (sample name: MP10-1) per tablet or 3 mg sodium starch glycolate (sample name: MP10-2) per tablet is used as a post-additive, 40 Even after storage for 7 days at 75 ° C. relative humidity, no increase in lactam over time was observed, which was the best in terms of preventing lactam formation over time, but the tablet hardness was insufficiently maintained Met.

  When 4 mg sodium starch glycolate (sample name: MP10-1) per tablet or 3 mg sodium starch glycolate (sample name: MP10-2) per tablet was used, the amount of sodium starch glycolate added was Although a tendency for the tablet hardness to decrease in proportion was observed, a prototype tablet (sample name: MP10-1) containing 4 mg of sodium starch glycolate per tablet was 4 mg of hydroxypropyl starch (sample name). MP10-3) 4 mg corn starch (sample name: MP10-4) per tablet 4 mg partially pregelatinized starch (sample name: MP10-5) per tablet 4 mg pregelatinized starch (sample name MP10) -6) Compared with the case where 4 mg of L-HPC was used per tablet, the disintegration was better. That is, when a disintegration time of 50 rotations was confirmed with a dissolution tester, a prototype tablet (sample 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 addition amount of sodium starch glycolate in the formulation of specimen name: MP10-1 or specimen name: MP10-2.

  In response to the results of Example 9 and Example 10, the sample name of Example 9: MP2-A prototype tablet (sample name: MP2 main drug granules, MP2 tableting powder, MP2 tablet, MP2 tablet pulverized product), and Specimen name of Example 10: Prototype tablet of MP10-2 prototype tablet in which the amount of sodium starch glycolate was reduced to 2 mg per tablet (Specimen name: MP8-1-4 main drug granule, for MP8-1-4 tableting) Powder, MP8-1-4 tablet, MP8-1-4 tablet pulverized product), the main drug granule, the tableting powder, tablet, and pulverized tablet in a mortar, 40 ° C 75% relative humidity The amount of lactam in the state before and after storage for 7 days was examined. Moreover, about the test tablet of sample name: MP2, and the test tablet of sample name: MP8-1-4, the tablet hardness of the state before and behind storage for 7 days was measured at 40 degreeC75% relative humidity.

  Additives used were hydroxypropylcellulose [HPC-L (trademark) normal particle type, Nippon Soda Co., Ltd.], reduced maltose starch syrup (Amalty MR100 (trademark), Mitsubishi Corporation Foodtech Co., Ltd.), sodium starch glycolate [primo Gel (trademark), Matsutani Chemical Industry], croscarmellose sodium (Ac-Di-Sol (trademark), Wilber Ellis Co., Ltd.), calcium stearate (Taihei Chemical Industry Co., Ltd.).

In accordance with Table 11, trial tablets were prepared using the main drug and additives in an amount of 8000 tablets. Specifically, for the specimen of specimen name: MP8-1-4, 600 g of pregabalin drug substance and 56 g of reduced maltose starch syrup are weighed and put into a fluidized bed (FD-MP-01 type, Paulek), Granulation was performed while spraying 800 g of 4 mass% HPC aqueous solution prepared for granulation at a speed of 12 grams per minute at an intake temperature of 80 ° C. and an exhaust temperature of 30 ° C. for about 67 minutes. Specimen name: For the specimen of MP2, 600 g of pregabalin drug substance is weighed and put into a fluidized bed (FD-MP-01 type, Paulek), and 800 g of a 4% by mass HPC aqueous solution prepared in advance for granulation is used. Granulation was carried out while spraying at a speed of 12 grams per minute 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 moisture content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). Dried to 1%. Thereafter, the mixture was sieved with a mesh 30 filter. The post-additives listed in Table 11 are added to the granulated product after drying and sieving in an amount of 8000 times the amount per tablet, mixed, and punched using a single tableting machine (AUTOTAB-500, Ichihashi Seiki). Tableting was performed at a tableting pressure of 0.8 t. The mass per tablet obtained as a result was as shown in Table 11.

  First, for samples whose sample name starts with MP2, a granulated product containing 4 mg of HPC per tablet and 75 mg of pregabalin per tablet is fluidized-bed granulated 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 t. Thus, a trial tablet was manufactured, and further, a “tablet pulverized product” was manufactured by pulverizing the tablet using a mortar.

  For samples whose sample name begins with MP8-1-4, granulate containing 4 mg of HPC per tablet, 7 mg of reduced maltose starch syrup and 75 mg of pregabalin per tablet is fluidized and granulated. To produce “powder granule”, add 2 mg sodium starch glycolate per tablet and 1 mg calcium stearate per tablet and mix to produce “tablet powder”. Trial tablets were produced by tableting with a tableting pressure of 0.8 t, and further a “tablet pulverized product” produced by pulverizing the tablets using a mortar was produced.

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

  The amount of lactam body of “main drug granules” (specimen name: MP2 main drug granules) obtained by fluidized bed granulation of granulate containing 4 mg HPC per tablet and 75 mg pregabalin per tablet, There was almost no change before and after storage at 40 ° C. and 75% relative humidity for 7 days.

  “Tablet powder” (sample name: obtained by adding 2 mg croscarmellose sodium per tablet and 1 mg calcium stearate per tablet to the “main drug granules” (sample name: MP2 main drug granules) and mixing. The amount of the lactam body of the MP2 tableting powder) hardly changed before and after storage at 40 ° C. and 75% relative humidity for 7 days.

  However, the “tablet” (sample name: MP2 tablet) obtained by compressing the “tablet powder” (specimen name: MP2 tableting powder) with a tableting pressure of 0.8 t is 40 ° C. and 75%. Storage for 7 days at relative humidity significantly increased the amount of lactam 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, even if croscarmellose was added alone, the formation of lactam body over time did not occur, but when this was tableted, the production of lactam body over time occurred. In addition, it was found that the tablet of the specimen name: MP2 containing croscarmellose is excellent in terms of maintaining tablet hardness.

The “tablet pulverized product” (specimen name: MP2 tablet pulverized product) obtained by pulverizing the “tablet” (specimen name: MP2 tablet) in a mortar was also stored for 7 days at 40 ° C. and 75% relative humidity. In particular, the amount of lactam increased significantly.
From this, the production of lactam body over time after tableting is not simply due to the compacted state, but the production of lactam body over time is promoted by the impact of tableting and the storage stability is impaired, and once tableted After that, it was found that even when pulverized to release the compacted state, the generation of lactam body over time is still promoted.

  On the other hand, a granulated product containing 4 mg of HPC per tablet, 7 mg of reduced maltose starch syrup and 75 mg of pregabalin per tablet is fluid bed granulated and dried to obtain a “main drug granule” (specimen name: The amount of the lactam body of MP8-1-4 main drug granule) hardly changed before and after storage at 40 ° C. and 75% relative humidity for 7 days.

  “Tablet powder” 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 granule) and mixing. The amount of the lactam body of (Specimen name MP8-1-4 Tableting Powder) also hardly changed before and after storage at 40 ° C. and 75% relative humidity for 7 days.

  “Tablets” (sample name: MP8-1-4 tablets) obtained by tableting the “tablet powder” (sample name: MP8-1-4 tableting powder) with a tableting pressure of 0.8 t. Also, the amount of lactam was almost unchanged before and after storage at 40 ° C. and 75% relative humidity for 7 days. The tablet hardness (sample name: MP8-1-4 tablet) decreased from 57.3N to 36.3N when stored for 7 days at 40 ° C and 75% relative humidity. Had.

  Therefore, the main drug granules were granulated using HPC and reduced maltose starch syrup, and the sample name: MP8-1-4, a prototype tablet with the amount of sodium starch glycolate per tablet in the post-additive suppressed to 2 mg, It was found that the prescription is compatible with both maintaining tablet hardness during the expiration date and suppressing the formation of lactam over time after tableting.

The amount of the lactam body of the “tablet pulverized product” (sample name: MP8-1-4 tablet pulverized product) obtained by pulverizing the “tablet” (sample name: MP8-1-4 tablet) in a mortar is also 40 ° C. There was little change before and after storage for 7 days at 75% relative humidity.
From this, it was found that if the formulation does not produce lactam body over time after tableting, even if this is pulverized, the production of lactam body over time after tableting will not occur. .

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

  On the other hand, a granulated product containing 4 mg of HPC per tablet and 75 mg of pregabalin per tablet is fluidized-bed granulated and dried to produce a “main drug granule”, to which 2 mg of croscarmellose per tablet is prepared. Sodium and 1 mg calcium stearate per tablet were added and mixed to produce a “tablet powder”, which was obtained by tableting with a tableting pressure of 0.8 t (specimen name: MP2 The tablet) had a sufficient tablet hardness after being stored at 40 ° C. and 75% relative humidity for 7 days, but a marked increase in lactam body over time was observed.

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

  In addition, even when the sample tablet of the sample name “MP2 tablet” was pulverized and the sample was released from the compacted state, a remarkable increase in lactam body over time was observed as in the case where the sample was not pulverized. This means that the increase in lactam body over time of the tablet product is not brought about by the “consolidation state” during storage, but it means that the lactam body starts to increase due to the impact of tableting. It was a result.

Trial production of compressed solid preparations ;
Established a pregabalin formulation that can maintain hardness when stored at 40 ° C and 75% relative humidity, and does not produce lactam over time after tableting. Therefore, the hardness and the amount of lactam body of various prototype tablets were examined under petri dish release conditions and aluminum sealing conditions.

Additives used were hydroxypropylcellulose [HPC-L (trademark) normal particle type, Nippon Soda Co., Ltd.], reduced maltose starch syrup (Amalty MR100 (trademark), Mitsubishi Corporation Foodtech Co., Ltd.), sodium starch glycolate [primo Gel (trademark), Matsutani Chemical Industry], croscarmellose sodium (Ac-Di-Sol (trademark), Wilber Ellis Co., Ltd.), calcium stearate (Taihei Chemical Industry Co., Ltd.).

  According to Table 12, trial tablets were prepared using the main drug and additives in an amount of 8000 tablets. Specifically, 600 g of pregabalin drug substance and 56 g of reduced maltose starch syrup are weighed and put into a fluidized bed (FD-MP-01 type, Paulek), and 4% by mass prepared in advance for granulation. The aqueous HPC 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. When adding 4 mg of HPC per tablet, the spray amount and spraying time of the HPC aqueous solution are those when granulating while spraying 800 g of 4% by weight of HPC aqueous solution for about 67 minutes and adding 8 mg of HPC per tablet. Is granulated while spraying 1600 g of 4% by weight aqueous HPC solution for about 133 minutes, and when adding 1.5 mg of HPC per tablet, it is granulated while spraying 300 g of 4% by weight aqueous HPC solution for about 25 minutes. did. The obtained granulated product was dried as it was at 80 ° C. using a fluidized bed, and the obtained granulated product was measured for moisture content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). Dried to 1%. Thereafter, the mixture was sieved with a mesh 30 filter. The post-additives listed in Table 12 are added to the granulated product after drying and sieving in an amount of 8000 times the amount per tablet, mixed, and punched using a single tableting machine (AUTOTAB-500, Ichihashi Seiki). Tableting was performed at a tableting 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 specimen name: MP8-1-3, a mixture containing 4 mg of HPC per tablet, 7 mg of reduced maltose starch syrup and 75 mg of pregabalin per tablet is fluidized and granulated. Thereafter, 1 mg of sodium starch glycolate per tablet and 1 mg of calcium stearate per tablet were added and mixed, and tableted with a tableting pressure of 0.8 t.

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

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

  Specimen name: MP8-3-3 In the test tablet: 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. -3.

  Specimen name: In a trial tablet of N3-9, a mixture containing 1.5 mg of HPC per tablet, 7 mg of reduced maltose starch syrup and 75 mg of pregabalin per tablet is fluidized and granulated, and dried. 2 mg sodium starch glycolate per tablet and 1 mg calcium stearate per tablet were added and mixed, and tableted with a tableting pressure of 0.8 t.

  Specimen name: N3-4 Trial tablet: Specimen name: N3-4, except that 2 mg sodium starch glycolate in the trial tablet of N3-9 specimen name was changed to 2 mg croscarmellose sodium per tablet. It was manufactured in the same manner as the 9 trial tablets.

Dissolvability of prototype solid preparation, hardness change over time and increase in lactam body:
Specimen name: MP8-1-3, Specimen name: MP8-1-4, Specimen name: MP8-1-5, and Specimen name: MP8-3-3 prototype tablets are respectively 40 ° C. and 75% relative humidity. The sample was stored in a petri dish open condition and sealed in an aluminum bag, and the tablet hardness and the amount of lactam after 7 days and 14 days were measured at the start of storage.

Specimen name: N3-9 trial tablet and specimen name: N3-4 trial tablet are stored at 40 ° C. and 75% relative humidity only under petri dish open conditions, tablet hardness at the start of storage and after storage for 7 days, and At the start of storage, the amount of lactam after 7 days and 14 days was measured.
The measurement results were as shown in Table 12.

  A mixture containing 4 mg of HPC per tablet, 7 mg of reduced maltose starch syrup and 75 mg of pregabalin per tablet is fluid bed granulated, dried, and then dried with 1 mg sodium starch glycolate per tablet and per tablet. A trial tablet (sample name: MP8-1-3), which was mixed with 1 mg of calcium stearate and mixed at a tableting pressure of 0.8 t, was stored for 14 days in a petri dish open condition at 40 ° C. and 75% relative humidity. After that, the lactam body increased little 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: Prototype tablet (specimen name: MP8-1-4) in which 1 mg of sodium starch glycolate was added to 2 mg per tablet to be added later in the trial tablet of MP8-1-3 was 75 ° C. at 40 ° C. Even after 14 days of storage in relative humidity under petri dish open conditions, there was almost no increase in lactam over time, and the tablet hardness after 7 days of storage also maintained a good tablet hardness of 36.3 N. However, the dissolution rate after 15 minutes in water was only 80.5%, and the dissolution property was insufficient.

Specimen name: Trial tablet (specimen name: MP8-1-5) obtained by increasing 1 mg of sodium starch glycolate to 4 mg per tablet to be added later in the trial tablet of MP8-1-3 is 40% 75%. Even after storage for 14 days in a petri dish under relative humidity, there was almost no increase in lactam over time, and the elution rate after 15 minutes in water reached 99.0%, which was very good. The tablet hardness after storage for 7 days in a petri dish open condition in 40 ° C. and 75% relative humidity was reduced to 23.3 N, and the tablet hardness could not be maintained at 20 N or higher. Therefore, when the tablet hardness after 14 days of storage at 40 ° C. and 75% relative humidity in a petri dish open condition was traced, the tablet hardness of 23.0 N was still maintained. It was confirmed that it did not progress.
From this, the sample name: MP8-1-3 prototype tablet can maintain hardness when stored at 40 ° C. and 75% relative humidity, and the lactam body can be produced over time after tableting. In addition, it was found to be a pregabalin preparation formulation having good dissolution properties.

  Specimen name: 1 mg of sodium starch glycolate per tablet added later in the trial tablet of MP8-1-3 was increased to 4 mg per tablet, and the amount of HPC in the granulated product was changed from 4 mg to 1 tablet per tablet. Prototype tablet (specimen name: MP8-3-3) increased to 8 mg per sample, and after 14 days storage at 40 ° C. and 75% relative humidity under petri dish open conditions, a slight increase in lactam over time was observed. The tablet hardness after storage for 7 days was maintained at 29.0 N, but the dissolution rate after 15 minutes in water 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 were sealed in an aluminum bag, and the environment was 40 ° C. and 75% relative humidity. In all of these prototype tablets, the amount of lactam after 14 days was remarkably increased.
Therefore, it is undesirable to store a tablet containing a γ-aminobutyric acid derivative in a sealed manner because it promotes the formation of a lactam body over time after tableting. Therefore, it is not a sealed package but an airtight package. It turned out to be desirable to have a form.

A mixture containing 1.5 mg HPC per tablet, 7 mg reduced maltose starch syrup, and 75 mg pregabalin per tablet is fluid bed granulated, dried, and then dried with 2 mg sodium starch glycolate and 1 1 mg of calcium stearate per tablet was added and mixed, and the prototype tablet (sample name: N3-9) tableted with a tableting pressure of 0.8 t was stored for 14 days in a petri dish open condition at 40 ° C. and 75% relative humidity. After that, the lactam body increased little over time, but the tablet hardness was only 20.5 N at the start of storage, and decreased to 10.5 N after 7 days. Hardness was insufficient.
From this, in order to maintain tablet hardness, it was found that the amount of HPC in the main drug granule was not sufficient at 1.5 mg per tablet, and 4 mg or more per tablet was necessary.

Specimen name: A prototype tablet (specimen name: N3-4) obtained by changing the post-additive of 2 mg sodium starch glycolate to 2 mg croscarmellose sodium per tablet in the prototype tablet of N3-9 Although the increase in lactam over time after storage for 14 days under petri dish open conditions in 75 ° C. relative humidity was only small, the tablet hardness was only 21.5 N even at the start of storage, and after 7 days had passed. Was reduced to 10.0 N, and the tablet hardness was insufficient.
Also from this fact, it was found that the amount of HPC in the main drug granules was not sufficient at 1.5 mg per tablet to maintain tablet hardness, and 4 mg or more of HPC per tablet was necessary.

  From the above experimental results, a granulated product containing 4 mg of HPC per tablet, 7 mg of reduced maltose starch syrup and 75 mg of pregabalin per tablet was fluidized and dried, and after drying, 4 mg per tablet. Prototype tablet (specimen name: MP8-1-5), in which starch starch glycolate and 1 mg of calcium stearate per tablet are added and mixed, and compressed at a tableting pressure of 0.8 t, has extremely good dissolution properties. In addition, it was confirmed that the lactam body hardly increased over time even after being stored in a petri dish open condition at 40 ° C. and 75% relative humidity for 14 days, and good tablet hardness could be maintained.

  However, it was found that if this is a packaging form that is sealed using an aluminum bag or the like, the lactam body significantly increases with time, so that it should not be sealed. In general, the preferred packaging forms for maintaining the stability of pharmaceutical preparations are (1) hermetic packaging, (2) hermetic packaging, and (3) hermetic packaging, and hermetic packaging is most preferred. It was surprising that the stability of pregabalin in pregabalin formulations was impaired.

Trial production of compressed solid preparations ;
In order to establish a pregabalin formulation that can maintain tablet hardness when stored at 40 ° C and 75% relative humidity, has good dissolution properties, and is stable in storage, a variety of prototype tablets are produced. And examined.

  Additives used were hydroxypropylcellulose [HPC-L (trademark) normal particle type, Nippon Soda Co., Ltd.], reduced maltose starch syrup (Amalty MR100 (trademark), Mitsubishi Corporation Foodtech Co., Ltd.), sodium starch glycolate [primo Gel (trademark), Matsutani Chemical Industry], calcium stearate [Taihei Chemical Industry Co., Ltd.], titanium oxide [Freund Sangyo Co., Ltd.], and talc [San-Eigen FFI Co., Ltd.].

In accordance with Table 13, trial tablets were prepared using the main drug and additives in an amount of 8000 tablets. Specifically, for each prototype tablet of specimen names: MP10S, MP10-1, MP10-2, MP10-3, and MP10-4, 600 g of pregabalin drug substance and 56 g of reduced maltose starch syrup are weighed and fluidized bed ( FD-MP-01 type, Paulek) and 800 g of a 4% by mass HPC aqueous solution prepared in advance for granulation at a speed of 12 grams per minute at an intake temperature of 80 ° C. and an exhaust temperature of 30 ° C. Granulation while spraying for about 67 minutes. Specimen name: For each of the prototype tablets of MP11S, MP11-1, MP11-2, and MP11-4, 600 g of pregabalin drug substance and 480 g of reduced maltose starch syrup powder were weighed and fluidized bed (FD-MP-01 type, Paulek) 1400 g of a 4% by weight HPC aqueous solution previously prepared for granulation is sprayed at a speed of 12 grams per minute at an intake temperature of 80 ° C. and an exhaust temperature of 30 ° C. for about 117 minutes. did. The obtained granulated product was dried as it was at 80 ° C. using a fluidized bed, and the obtained granulated product was measured for moisture content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). Dried to 1%. Thereafter, the mixture was sieved with a mesh 30 filter. The post-additives listed in Table 13 are added to the granulated product after drying and sieving in an amount of 8000 times the amount per tablet, mixed, and punched using a single tableting machine (AUTOTAB-500, Ichihashi Seiki). Tableting was performed at a tableting pressure of 0.8 t. The mass per tablet of the resulting uncoated tablets and film-coated tablets was as shown in Table 13.

The manufacturing method of each trial manufacture tablet was as follows.
First, in a sample tablet (uncoated tablet) of sample name: MP10S, a mixture containing 4 mg of HPC per tablet, 7 mg of reduced maltose starch syrup and 75 mg of pregabalin per tablet is fluid bed granulated and dried. Thereafter, 4 mg of sodium starch glycolate per tablet and 1 mg of calcium stearate per tablet were added and mixed, and tableted with a tableting pressure of 0.8 t.

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

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

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

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

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

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

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

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

Dissolvability of prototype solid preparation, hardness change over time and increase in lactam body:
A mixture containing 4 mg of HPC per tablet, 7 mg of reduced maltose starch syrup and 75 mg of pregabalin per tablet is fluid bed granulated, dried, and then dried with 4 mg sodium starch glycolate per tablet and per tablet. Prototype tablets (sample names: MP10S, MP10-1, MP10-2) having uncoated tablets (sample name: MP10S prototype tablets) added with 1 mg of calcium stearate, mixed, and compressed with a tableting pressure of 0.8 t , MP10-3 and MP10-4) all showed only a very small increase in lactam over time after storage for 7 days under petri dish open conditions in 40 ° C. and 75% relative humidity.

  Among these, the prototype tablets of specimen names: MP10S, MP10-2, MP10-4 were eluted 95% after 15 minutes with respect to water at the start of storage, and showed very good dissolution properties ( Specimen name: The elution properties of MP10-1 and MP10-3 have not been confirmed.)

  Similarly, prototype tablets of specimen names: MP10S, MP10-2, and MP10-4, after being stored for 7 days in a petri dish open condition in 40 ° C. and 75% relative humidity, 20.0N, 23.0N, It had a tablet hardness of 23.0 N, and both were acceptable tablet hardness (sample names: MP10-1 and MP10-3 have not been confirmed yet).

  Based on these facts, the sample name: MP10S prototype tablet and the sample tablet (sample names: MP10-1, MP10-2, MP10-3, MP10-4) coated with a film are 40 ° C. and 75% relative humidity. It was found that it was a pregabalin formulation that was able to maintain tablet hardness, had good dissolution properties, and was stable when stored.

  A mixture containing 7 mg of HPC per tablet, 60 mg of reduced maltose starch syrup and 75 mg of pregabalin per tablet is fluidized and granulated, dried, and then dried with 7 mg sodium starch glycolate and 1 tablet. Prototype tablets (sample names: MP11S, MP11-1, MP11-2) having uncoated tablets (sample name: MP11S prototype tablets) mixed with 2 mg calcium stearate added and mixed at a tableting pressure of 0.55 t , MP11-4) all had a small increase in lactam over time after storage for 7 days in a petri dish open condition in 40 ° C. and 75% relative humidity, but the specimen names: MP10S, MP10− 1, MP10-2, MP10-3, MP10-4 was clearly more than the prototype tablets.

  Moreover, among these, as for the trial tablet of specimen name: MP11S, MP11-2, MP11-4, the elution rate after 15 minutes with respect to water at the time of a storage start is 77.0%, 73.0, respectively. %, 79.0%, and insufficient dissolution was less than 85%.

  The tablet hardness after the test tablets of these specimen names: MP11S, MP11-2, and MP11-4 were stored in 40 ° C. and 75% relative humidity for 7 days under petri dish release conditions was 30.0N, 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 test 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 body over time after tableting. It was found that the production of was limited to a small amount, and although sufficient tablet hardness could be maintained, it was not preferable in terms of dissolution.

  Moreover, tablet hardness can be maintained when the addition amount of HPC is about 4.4% (4 mg per tablet) in 1 tablet weight, and the addition amount of sodium starch glycolate is 4 in 1 tablet weight. It was found that good dissolution was obtained when the concentration 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 lactam over time after tableting, it is sufficient to contain about 7.7% (7 mg per tablet) of reduced maltose starch syrup (sample name). : MP10-1, MP10-2, MP10-3, MP10-4) and about 40% of reduced maltose starch syrup contained in one tablet mass (60 mg per tablet) (Sample names: MP11S, MP11-1, MP11-2, MP11-4).

  Thus, each sample tablet of specimen name: MP10S, MP10-1, MP10-2, MP10-3, MP10-4 and the prototype tablet of specimen name: MP11S, MP11-1, MP11-2, MP11-4 are compared. Therefore, even if the amount of reduced maltose starch syrup is increased, the increase in lactam body over time after tableting is not suppressed, the decrease in tablet hardness over time is not suppressed, and the dissolution is rather decreased. I found out that

  On the other hand, if the mixing ratio of the trial tablets of MP10S, MP10-1, MP10-2, MP10-3, MP10-4 with a small amount of reduced maltose starch syrup in the main drug granule, the increase in lactam body over time is extremely small, It was found that it has very good dissolution properties and has sufficient tablet hardness even after storage under accelerated conditions. The tablet hardness was found to be improved by film coating.

Trial production of compressed solid preparations ;
From the results of Examples 1 to 13, the sample name of Example 13: MP10S prototype tablet was determined as a prescription for a tablet containing 75 mg pregabalin per tablet (hereinafter referred to as “75 mg tablet”). Accelerated testing was performed by determining the tablets with double the amount of each additive as a provisional final formulation (manufacturing formulation) of tablets containing 150 mg of pregabalin per tablet (hereinafter referred to as “150 mg tablets”). did. In addition, the same additive as was used for Example 13 was used for the following manufacture prescriptions.

  As an actual production formulation of 75 mg tablets, 2 batches were produced on a scale of 50,000 tablets. Specifically, 3750 g of pregabalin drug substance and 350 g of reduced maltose starch syrup are weighed and put into a fluidized bed (FLO-5, Freund Sangyo) and 5000 g of a 4% by mass HPC aqueous solution prepared in advance for granulation. Was granulated while spraying at a speed of 50 grams per minute at an intake temperature of 80 ° C. and an exhaust temperature of 30 ° C. 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 moisture content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). Dried to 1%. Thereafter, the mixture was sieved with a mesh 30 filter. This was repeated twice, and after adding 2 batches of dried and sieved granules, 400 g of sodium starch glycolate and 100 g of calcium stearate were added and mixed, and using a tableting machine (HT-P18A, Hata Plant). Tableting was performed at a tableting pressure of 0.8 t at a mass of 91 mg per tablet.

  As an actual production formulation of 150 mg tablets, 2 batches were produced on a scale of 25,000 tablets. Specifically, 3750 g of pregabalin drug substance and 350 g of reduced maltose starch syrup are weighed and put into a fluidized bed (FLO-5, Freund Sangyo) and 5000 g of a 4% by mass HPC aqueous solution prepared in advance for granulation. Was granulated while spraying at a speed of 50 grams per minute at an intake temperature of 80 ° C. and an exhaust temperature of 30 ° C. 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 moisture content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). Dried to 1%. Thereafter, the mixture was sieved with a mesh 30 filter. This was repeated twice, and after adding 2 batches of dried and sieved granules, 400 g of sodium starch glycolate and 100 g of calcium stearate were added and mixed, and using a tableting machine (HT-P18A, Hata Plant). The tablet was compressed with a tableting pressure of 0.8 t at a mass of 182 mg per tablet.

  On the other hand, as a prescription for a tablet containing 25 mg pregabalin per tablet (hereinafter referred to as “25 mg tablet”), the amount of each additive in the prototype tablet of specimen name of Example 13: MP10S was simply 3 of 75 mg tablet. If it is reduced to a fraction, the mass per tablet will be only 30.3 mg, and it will be too small, so the main drug granules in the 25 mg tablet will contain the contents of pregabalin, HPC and reduced maltose starch syrup added. While it is simply reduced to a third of 75 mg tablets (25 mg pregabalin, 1.3 mg HPC, 2.3 mg reduced maltose starch syrup), the post-additives for 25 mg tablets are simply one third. The amount of sodium starch glycolate is 3 mg per tablet, which is more than 1.3 mg per tablet. For calcium phosphate, 0.7 mg per tablet, more than 0.3 mg per tablet, which is one third of the amount, and 37.7 mg of D-mannitol for direct compression per tablet was added as a post-additive. The tablets prepared in this manner were determined as a temporary final formulation of 25 mg tablets, and an accelerated test was performed.

  The actual formulation of 25 mg tablets is manufactured at a scale of 100,000 tablets, 2500 g of pregabalin drug substance and 230 g of reduced maltose starch syrup are weighed and put into a fluidized bed (FLO-5, Freund Industries), and granulated in advance. Then, 3250 g of a 4% by mass aqueous HPC solution prepared for use was granulated at a speed of 50 grams per minute while spraying at an intake temperature of 80 ° C. and an exhaust temperature of 30 ° C. for about 65 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 moisture content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). Dried to 1%. Thereafter, the mixture was sieved with a mesh 30 filter. Add and mix 3770 g of D-mannitol for direct compression, 300 g of sodium starch glycolate and 70 g of calcium stearate to the granulated product after drying and sieving, and use a tableting machine (HT-P18A, Hata Plant). Tableting was performed at a tableting pressure of 0.8 t at a mass of 70 mg per tablet.

  About the temporary final prescription of said 25 mg tablet, 75 mg tablet, and 150 mg tablet, these were manufactured on the actual production scale, and the detailed confirmation was performed.

  Specifically, (1) Presence or absence of defects in the granulation / drying process, (2) Particle size distribution of dry granules, (3) Mixing uniformity after post-addition, (4) Mixture after adding calcium stearate ( Bulk density and angle of repose of tablet powder), (5) presence or absence of tableting failure, (6) variation in the mass of each tablet, (7) solubility in water, (8) dissolution in pH 1.2 dissolution test solution (9) Dissolution to pH 4.0 dissolution test solution, (10) Dissolution to pH 6.8 dissolution test solution, (11) Change in tablet hardness over time, (12) Lactam body weight over time (13) Bitterness was confirmed.

  The specific production process for the 75 mg tablet was as follows. The production process was the same for the production of 25 mg tablets and 150 mg tablets except that the amount of additives was different.

(1) Manufacture of main drug granules 3750 g of pregabalin drug substance powder and 350 g of reduced maltose starch syrup (Amalty MR100) were mixed using a fluidized bed granulator (FLO-5, Freund Sangyo), and 4800 g of 200 g of HPC was mixed. Granulation was carried out while spraying the solution dissolved in water. After granulation, dry with a fluidized bed granulator, sample approximately 10 g, measure the loss on drying using a loss on drying measuring device (MOC-120H, manufactured by Shimadzu Corporation), and the loss on drying is 1% or less. I confirmed that. This was repeated twice.

  Subsequently, using an ND-30S granulator, the granules were sized using a screen with a diameter of 0.5 mm, and this was used as the main drug granule. About 10 g was sampled, and the particle size distribution of the main drug granule after sizing was measured with Microtrac MT3000. (Microtrack Bell Co., Ltd.) was used and measured under dry conditions.

(2) Addition and mixing of post-additives (tablet powder)
The whole 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 mixed for 10 minutes using a V-20 mixing device (Tokuju Kogakusho). And post-added mixture A. As a result of sampling about 10 g from 5 locations and confirming the mixing uniformity, the average value of the mixing uniformity is 97.5% to 102.5%, and the content of each tablet is also in the range of 95% to 105%. Confirmed that it was within.

  100 g of calcium stearate was further added to the post-addition mixture A and mixed using a V-20 mixing apparatus (Tokuju Kogakusho) to obtain a tableting powder. About 60 g was sampled from the tableting powder and the loose bulk density and the tap bulk density were measured. In addition, about 500 g was sampled from the end of tableting and the angle of repose was measured with an angle of repose measuring instrument.

(3) Tableting A punch was set in a tableting machine (HT-P18A, Hata Seisakusho), and tableting was performed at a tableting pressure of 0.8 to 0.9 t. The scissors used were a 25 mg tablet with a 6.0 mm diameter double-sided round scissors, a 75 mg tablet with a 6.5 mm diameter both-sided scissors, and a 150 mg tablet with a score of only 8.0 mm on the top. A circular ridge 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: 25 mg capsule is approximately 5.3 mm in diameter and 14.3 mm in length, 75 mg capsule is approximately 5.3 mm in diameter and approximately 14.3 mm in length, and 150 mg capsule is 6.4 mm in length. Since it is a 18.0 mm substantially cylindrical shape, it is smaller than a capsule and is an uncoated tablet that is not a gelatin material such as a capsule.

(4) Packaging As packaging forms, PTP packaged products and loose packaged products were produced. For PTP packaged products, each tablet was made into a PTP sheet using a polyvinyl chloride film having a thickness of 0.2 mm and an aluminum foil, and placed in a paper box. As for the rose packaged product, each tablet was directly put into a polyethylene container, plugged, and placed in a paper bag.

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

  The pregabalin free drug substance was a drug substance having a particle size of 0.1% impurities, D10 of 12.6 μm, D50 of 64.8 μm, and D90 of 218.3 μm.

  The additive used was hydroxypropyl cellulose [HPC-L (trademark) normal particle type, Nippon Soda Co., Ltd.], reduced maltose starch syrup (Amalty MR100 (trademark), Mitsubishi Corporation Foodtech Co., Ltd.), D-mannitol for direct hitting. [Partek M100 (trademark), Merck Millipore Corporation], sodium starch glycolate [Primogell (trademark), Matsutani Chemical Industry], calcium stearate [Taihei Chemical Industry Co., Ltd.].

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

(2) Particle size distribution of the dried granule after sizing The particle size distribution of the dried granule after sizing obtained a good particle size distribution having a sharp peak at about 200 μm.

(3) Mixing uniformity after post-addition The average value of the mixing uniformity of post-addition mixture A was 97.5% to 102.5% for any of 25 mg tablets, 75 mg tablets, and 150 mg tablets. It was confirmed that the tablet content was also in the range of 95% to 105%.

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

(5) Presence or absence of tableting failure The 25 mg tablet was 100,000 tablets, capping was 0 tablets, sticking was 0 tablets, and lamination was 0 tablets.
The 75 mg tablet was tableted with 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 wrinkles coated with chromium nitride on the surface.
The 150 mg tablet was tableted with 50,000 tablets, capping was 0 tablets, sticking was 2 tablets, and lamination was 0 tablets.

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

(7) Dissolvability in water Dissolution in water is good, and for each of 25 mg tablets, 75 mg tablets, and 150 mg tablets, after storage for 1 month at 40 ° C. and 75% relative humidity, after storage for 3 months, At each time point after storage for 6 months, more than 85% was eluted after 15 minutes (see Table 15).

Lactam body after storage at 40 ° C. and 75% relative humidity for 1 month, storage at 40 ° C. and 75% relative humidity for 3 months, and storage at 40 ° C. and 75% relative humidity for 6 months at the start of storage of the final formulation of Example 14 (%), Dissolution test result (%), and tablet hardness (N).
(Quantification of lactam is a test result of 1 time. Dissolution test is a test result of 18 vessels (paddle method 50 rpm, water, 15 minutes). Tablet hardness is a test result of 10 tablets. .)

(8) Dissolution for pH 1.2 dissolution test solution Dissolution for pH 1.2 dissolution test solution is good, and 25%, 75 mg, and 150 mg tablets were eluted at 85% or more after 15 minutes. It was.

(9) Dissolution to pH 4.0 dissolution test solution Dissolution to pH 4.0 dissolution solution is good, and all 25 mg, 75 mg and 150 mg tablets were eluted at 85% or more after 15 minutes. It was.

(10) Dissolution to dissolution test solution at pH 6.8 Dissolution to pH 4.0 dissolution solution is good, and 25%, 75mg and 150mg tablets were eluted at 85% or more after 15 minutes. It was.

(11) Change in tablet hardness over time The tablet hardness was good, and the average tablet hardness immediately after tableting was 64.9N for the 25 mg tablet, 64.4N for the 75 mg tablet, and 70.0N for the 150 mg tablet. (See Table 15).

  The tablet hardness after storing for 1 month in a PTP sheet at 40 ° C. and 75% relative humidity is also good. 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. .6N (see Table 15).

  The tablet hardness after storage for 3 months in a PTP sheet at 40 ° C. and 75% relative humidity is also good. The average tablet hardness is 34.2N for the 25 mg tablet, 39.4N for the 75 mg tablet, and 47 for the 150 mg tablet. .5N (see Table 15).

  The tablet hardness after storage for 6 months in a PTP sheet at 40 ° C. and 75% relative humidity is also good. The average tablet hardness is 26.6 N for 25 mg tablets, 26.6 N for 75 mg tablets, and 44 for 150 mg tablets. 3N (see Table 15).

(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 packaged and stored in a PTP sheet made of a polyvinyl chloride film and aluminum foil in 40 ° C. and 75% relative humidity is 25 mg. The amount of lactam after one month of storage was 0.018% and 75 mg for the 25 mg tablet, compared to 0.007% for the tablet, 0.005% for the 75 mg tablet, and 0.005% for the 150 mg tablet. The tablets were 0.011% and the 150 mg tablets were 0.010% (see Table 15).

  Similarly, the average value of the amount of lactam after packaging with a PTP sheet made of a polyvinyl chloride film and aluminum foil at 40 ° C. and 75% relative humidity for 3 months is 0.036% for 25 mg tablets. The 75 mg tablet was 0.022% and the 150 mg tablet was 0.021% (see Table 15).

  Similarly, the average value of the amount of the lactam body after being packaged with a PTP sheet made of a polyvinyl chloride film and aluminum foil at 40 ° C. and 75% relative humidity for 6 months is 0.059% for 25 mg tablets. The 75 mg tablet was 0.036%, and the 150 mg tablet was 0.027%.

(13) Bitter taste masking
For each of pregabalin drug substance 150 mg and pregabalin 150 mg tablet, a bitter evaluation test was conducted by 10 healthy volunteers. The reason why the 150 mg tablet was selected is that the content of the drug substance is the highest in the standard of pregabalin tablets, and it was considered that the worst case could be assumed as an evaluation of bitterness.

Ten healthy volunteers evaluated bitterness according to the following evaluation procedure.
(1) Rinse mouth thoroughly with water.
(2) Contains 150 mg of pregabalin drug substance in its mouth.
(3) Evaluate the bitterness of pregabalin drug substance 150 mg 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 (until the afterglow of pregabalin drug substance disappears).
(5) One pregabalin tablet 150 mg in the mouth.
(6) Evaluate the bitterness when pregabalin tablets 150 mg 1 tablet is contained in the mouth for 5 seconds (relative bitterness is evaluated when the bitterness of the drug substance is 5 in 5 steps).

The evaluation of bitterness was performed in the following five stages.
1: No bitterness 2: Feel bitterness slightly 3: Feel bitterness 4: Feel bitterness slightly 5: Feel bitterness strongly

As a result, the bitterness of pregabalin tablets 150 mg was significantly suppressed compared to the pregabalin drug substance (Table 16). On the other hand, for 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 16).
The reason why the bitterness was suppressed was considered to be that pregabalin drug substance was made less likely to feel bitterness by being covered with HPC, reduced maltose starch syrup, and sodium starch glycolate by using pregabalin tablets.

Bitter sensitivity test

  From the above experimental results, all of the 25 mg tablet, 75 mg tablet and 150 mg tablet shown in Table 14 can maintain the production of lactam body at 1.0% or less throughout the period until the expiration date of 3 years. Sufficient hardness can be maintained throughout the period up to the expiration date of the year, it has sufficient dissolution properties throughout the period of expiration of 3 years, there is no tableting trouble such as capping, sticking, lamination, etc. It was found that the tablet can be stably produced with a good yield without loss, and there is no variation in the mass of each tablet, and it has a good content uniformity.

  In addition, the 25 mg tablet, 75 mg tablet, and 150 mg tablet shown in Table 14 all maintain the production of lactam body at 1.0% or less even after being divided or disintegrated to be in an uncompressed state. It was confirmed that it was possible.

  In addition, the 25 mg tablet, 75 mg tablet, and 150 mg tablet shown in Table 14 were smaller than the capsules, were less likely to adhere to the throat, could be film-coated, and could be divided by inserting a secant.

Furthermore, it was confirmed that the 25 mg tablets, 75 mg tablets, and 150 mg tablets listed in Table 14 were able to sufficiently suppress bitterness.

Trial manufacture of orally disintegrating solid preparation
(Effect of dry coating of active ingredient core granule with calcium stearate) ;
In Example 15, as a means for preventing contact between a compound having a γ-aminobutyric acid structure and a pharmaceutically acceptable salt thereof, and a cellulose-based additive other than hydroxypropyl-substituted cellulose, By mixing with calcium phosphate powder, the surface of the active ingredient granules was coated with calcium stearate to delay the elution of the active ingredient, thereby trying to prevent the bitter taste from spreading in the mouth after disintegrating in the oral cavity.

  The additive used was hydroxypropylcellulose [HPC-SL (trademark) normal particle type, hydroxypropylcellulose [HPC-SSL (trademark) normal particle type, Nippon Soda Co., Ltd.], reduced maltose syrup (Amalty MR100 (trademark), Mitsubishi Corporation Foodtech Co., Ltd.], calcium stearate [Taihei Chemical Industry Co., Ltd.], saccharin sodium hydrate [A-2, Daiwa Kasei Co., Ltd.], Eudragit E [EVONIK Co.], D-mannitol [Mannit P (trademark) ), Mitsubishi Corporation Foodtech Co., Ltd.], D-mannitol [Pairitol 200SD (trademark), Roquette Co., Ltd.], Light Silicic Acid [AdSolider 101 (trademark), Freund Sangyo Co., Ltd.], Crospovidone (Collidon CL-F, BASF) Company), crystalline cellulose CEOLUS KG-802 (trade mark), Asahi Kasei Corporation], grapefruit oil [San-Ei Gen FFI, Inc.] was sucralose [San-Ei Gen FFI, Inc.].

  Prototype tablets containing 75 mg of pregabalin were prepared using the main drug and additives in an amount of 5000 tablets according to Table 15. In outline of the production method, the main drug granule containing pregabalin, the shaped granule for imparting orally disintegrating property, and the post-additive were mixed and tableted so that the weight of one tablet was 190 mg.

  As described below, the main drug granule is prepared by granulating the main drug core granule 1 containing pregabalin in the first step, and mixing the core granule with calcium stearate in the second step to produce the main drug core granule 2, Using the fluidized bed granulation / drying / fine particle coating device in the third step, the core granule 2 is coated with the coating liquid 1 to produce the active agent coated granule 1, and the fluidized bed granulation / drying in the fourth step. -Using a fine particle coating apparatus, the coated granule 1 was coated with the coating liquid 2 to prepare a main drug granule (main drug coated granule 2).

In order to verify the effect of dry coating of the active ingredient core granule with calcium stearate, in the second step, the amount of calcium stearate powder dry-mixed with the active ingredient granule is 7.5 mg per tablet (prototype tablet S-1), Three types of trial tablets were prepared with 0 mg per tablet (trial tablet S-2) and 2.5 mg per tablet (trial tablet S-3).

  In the first step, 37.5 g of hydroxypropyl cellulose (HPC-SL) (7.5 mg per tablet) and 7.5 g of saccharin sodium hydrate (A-2) (1.5 mg per tablet) were weighed. , 337.5 g (67.5 mg per tablet) was dissolved in purified water to prepare a granulation liquid of the active ingredient. Separately, 375 g of pregabalin (75 mg for one tablet), 18.75 g of powdered reduced maltose starch syrup (Amalty MR100) (3.75 mg for one tablet), and 7.5 g of calcium stearate (1.5 mg for one tablet) were mixed. A granulation / drying / coating device (FD-MP-01-SFP) was charged, and 382.5 g of the main granule granulation liquid prepared for granulation in advance at a speed of 12 g / min. Granulation was carried out while spraying at 35 ° 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 moisture content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). Dried to 1%. Then, the active ingredient core granule 1 was produced by sieving with a screen of mesh 30 (diameter 0.5 mm).

  In the second step, about 460.25 g (one tablet formulation 89.25 mg) of dried and sized particles, the trial tablet S-1 that dry coats the core drug granule 1 with 0.75 mg of calcium stearate in one tablet formulation The main drug core granule 1 and 3.75 g of calcium stearate (one tablet formulation 0.75 mg) are weighed and mixed in a plastic bag to produce the main drug core granule 2 for the trial tablet S-1, -1 main drug core granule 2 ”.

  In addition, the main drug core granule 2 in which the main drug core granule 1 is not dry-coated with calcium stearate and the main drug core granule 2 in which the main drug core granule 1 is dry-coated with half the standard amount of calcium stearate are prepared. The main drug core granule 2 for S-2 ”and“ main drug core granule 2 for trial tablet S-3 ”were used. For “main drug core granule 2 for trial tablet S-2”, main drug core granule 1 without performing the second step was used as “main drug core granule 2 for trial tablet S-2” as it was. As for “main drug core granule 2 for trial tablet S-3”, 446.25 g (one tablet formulation 89.25 mg) of dried and sized main drug core granule 1 and calcium stearate 1.25 g (one tablet formulation 0) .25 mg) was weighed and mixed in a plastic bag to produce the main drug core granule 2 for trial tablet S-3, which was designated as “main drug core granule 2 for trial tablet S-3”.

  In the third step, 840 g of anhydrous ethanol (168 mg of one tablet formulation) and 105 g of purified water (21 mg of one tablet formulation) were mixed, and then 105 g of aminoalkyl methacrylate E (Eudragit E) (21 mg of one tablet formulation) was dissolved. Coating liquid 1 was prepared by dispersing 9 g of calcium phosphate (1.8 mg per tablet).

  Next, 450 g of “main drug core granule 2 for trial tablet S-1” was weighed out to produce main drug coated granule 1 for trial tablet S-1, and fluidized bed granulation / drying / coating apparatus (FD) -MP-01-SFP), 1059 g of the coating liquid 1 prepared for granulation in advance at a speed of 8 grams per minute at an intake temperature of 60 ° C. and an exhaust temperature of 30 ° C. for about 135 minutes. Granulated 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 moisture content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). Dried to 1%. Then, it was sieved with a screen of mesh 30 (diameter 0.5 mm) to produce “Coated Granule 1 for Prototype Tablet S-1”.

The production of “main drug coated granule 1 for trial tablet S-2” was carried out using “main drug core granule 2 for trial tablet S-2” and production of “main drug coated granule 1 for trial tablet S-1”. The same method was used.
Production of “main drug coated granule 1 for trial tablet S-3” was carried out using “main drug core granule 2 for trial tablet S-3” and production of “main drug coated granule 1 for trial tablet S-1” The same method was used.

In the fourth step, 45 g of D-mannitol (Mannit P) (9 mg of 1 tablet formulation) was weighed and dissolved in 180 g of purified water (36 mg of 1 tablet formulation) to prepare a coating solution 2.
Next, 564 g of “coated granule 1 for trial tablet S-1” (1 tablet formulation 112.1) was prepared for preparation of active ingredient coated granule 2 for trial tablet S-1 (main drug granule for trial tablet S-1). 8 mg) is weighed and put into a fluidized bed granulation / drying / coating apparatus (FD-MP-01-SFP), and 225 g (one tablet formulation 45 mg) of coating liquid 2 prepared in advance for granulation Was granulated while spraying at a speed of 6 grams per minute 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 moisture content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). Dried to 1%. Thereafter, the mixture was sieved with a screen of mesh 22 (diameter 0.7 mm) to prepare an active ingredient coated granule 2 for an experimental tablet S-1 (an active ingredient granule for the experimental tablet S-1).

The production of “main drug coated granule 2 for trial tablet S-2 (main drug granule for trial tablet S-2)” was carried out using “main drug coated granule 1 for trial tablet S-2”. It was produced by the same method as the production of “main drug coated granule 2 for No. 1 (main drug granule for trial tablet S-1)”.
The production of “main drug coated granule 2 for trial tablet S-3 (main drug granule for trial tablet S-2)” was carried out using “main drug coated granule 1 for trial tablet S-3”. It was produced by the same method as the production of “main drug coated granule 2 for No. 1 (main drug granule for trial tablet S-1)”.

  For the production of shaped granules, first, 16 g of hydroxypropylcellulose (HPC-SSL) (0.4 mg of one tablet formulation) was dissolved in 304 g of purified water (7.6 mg of one tablet formulation), Produced. Then, 1168 g of D-mannitol (19.2 mg of one tablet), 44 g of light anhydrous silicic acid (1.1 mg of one tablet), and 292 g of crospovidone (7.3 mg of one tablet) were mixed with a high speed mixer (Fukae Pautech Earth Technica, FS-GS-10J) and stirred and granulated while adding 320 g of a shaped granule granulating liquid prepared in advance for granulation at a speed of 320 grams per minute. The obtained granulated material is put into a fluidized bed granulating / drying / coating apparatus (Freund Sangyo, FLO-5), dried at 80 ° C., and the obtained granulated product is subjected to a moisture meter (MOC-120H, Shimadzu Corporation). The product was dried until the water content became 1%. Then, it was sieved with a screen of mesh 30 (diameter 0.5 mm) to produce shaped granules.

  Thereafter, 609 g (main drug granule for trial tablet S-1 for trial tablet S-1) 609 g (one tablet formulation 121.8 mg), shaped granule 190 g (one tablet formulation 38 mg), and As additives, 146.5 g of crystalline cellulose (Theorus KG-802) (19.3 mg of one tablet), 0.45 g of grapefruit oil (0.09 mg of one tablet), 0.9 g of sucralose (0.18 mg of one tablet) and Calcium stearate 4.5g (0.9mg per tablet) was mixed in a plastic bag, 190mg per tablet was weighed, and the tableting pressure was 0 using a single tableting machine (AUTOTAB-500, Ichihashi Seiki). Trial tablet S-1 was obtained by tableting at .5t.

For trial tablet S-2, trial production was performed except that 605.25 g (one tablet formulation 121.05 mg) of “main drug coated granule 2 for trial tablet S-2 (main drug granule for trial tablet S-2)” was used. Prototype tablet S-2 was prepared by the same method as preparation of tablet S-1.
For trial tablet S-3, trial production was performed except that 606.5 g (one tablet formulation 121.3 mg) of “main drug coated granule 2 for trial tablet S-3 (main drug granule for trial tablet S-3)” was used. Prototype tablet S-3 was produced by the same method as the production of tablet S-1.

Table 15A shows the composition per tablet of the trial tablet S-1, the trial tablet S-2, and the trial tablet S-3.

  In order to verify whether or not the main drug granule was mixed with calcium stearate powder to coat the surface of the main drug granule with calcium stearate to delay the elution of the main drug, trial tablet S-1, trial tablet S-2, and The dissolution rate of prototype tablet S-3 with purified water at 50 rpm was measured at 0 minutes (before 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 stearate 0.75 mg / tablet” is “prototype tablet S-1”, and the prototype tablet described as “no stearate Ca” is “prototype tablet”. The prototype tablet described as “Tablet S-2” and “Ca stearate 0.25 mg / tablet” is “Prototype tablet S-3”.

  As can be seen from FIG. 2, the elution of pregabalin could be delayed by dry-coating the core drug granule containing pregabalin with calcium stearate. However, the dissolution rate of pregabalin with respect to purified water after 15 minutes was almost 100%, and it was considered that the same pregabalin effect as 75 mg of Lyrica (trademark) capsule could be obtained.

In order to compare dissolution properties with a formulation obtained by tableting the contents of 75 mg of Lyrica (trademark) capsules, a trial tablet (prototype tablet) obtained by directly compressing the contents of 75 mg of Lyrica (trademark) capsules at a tableting pressure of 0.5 t. L13994) was produced.
Table 15B shows the verification results including the dissolution rate of the formulation obtained by tableting the contents of 75 mg of Lyrica ™ capsules. In Table 15B, the prototype tablet described as “Ca stearate 0.75 mg / tablet” is “prototype tablet S-1” and the prototype tablet described as “no stearate Ca” is “prototype tablet”. The prototype tablet described as “Tablet S-2”, “Ca stearate 0.25 mg / tablet” is “prototype tablet S-3”, and the prototype tablet described as “original formulation 75 mg tablet” is “Formulation of the contents of 75 mg of Lyrica ™ capsules tableted”.

As can be seen from Table 15B, the dissolution rate of pregabalin in purified water after 15 minutes is equivalent to the “formulation of 75 mg of Lyrica ™ capsules tableted”, and the efficacy of pregabalin similar to 75 mg of Lyrica ™ capsules Was thought to be obtained.

  Next, the active ingredient granule containing pregabalin is mixed with calcium stearate powder to coat the surface of the active ingredient granule with calcium stearate to delay the elution of the active ingredient and thereby bitter in the mouth after disintegrating in the oral cavity. In order to verify whether or not the spread was suppressed, three test subjects were double-blinded with the trial tablet S-1, the trial tablet S-2, the trial tablet S-3, and “Rilica ™ capsule 75 mg” The sensory evaluation of the bitter taste of “the tableted contents” was performed. Each test tablet is held in the oral cavity for 1 minute and evaluated as 0 bitterness when no bitterness is felt, and as bitterness 5 when strongly bitterness is felt according to the degree of bitterness. Of bitterness 1 (feeling slightly bitter), bitterness 2 (feeling weak bitterness), bitterness 3 (feeling moderate bitterness), and bitterness 4 (feeling slightly bitter). The results are shown in Table 15C.

As can be seen from Table 15C, the trial tablet S-2 not dry-coated with calcium stearate has a very strong bitterness of 4.67 on average, and is “a formulation in which the contents of 75 mg of Lyrica ™ capsules are tableted”. The bitterness was almost the same.
On the other hand, the bitterness of the trial tablet S-1 in which the main drug core granules were dry-coated with 0.75 mg of calcium stearate per tablet was only 1.67.
In addition, since the bitterness of the trial tablet S-3 in which the main drug core granules were dry-coated with 0.25 mg of calcium stearate per tablet was 2.67, the bitterness suppressing effect of the main drug core granules by the calcium stearate was dry-coated. It was found to depend on the amount of calcium stearate used in The bitterness of the trial tablet S-1 dry-coated with 0.75 mg of calcium stearate per tablet is the mildest, and the bitterness of bitterness 1 (feeling slightly bitter) to bitterness 2 (feeling weak bitterness) is suppressed. did it.

From the above results, by forming a hydrophobic coating of calcium stearate on the surface of the core drug core granules, the dissolution of the main ingredient is delayed by suppressing the infiltration of saliva into the granules while disintegrating in the oral cavity. I found that it was difficult to feel bitterness.

Trial manufacture of orally disintegrating solid preparation
(Improvement of oral disintegration and mouthfeel by coating core drug granules with D-mannitol) ;
In the trial tablet S-1 of Example 15, a means for preventing a compound having a γ-aminobutyric acid structure and a pharmaceutically acceptable salt thereof from contacting a cellulosic additive other than hydroxypropyl-substituted cellulose. In addition to the dry coating of the main drug core granules with calcium stearate, it was coated with a coating solution 1 containing Eudragit E and calcium stearate, and further coated with a coating solution 2 containing D-mannitol.

The coating with Eudragit E masks the bitter taste of pregabalin in addition to the purpose of blocking the contact between the γ-aminobutyric acid structure compound and pharmaceutically acceptable salts thereof and cellulosic additives other than hydroxypropyl-substituted cellulose. It is to do.
Similarly, the dry coating of the active ingredient core granule with calcium stearate is intended to block the contact of the compound having γ-aminobutyric acid structure and pharmaceutically acceptable salts thereof with cellulosic additives other than hydroxypropyl-substituted cellulose, And it is for further strengthening the purpose of masking the bitter taste of pregabalin.

However, when a trial tablet using the main drug granule was prepared by simply subjecting the main drug core granule to dry coating with calcium stearate and wet coating with Eudragit E, disintegration in the oral cavity was slow, and when it was contained in the mouth, It was found that an unpleasant mouth feel (mouse feel) was generated.
Therefore, in the trial tablet S-1, in addition to performing dry coating with calcium stearate and wet coating with Eudragit E on the main drug core granule, the outer side thereof is further coated with D-mannitol.

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

  The additive used was hydroxypropylcellulose [HPC-SL (trademark) normal particle type, hydroxypropylcellulose [HPC-SSL (trademark) normal particle type, Nippon Soda Co., Ltd.], reduced maltose syrup (Amalty MR100 (trademark), Mitsubishi Corporation Foodtech Co., Ltd.], calcium stearate [Taihei Chemical Industry Co., Ltd.], saccharin sodium hydrate [A-2, Daiwa Kasei Co., Ltd.], Eudragit E [EVONIK Co.], D-mannitol [Mannit P (trademark) ), Mitsubishi Corporation Foodtech Co., Ltd.], D-mannitol [Pairitol 200SD (trademark), Roquette Co., Ltd.], Light Silicic Acid [AdSolider 101 (trademark), Freund Sangyo Co., Ltd.], Crospovidone (Collidon CL-F, BASF) Company), crystalline cellulose CEOLUS KG-802 (trade mark), Asahi Kasei Corporation], grapefruit oil [San-Ei Gen FFI, Inc.] was sucralose [San-Ei Gen FFI, Inc.].

  Prototype tablets containing 75 mg of pregabalin were prepared using the main drug and additives in an amount of 5000 tablets according to Table 16A. As in Example 15, the outline of the production method is as follows. For the trial tablet S-1, the main drug granule containing pregabalin, the shaped granule for imparting orally disintegrating property, and the post-additive are mixed. Tableting was performed so that the tablet weight was 190 mg.

  As described below, the main drug granule is prepared by granulating the main drug core granule 1 containing pregabalin in the first step, and mixing the core granule with calcium stearate in the second step to produce the main drug core granule 2, Using the fluidized bed granulation / drying / fine particle coating device in the third step, the core granule 2 is coated with the coating liquid 1 to produce the active agent coated granule 1, and the fluidized bed granulation / drying in the fourth step. -Using a fine particle coating apparatus, the coated granule 1 was coated with the coating liquid 2 to prepare a main drug granule (main drug 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 on the active ingredient coated granule 1 is 9 mg per tablet (trial tablet S-1), 1 tablet Three types of trial tablets were prepared at 0 mg per tablet (trial tablet T-1) and 12 mg per tablet (trial tablet T-2).

The first step was performed in the same manner as in Example 15.
That is, in the first step, 37.5 g of hydroxypropyl cellulose (HPC-SL) (7.5 mg per tablet) and 7.5 g of sodium saccharin hydrate (A-2) (1.5 mg per tablet) were weighed. It was taken up and dissolved in 337.5 g (67.5 mg of 1 tablet) of purified water to prepare a granule granulation liquid for the active ingredient. Separately, 375 g of pregabalin (75 mg for one tablet), 18.75 g of powdered reduced maltose starch syrup (Amalty MR100) (3.75 mg for one tablet), and 7.5 g of calcium stearate (1.5 mg for one tablet) were mixed. A granulation / drying / coating device (FD-MP-01-SFP) was charged, and 382.5 g of the main granule granulation liquid prepared for granulation in advance at a speed of 12 g / min. Granulation was carried out while spraying at 35 ° 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 moisture content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). Dried to 1%. Then, the active ingredient core granule 1 was produced by sieving with a screen of mesh 30 (diameter 0.5 mm).

The 2nd process was also performed by the same method as preparation of trial manufacture tablet S-1 of Example 15.
That is, in the second step, the trial tablet S-1, the trial tablet T-1, and the trial tablet T-2 are all coated with 446 mg of calcium stearate in a tablet formulation in order to coat the main drug core granule 1 dry. .25 g (1 tablet formulation 89.25 mg) of dried and sized main drug core granule 1 and calcium stearate 3.75 g (1 tablet formulation 0.75 mg) were weighed and mixed in a plastic bag, and the prototype tablet The main drug core granule 2 common to S-1, trial tablet T-1 and trial tablet T-2 was produced.

The third step was performed in the same manner as in Example 15.
In the third step, 840 g of anhydrous ethanol (168 mg of one tablet formulation) and 105 g of purified water (21 mg of one tablet formulation) were mixed, and then 105 g of aminoalkyl methacrylate E (Eudragit E) (21 mg of one tablet formulation) was dissolved. Coating liquid 1 was prepared by dispersing 9 g of calcium phosphate (1.8 mg per tablet).

  Next, 450 g of the active ingredient core granule 2 is weighed out together with the trial tablet S-1, the trial tablet T-1, and the trial tablet T-2, and fluidized bed granulation / drying / coating apparatus (FD-MP-01- Granulated while spraying 1059 g of coating solution 1 prepared for granulation at a speed of 8 grams per minute at an intake temperature of 60 ° C. and an exhaust temperature of 30 ° C. for about 135 minutes. did. The obtained granulated product was dried as it was at 60 ° C. using a fluidized bed, and the obtained granulated product was measured for moisture content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). Dried to 1%. Thereafter, the mixture was sieved with a screen of mesh 30 (diameter 0.5 mm) to prepare “main drug coated granule 1” common to the trial tablet S-1, the trial tablet T-1, and the trial tablet T-2.

In the fourth step, 45 g of D-mannitol (Mannit P) (9 mg of 1 tablet formulation) was weighed and dissolved in 180 g of purified water (36 mg of 1 tablet formulation) to prepare a coating solution 2.
Next, 564 g of the active ingredient coated granule 1 (1 tablet formulation 112.8 mg) was weighed and flowed to prepare the active ingredient coated granule 2 for the experimental tablet S-1 (the active ingredient granule for the experimental tablet S-1). 225g (one tablet formula 45mg) of coating liquid 2 prepared in advance for granulation was put into a layer granulation / drying / coating apparatus (FD-MP-01-SFP) at a speed of 6 grams per minute. The mixture was granulated 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 moisture content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). Dried to 1%. Thereafter, the mixture was sieved with a screen of mesh 22 (diameter 0.7 mm) to prepare an active ingredient coated granule 2 for an experimental tablet S-1 (an active ingredient granule for the experimental tablet S-1).

  The active ingredient coated granule 2 for the trial tablet T-1 (the active ingredient granule for the experimental tablet S-1) is the active ingredient coated granule 1 for the experimental tablet T-1 as it is. Used as the main drug granule).

  Fluidized bed granulation by weighing 564 g of active ingredient coated granule 1 (12.8 mg 1 tablet formulation) for preparation of active ingredient coated granule 2 for experimental tablet T-2 (active ingredient granule for experimental tablet S-1)・ Inhalation temperature of 300g (45mg per tablet) of coating solution 2 prepared in advance for granulation at a speed of 6g / min, put into drying / coating equipment (FD-MP-01-SFP) Granulation was carried out 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 moisture content using a moisture meter (MOC-120H, manufactured by Shimadzu Corporation). Dried to 1%. Thereafter, the mixture was sieved with a screen of mesh 22 (diameter 0.7 mm) to prepare an active ingredient coated granule 2 for an experimental tablet T-2 (an active ingredient granule for an experimental tablet T-2).

The shaped granules were produced in the same manner as in Example 15.
That is, for the production of shaped granules, firstly, 16 g of hydroxypropylcellulose (HPC-SSL) (0.4 mg of one tablet formulation) was dissolved in 304 g of purified water (7.6 mg of one tablet formulation), and the shaped granules were granulated. A liquid was prepared. Then, 1168 g of D-mannitol (19.2 mg of one tablet), 44 g of light anhydrous silicic acid (1.1 mg of one tablet), and 292 g of crospovidone (7.3 mg of one tablet) were mixed with a high speed mixer (Fukae Pautech Earth Technica, FS-GS-10J) and stirred and granulated while adding 320 g of a shaped granule granulating liquid prepared in advance for granulation at a speed of 320 grams per minute. The obtained granulated material is put into a fluidized bed granulating / drying / coating apparatus (Freund Sangyo, FLO-5), dried at 80 ° C., and the obtained granulated product is subjected to a moisture meter (MOC-120H, Shimadzu Corporation). The product was dried until the water content became 1%. Then, it was sieved with a screen of mesh 30 (diameter 0.5 mm) to produce shaped granules.

  Thereafter, 609 g (main drug granule for trial tablet S-1 for trial tablet S-1) 609 g (one tablet formulation 121.8 mg), shaped granule 190 g (one tablet formulation 38 mg), and As additives, 146.5 g of crystalline cellulose (Theorus KG-802) (19.3 mg of one tablet), 0.45 g of grapefruit oil (0.09 mg of one tablet), 0.9 g of sucralose (0.18 mg of one tablet) and Calcium stearate 4.5g (0.9mg per tablet) was mixed in a plastic bag, 190mg per tablet was weighed, and the tableting pressure was 0 using a single tableting machine (AUTOTAB-500, Ichihashi Seiki). Trial tablet S-1 was obtained by tableting at .5t.

For trial tablet S-2, trial tablet S-2 was used except that 564 g (one tablet prescription 112.8 mg) of “main drug coated granule 2 for trial tablet S-2 (main drug granule for trial tablet S-2)” was used. Prototype tablet S-2 was produced by the same method as that for producing -1.
For the trial tablet S-3, the trial tablet S-3 was used except that 624 g (one tablet prescription 124.8 mg) “the main drug coated granule 2 for the trial tablet S-3” (the main drug granule for the trial tablet S-3) was used. Prototype tablet S-3 was produced by the same method as production of -1.

Table 16A shows the composition per tablet of the trial tablet S-1, the trial tablet T-1, and the trial tablet T-2.

In addition to performing dry coating with calcium stearate and wet coating with Eudragit E on the active ingredient core granules, the outer side is further coated with D-mannitol, so that the bitterness-inhibiting effect is not lost and oral disintegration and uncomfortable. Whether or not the tactile sensation (mouth feel) in the oral cavity can be improved was determined by the method <>.
In addition, a sensory test for bitterness evaluation was performed on three subjects with a double blind. Each test tablet is held in the oral cavity for 1 minute and evaluated as 0 bitterness when no bitterness is felt, and as bitterness 5 when strongly bitterness is felt according to the degree of bitterness. Of bitterness 1 (feeling slightly bitter), bitterness 2 (feeling weak bitterness), bitterness 3 (feeling moderate bitterness), and bitterness 4 (feeling slightly bitter). The results are shown in Table 16B. In addition, the value of the bitterness evaluation in Table 16B shows an average value.

As can be seen from Table 16B, the disintegration time in the oral cavity of the trial tablet T-1 which was not subjected to the active ingredient coating (2) with D-mannitol took 1 minute or more, whereas the active ingredient due to 9 mg of D-mannitol per tablet. Since the orally disintegrating time of the trial tablet S-1 subjected to coating (2) was 25 seconds, the disintegration in the oral cavity is sufficient as an orally disintegrating tablet by applying the active ingredient coating (2) with D-mannitol. We were able to confirm that we were able to improve to a proper level.
On the other hand, since the oral disintegration time was 24 seconds when the amount of the active ingredient coating (2) was increased to 12 mg of D-mannitol per tablet, the amount of D-mannitol in the active ingredient coating (2) It was found that 9 mg per tablet was sufficient, and even when the dose was increased to 12 mg, the improvement in oral disintegration was slight.
As well as improving the disintegration property in the oral cavity, it was confirmed that the unpleasant intraoral feel (mouth feel) of “Rough” and “Mota-Mota” when it was put in the mouth was also reduced.
Regarding the evaluation of bitterness, since both the trial tablet S-1 and the trial tablet T-1 were bitter 2 (feeling weak bitterness), the presence or absence of the active ingredient coating (2) may not affect the bitterness of the trial tablet. all right.
In contrast, the bitterness of the trial tablet T-2 in which the amount of the active ingredient coating (2) was increased to 12 mg D-mannitol per tablet was bitter taste 3 (feeling moderate bitterness). It was found that when the amount of D-mannitol in the coating (2) was increased to 12 mg per tablet, the bitterness slightly increased.

  Furthermore, in order to obtain objective data on unpleasant intraoral tactile sensation (mouse feel) as "gritty" or "motamota" when contained in the mouth, trial tablet T-1 was subjected to dry coating with calcium stearate. Scanning electron micrographs of the main drug core granule 2, the main drug coated granule 1 after coating with Eudragit E (1), and the main drug coated granule 2 after coating with D-mannitol (2) Photographed (FIG. 3). In FIG. 3, “after granulation” means the active ingredient core granule 2 after dry coating with calcium stearate, and “after Eudra coat” means the active ingredient coated granule 1 after coating with Eudragit E (1). "After D-mannitol coating" means the active ingredient coated granules 2 after coating (2) with D-mannitol.

  As can be seen from FIG. 3, the main drug core granule 2 after coating (1) with Eudragit E had a smoother surface compared to the main drug core granule 2 after dry coating with calcium stearate. The main drug-coated granules 2 after coating with D-mannitol (2) had increased surface roughness compared to the main drug core granules 2 after coating with Eudragit E (1). Coat of D-mannitol increases surface irregularities, and when tableted, saliva tends to infiltrate from the gaps, disintegrates quickly, and is unpleasant as “gritty” or “motamota” when contained in the mouth It was confirmed that the mouth feel (mouth feel) in the oral cavity was improved.

  From the above results, in addition to performing the dry coating with calcium stearate and the wet coating with Eudragit E on the active ingredient core granules, the outer side is further coated with D-mannitol, without losing the bitter taste suppressing effect. It was found that disintegration could be improved. Moreover, it was found that the amount of D-mannitol was 9 mg per tablet, which was an amount suitable for both improvement of oral disintegration and suppression of bitterness.

Confirmation of storage stability of orally disintegrating solid preparations The storage stability of the tableting tablet of prototype tablet S-1 after 1 week and 2 weeks after storage at 60 ° C. (glass bottle cap) The amount was evaluated, and this was combined with pregabalin and crystalline cellulose (1: 1), pregabalin and light silicic acid (1: 0.1), and pregabalin and crospovidone (1: 1). Contrast with test results. The results are shown in Table 17.

As can be seen from Table 17, the trial tablet S-1 is a crystalline cellulose (KG-802), a light anhydrous silicic acid (ADSOLIDAR) that promotes the production of lactam over time in a solid preparation containing pregabalin and impairs storage stability. 101) and crospovidone (Collidon CL-F), the production of lactams remained at a low level because the contact between these additives and pregabalin was blocked.
In particular, when light anhydrous silicic acid was added, the amount of lactam after storage for 2 weeks at 60 ° C. (glass bottle cap) was 1.640%, whereas the trial tablet S-1 The fact that it remained at 0.067% was a remarkable effect of improving storage stability over time.

  In order to confirm the storage stability of prototype tablet S-1 over time, trial tablet S-1, Lyrica (trademark) OD tablet 25 mg, Lyrica (trademark) OD tablet 75 mg, and Lyrica (trademark) OD tablet 150 mg The bag was sealed and stored under accelerated conditions of 40 ° C. and 75% relative humidity, and the formation of lactam bodies 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 product 150 mg tablet means Lyrica ™ OD tablet 150 mg. To do. In FIG. 4, the prototype 75 mg tablet means trial tablet S-1.

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

  In order to confirm the storage stability of the trial tablet S-1 over time, the trial 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 was measured after storage in May and one month after storage. The test conditions were a 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 (trademark) OD tablet 75 mg. Moreover, in FIG. 5, the lines other than the starting OD 75 mg mean trial tablet S-1. The “starting OD 75 mg start” is a measurement of the dissolution rate of Lyrica (trademark) OD tablets 75 mg not stored under accelerated conditions as a control group. “Beginning”, “4075-0.5M”, and “4075-1M” are respectively before the trial tablet S-1 is sealed in an aluminum bag and stored under accelerated conditions of 40 ° C. and 75% relative humidity. The dissolution rate after 0.5 month storage and after 1 month storage is measured.

  As can be seen from FIG. 5, even after storage for 1 month under the accelerated condition of 40 ° C. and 75% relative humidity, good storage stability with no elution delay was observed.

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

Summary of examples:
As described above, the pharmaceutical preparation of the present application containing a γ-aminobutyric acid derivative or a pharmaceutically acceptable salt thereof increases the lactam body over time by tableting with the addition of a cellulose-based additive. 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, since the production of lactams occurring with time is negligible. I was able to.

  Therefore, it was found that by adding no cellulosic additives other than hydroxypropyl-substituted cellulose, a storage-stable compressed solid preparation that does not produce a lactam body over time due to tableting can be produced.

  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. It was found that a tablet hardness of 20 N or more can be maintained.

  The pharmaceutical preparation containing the γ-aminobutyric acid derivative of the present application or a pharmaceutically acceptable salt thereof contains sugar alcohol such as mannitol, reduced maltose starch syrup, maltitol, hydroxypropyl starch, or sodium starch glycolate. Thus, it was found that the production of lactam body over time after tableting can be remarkably suppressed.

  In addition, 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 press-bonding polyvinyl chloride, polypropylene, polyethylene or the like and an aluminum sheet. As a result, it was found that the production of lactam bodies over time after tableting is suppressed.

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

  In addition, 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, capping, It was found that tableting troubles such as sticking and lamination do not occur, the mass of each tablet does not vary, and it can be stably produced with a good yield without any loss.

  It was also found that the 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 (26)

  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, wherein the active ingredient is one of cellulose-based additives other than hydroxypropyl-substituted cellulose A solid preparation having a preparation structure that does not come into contact with 2, 3 or more.   containing at least one active ingredient selected from the group consisting of a compound having a γ-aminobutyric acid structure and a pharmaceutically acceptable salt thereof, wherein the active ingredient is crystalline cellulose, cellulose acetate, carmellose, carmellose calcium, Carmellose sodium, carmellose potassium, croscarmellose sodium, croscarmellose calcium, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hypromellose acetate succinate, cellulose acetate, cellulose acetate phthalate, hypromellose phthalate , Selected from the group consisting of carboxymethyl ethyl cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose, powdered cellulose, lactose / crystalline cellulose spherical granules That 1, 2 or with a formulation structure that is not in contact with three or more cellulosic additives, solid preparation according to claim 1.   Containing at least one active ingredient selected from the group consisting of pregabalin, gabapentin, baclofen and pharmaceutically acceptable salts thereof, wherein the active ingredient is crystalline cellulose, cellulose acetate, carmellose, carmellose calcium, carmellose Sodium, carmellose potassium, croscarmellose sodium, croscarmellose calcium, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hypromellose acetate succinate, cellulose acetate, cellulose acetate phthalate, hypromellose phthalate, carboxy Consists of methyl ethyl cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose, powdered cellulose, lactose / crystalline cellulose spherical granules Having the formulation structure that is not in contact with 1, 2, or 3 or more cellulosic additives selected from solid dosage form according to claim 1 or 2.   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 are magnesium aluminate metasilicate, light silicic anhydride, hydrous silicon dioxide, titanium oxide, povidone , Crospovidone, macrogol, sucrose fatty acid ester, stearic acid, gelatin, starch, partially pregelatinized starch, one, two or more additives selected from the group consisting of calcium dihydrogen phosphate The solid formulation as described in any one of Claims 1-3 which has a structure.   The solid preparation according to any one of claims 1 to 4, which does not contain one, two, or three or more additives selected from the group consisting of pregelatinized starch, sucrose, and gum arabic.   The solid formulation as described in any one of Claims 1-5 containing a hydroxypropyl substituted cellulose.   A starch or a pharmaceutically acceptable salt thereof modified with a carboxymethyl group or a hydroxypropoxyl group, and one or more components selected from sugar alcohols. The solid preparation described.   The solid formulation as described in any one of Claims 1-7 containing the starch or pharmacologically acceptable salt modified with the carboxymethyl group or the hydroxypropoxyl group, and sugar alcohol.   The solid preparation according to any one of claims 1 to 8, comprising one or more modified starches selected from the group consisting of sodium carboxymethyl starch and hydroxypropyl starch.   It contains 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, sorbitol. The solid formulation as described in any one.   The solid preparation according to any one of claims 1 to 10, which is immediate release.   The solid preparation according to any one of claims 1 to 11, which is not sealed and packaged.   The solid preparation according to any one of claims 1 to 12, which is air-tightly packaged.   The solid formulation as described in any one of Claims 1-13 currently airtightly packaged using the blister packaging which uses a polyvinyl chloride, a polyvinylidene chloride, a polypropylene, or polyethylene.   The solid preparation according to any one of claims 1 to 14, which is a tablet.   The solid preparation according to any one of claims 1 to 15, which is a film-coated tablet.   The solid preparation according to any one of claims 1 to 16, which has a hardness of 20N or more.   The solid formulation as described in any one of Claims 1-17 containing the hydroxypropyl substituted cellulose whose viscosity of 2% aqueous solution measured at 20 degreeC is 2-400 mPa * s.   The solid formulation according to any one of claims 1 to 18, wherein the content of hydroxypropyl-substituted cellulose per solid formulation is 1 to 15% by mass of the total mass of the solid formulation.   The amount ratio of hydroxypropyl-substituted cellulose and starch modified with carboxymethyl group or hydroxypropoxyl group is 0.1-10 parts by mass of carboxymethyl group or hydroxypropoxyl with respect to 1 part by mass of hydroxypropyl-substituted cellulose. The solid preparation according to any one of claims 1 to 19, which is a starch modified with a group.   A 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 an optional additive The solid formulation as described in any one of Claims 1-20 containing this.   Fluidized bed 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 an optional additive The solid formulation as described in any one of Claims 1-21 containing a thing. It is a manufacturing method of the solid formulation as described in any one of Claims 1-22, Comprising: The method including the following processes.
(4) A step of mixing one or more active ingredients selected from a compound having a γ-aminobutyric acid structure or a pharmaceutically acceptable salt thereof together with an optional additive,
(5) A step of granulating the mixture by spraying a hydroxypropyl-substituted cellulose solution,
(6) Optionally, mixing the granulated product with one or more optional additives or granulated products. It is a manufacturing method of the solid formulation as described in any one of Claims 1-23, Comprising: The method including the following processes.
(4) A step of mixing one or more active ingredients selected from a compound having a γ-aminobutyric acid structure or a pharmaceutically acceptable salt thereof together with an optional additive,
(5) A step of granulating the mixture by spraying a hydroxypropyl-substituted cellulose solution,
(6) Optionally, mixing the granulation with one or more optional additives or granules comprising starch modified with carboxymethyl groups. It is a manufacturing method of the solid formulation as described in any one of Claims 1-24, Comprising: The method including the following processes.
(4) one or more active ingredients selected from a compound having a γ-aminobutyric acid structure or a pharmaceutically acceptable salt thereof, magnesium aluminate metasilicate, light anhydrous silicic acid, hydrous silicon dioxide, titanium oxide, 1 selected from the group consisting of povidone, crospovidone, macrogol, sucrose fatty acid ester, stearic acid, gelatin, starch, partially pregelatinized starch, calcium dihydrogen phosphate, and cellulosic additives other than hydroxypropyl substituted cellulose Mixing with any additive that does not contain 2, or 3 or more additives,
(5) A step of granulating the mixture by spraying a hydroxypropyl-substituted cellulose solution,
(6) Optionally, mixing the granulated product with one or more optional additives or granulated products. The solid formulation manufactured by the manufacturing method as described in any one of Claims 23-25.