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    • 专利摘要:
    The present invention relates to a sustained release formulation that is intended to release zolpidem or its salts for a predetermined time by a biphasic dissolution profile, wherein the first phase is an immediate release phase and the second phase is a delayed release phase. While certain embodiments are designed to prevent abuse.
    公开号:KR20010080640A
    申请号:KR1020017006799
    申请日:1999-12-01
    公开日:2001-08-22
    发明作者:제라드 알럭스；가레트 루이스；프레데릭 안드레
    申请人:고든 라이트；사노피-신델라보；
    IPC主号:
    专利说明:

    Sustained-release preparations comprising zolpidem or salts thereof CONTROLLED-RELEASE DOSAGE FORMS COMPRISING ZOLPIDEM OR A SALT THEREOF
    [2] EP 173 928 is a biphasic release comprising a core containing an active agent and a coating applied thereon, consisting of a film forming polymer insoluble in water and gastrointestinal fluids and a water soluble pore generating material comprising the active agent. Sustained release oral pharmaceutical formulations with pharmacologically active agents of the profile are disclosed.
    [3] EP 361 910 discloses granules having a layer comprising a spray dried material and a pharmaceutically acceptable excipient and medicament carrying the adsorbed medicament.
    [4] GB 2 245 492 discloses orally administrable pharmaceutical formulations which are intended for release (ie, release after a predetermined time), comprising a core coated with a hydrophobic substance and a surfactant.
    [5] Zolpidem is a fast-acting sleeping pill suitable for the sustained release preparation according to the present invention. Zolpidem is a sleeping agent belonging to an imidazopyridine-based therapeutic agent. It is administered orally by tablet or other solid preparation. Indeed, pharmacokinetic and pharmacodynamic data show that zolpidem is rapidly absorbed and rapidly absorbed, resulting in a rapid sleep effect. Bioavailability is 70% after oral administration and within the therapeutic dosage range between 5 and 10 mg in conventional formulations. Exhibits a linear dynamic at, the peak plasma concentration is reached in 0.5 to 3 hours, the excretion half-life is short, average 2.4 hours and duration of action is 6 hours or less.
    [6] For the sake of simplicity when there is no indication, the term "zolpidem" or "medicament" in the entire specification means zolpidem itself and salts thereof. A preferred salt of zolpidem is zolpidem hemitartrate.
    [7] To date, only formulations which are released immediately by the rapid action of zolpidem have been developed. In other words, they are rapidly degraded in the gastrointestinal tract, dissolved in gastrointestinal fluids, undergoing systemic absorption, and zolpidem exhibits a pharmacological effect to induce sleep of the patient.
    [1] The present invention relates to a sustained release preparation comprising zolpidem or a salt thereof.
    [8] The novel formulations according to the present invention can delay release over a period of time suitable for the desired sleeping time and the time required for the drug to be excreted from the human body to a sufficiently low level.
    [9] Therefore, as a first object, the present invention provides a sustained release formulation comprising zolpidem or a salt thereof, which is intended to be released for a predetermined time, and according to the biphasic profile, the first phase is an immediate release phase and the second The phase is a delayed release phase.
    [10] "Total amount of medicament" means the weight of a medicament included in the total formulation according to the present invention.
    [11] The first phase or immediate release phase is the portion of the dissolution profile obtained in 0-30 minutes in a suitable in vitro dissolution test. Suitable elution tests are, for example, one of the methods described in Example 1: The measurement is performed here at 37 ° C., in an aqueous buffer, in a type II elution apparatus according to the US Pharmacopoeia, or to such an extent that it is well known to those skilled in the art. How to add. The ratio of the drug eluted during the first phase is the ratio of the total amount of the drug eluted at 30 minutes. In an advantageous embodiment of the formulation according to the invention, at least 90% of the medicament portion assigned to the first phase is eluted within 20 minutes and preferably 15 minutes.
    [12] The second phase or delayed release phase is that portion of the dissolution profile after 30 minutes, measured in a suitable in vitro dissolution test, as described in Example 1. The present invention then proposes a pharmaceutical formulation wherein the complete dissolution time for the second phase is 2 to 6 hours, and preferably 2.25 to 3.5 hours.
    [13] The second, delayed release phase profile is defined by the percentage released at times T 1 , T 2 and T 3 , defined as follows.
    [14] T 1 is the initial of the second phase of drug release and is 30 minutes.
    [15] T 3 is near the end of the drug release second phase and is the time at which 85% of the medication allocated for the second phase is released.
    [16] T 2 is the time at which 50% of the medication allocated for the second phase is released. For example, if 50% of the total drug release is released in 30 minutes, then 50% remains in the second phase of release. Therefore T 3 is the time for 92.5% elution [50% + 0.85 x 50%] and T 2 is the time for 75% elution.
    [17] The second phase is often referred to as matrix emission, as described in T. Higuchi, J. Pharm. Sci. 52 , 1145 (1963), according to the equation (T 1 -T 2 ) = 0.35 (T 3 -T 1 ), which shows the profile of the release rate over the square root of time. More conveniently, the second phase can be a first-order release, (T 2 -T 1 ) = 0.37 (T 3 -T 1 ). Even more conveniently, the second phase may represent an order zero profile or an S-shaped profile. The zero order profile is a constant or nearly constant release rate and (T 2 -T 1 ) = 0.59 (T 3 -T 1 ). S-shaped profile is the release rate over the second is to facilitate greater than - - (T 1 T 3) (T 2 T 1) is 0.59. Intermediate profiles between these different types are also covered.
    [18] Rapid release in phase 1 induces immediate sleep of the patient and phase 2 maintains the medicinal concentration of blood at or below the peak level after administration, but at a higher peak level than that obtained with an immediate release agent to maintain sleep. Be sure to
    [19] The present invention proposes a preparation of zolpidem or a salt thereof having a complete dissolution time of 2 to 6 hours and preferably 2.25 to 3.5 hours, defined as the time for 90% release of the total amount of medicament.
    [20] 40 to 70% of the total amount of medicament may be released in the immediate release phase, preferably 50 to 60%.
    [21] 1 shows an example of such an in vitro release profile. Here, 60% of the total drug amount is released in the immediate release phase, and the second phase is the zero order release in which 90% of the total drug amount elutes in 3 hours. 2 shows another example of such a profile. Where 50% of the total drug dose elutes in the immediate release phase, and the second phase release is due to three different types of profiles; Emission (matrix emission), primary emission, and S-type emission profiles proportional to the square root of time.
    [22] As a second object, the present invention provides a sustained release formulation of zolpidem or a salt thereof comprising two pharmaceutical entities: the formulation delays the release of one entity of the medicament and the delay of the other entity. Is released. Medications eluting in the immediate release phase (30 minutes before) are contained in the immediate release entity, while medications released in the delayed release phase (after 30 minutes) are contained in the delayed release entity.
    [23] In formulations for rapid release a small amount of medicament may be retained in the formulation and therefore released 30 minutes after the start of dissolution, and thus included in the delayed release phase. Similarly, a small amount of medicament incorporated into a delayed release pharmaceutical entity may be released 30 minutes ago and thus form part of the immediate release phase.
    [24] According to the invention, the proportion of medicament contained in the immediate release entity and eluted within 30 minutes is at least 90%. The proportion of medicament contained within the delayed release entity and released within 30 minutes constitutes 0 to 35%, and preferably 1 to 25%.
    [25] Among the formulations that meet the requirements of the biphasic profile and may comprise the two types of pharmaceutical entities defined above, capsules, tablets, multilayer tablets, multi-coated tablets may be mentioned below.
    [26] The immediate release entity may be used in the present invention as a single pharmaceutical immediate release unit, for example as an immediate release tablet or pellet, or as several such units formulated into capsules or tablets; As an immediate release matrix in tablets; As an immediate release layer that can be incorporated into a multilayer tablet; It can be understood as an immediate release coating layer in multi-coated tablets or pellets.
    [27] Delayed release entities are used herein as pharmaceutical delayed release units such as, for example, delayed release tablets or pellets, or as several such units formulated into capsules or tablets; As a delayed release layer that can be incorporated into a multilayer tablet; As a delayed release core or delayed release coating layer in a multiple coated tablet; Disintegrating can be understood as delayed release pellets in tablets.
    [28] Also included in the present invention are agents in which the immediate release entity and the delayed release entity are administered simultaneously but separately.
    [29] drawing
    [30] 1 shows an example of an in vitro release profile of two phases, where the immediate release phase is 60% of the total amount of zolpidem and the second phase is the zero order profile in which 90% of the total amount of zolpidem is eluted within 3 hours.
    [31] 2 shows an example of an in vitro release profile of two phases, with 50% eluting in the first phase, the second emission phase being (i) proportional to the square root of time (continuous line), (ii) primary profile (dashed line) , And S-type emission profile (discontinuous line).
    [32] 3 shows the in vitro dissolution profile of the Example 1 tablet in 0.01 M hydrochloric acid and pH 6.8 phosphate buffer as described in Example 1. FIG.
    [33] FIG. 4 shows the in vitro dissolution profile of Comparative Example 1 tablets in 0.01 M hydrochloric acid and pH 6.8 phosphate buffer as described in Comparative Example 1. FIG.
    [34] FIG. 5 shows the results of a single dosage pharmacokinetic study comparing the combination of the immediate release formulation of Example 2 and the immediate release tablet and delayed release tablet of Example 3.
    [35] 6 shows the elution profile of the mixture of the immediate release and delayed release ellipsoids of Example 4 in 0.01 M hydrochloric acid.
    [36] 7 shows bilayer and multilayer tablets. (a) Two layer tablet consisting of one immediate release layer and one delayed release layer. (b) a three layer tablet consisting of two external intermediate release layers and one internal delayed release layer. (c) a three-layer tablet consisting of an outer intermediate release layer, an internal delayed release layer, and an outer layer containing no active ingredient, controlling the release profile. (d) A three layer tablet consisting of an outer intermediate release layer, an externally delayed release layer, and an inner layer containing no active ingredient, controlling the release profile.
    [37] FIG. 8 shows the elution profile of the bilayer tablet of Example 6 in 0.01 M hydrochloric acid and phosphate buffer at pH 6.8 and 7.5.
    [38] 9 shows the elution profile of a combination of two layer tablets and the intermediate release and delayed release tablets of Comparative Example 2, in 0.01 M hydrochloric acid.
    [39] 10 shows the elution profile of the bilayer tablet of Comparative Example 3 in 0.01 M hydrochloric acid and pH 6.8 phosphate buffer.
    [40] FIG. 11 shows the elution profile of the bilayer tablet of Example 8 in 0.01 M hydrochloric acid.
    [41] The preparations according to the invention usually contain 4-16 mg, preferably 6-12 mg zolpidem, as zolpidem base. Zolpidem may be incorporated as a base or as a pharmaceutically acceptable zolpidem salt. Of the preparations comprising zolpidem salts other than zolpidem bases according to the invention, those comprising zolpidem hemitartrate are particularly preferred.
    [42] In an advantageous embodiment, the formulation may be formulated to obtain pH independent dissolution in the second phase. Preferred methods for obtaining such elution are, in the case of basic medicines such as zolpidem, the addition of pharmaceutically acceptable organic acids to the formulation according to methods known to those skilled in the art. Such agents are preferred.
    [43] These pharmaceutically acceptable organic acids can be selected, for example, from maleic acid, tartaric acid, malic acid, fumaric acid, lactic acid, citric acid, adipic acid or succinic acid and their acid salts, if present, and in racemic or isomeric forms, if present. Can be. According to the invention, particularly preferred acids are tartaric acid, fumaric acid, citric acid, and succinic acid and their acid salts.
    [44] Without limiting the scope of the invention, various formulations illustrating the invention are described below:
    [45] (1) Capsules comprising one or more intermediate release tablets and one or more delayed release tablets: Intermediate release tablets are obtained by directly compressing a mixture of medicament and salts thereof with excipients, such as microcrystalline cellulose, mannitol, sorbitol, and lactose Can be prepared. Other functional excipients such as disintegrants and lubricants may be added. The selection of these functional excipients and diluents is well known to those skilled in the art. Optionally, the tablet may comprise granulating the medicament and its salt mixture with water with a suitable diluent, disintegrant and binding polymer; Calibration and drying of granules; By lubricant addition, compression on a tablet machine. The methods used are those which are generally well described in the pharmaceutical literature. See, eg, B. B. Sheth, F. J. Bandelin and R. JF. Shangraw, Compressed Tablets, in Pharmaceutical Dosage Forms: Tablets, Vol 1, edited by H. A. Lieberman and L. Lachman, Dekker N.Y. (1980)].
    [46] Delayed release tablets can be prepared by coating the immediate release tablets with a diffusion limiting polymer coating. Suitable polymers are Eudragit sold by Ethylcellulose, Lom Parma. RS, Eudragit RL, Eudragit May be selected from methyl methacrylate copolymers, such as NE. The coating method may be spraying the polymer solution onto the tablet in a pan coater or fluid bed coating apparatus. The solvent may be oily or aqueous, depending on the nature of the polymer used. Coating methods are described in the literature: JM Bakan, Microencapsulation, in L. Lachman, H. Lieberlmman and JL Kanig (edit) The Theory and Practice of Industrial Pharmacy, Lea & Febinger, Philadelphia, USA, 1986; JM McGinity, Aqueous polymer coatings for Pharmaceutical Dosage Forms, Dekker NY, 1989.
    [47] Alternatively, delayed release tablets can be prepared by incorporating a matrix forming excipient into the formulation and subtracting a disintegrant. Such matrix forming excipients may be hydrophilic polymers, which include hydroxypropylmethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, swelling in contact with an aqueous liquid, and medicament by diffusion through the swollen polymer network. Release is controlled and incorporated at levels of 10-30% by weight compared to delayed release tablets.
    [48] Otherwise the matrix forming excipient may be a liquid component, such as hydrogenated castor oil, or carnuba wax and may be incorporated at 10-40% by weight compared to delayed release tablets.
    [49] Since zolpidem is a basic medicament, optionally with a pharmaceutically acceptable organic acid, selected from those listed above to maintain the micro-pH of the tablet while eluting at neutral pH conditions of the small intestine, delayed release tablets may be formulated.
    [50] (2) a capsule comprising a mixture of delayed release pellets and immediate release pellets:
    [51] Immediate release pellets can be prepared by depositing a medicament suspended in an organic solvent such as water or ethanol into spherical granules with hydroxypropylmethylcellulose or another suitable polymer that acts as a povidone or a binder. Solution phase coating apparatus is generally used. The particles may be agglomerated to form spherical granules or pellets in a high speed mixer granulator or a rotary solution phase flocculator. These methods are described in K. W. Olson and A. M. Mehta, Int. J. Pharm. Tech & Prod. Mfr. 6, 18-24, 1985. Pellets are described, for example, in C. Vervaet, L. Baert & J. P. Remon, Int. J. Pharm. 116 (1995) 131-146, wet lumps or melts can be prepared by extrusion, followed by spheroisation.
    [52] Excipients used are generally those having plastic properties such as microcrystalline cellulose, but mannitol is also used. Small amounts of polymeric binders are generally added. Surfactants such as sodium dodecyl sulfate may also be incorporated to allow easier extrusion.
    [53] Delayed release pellets are prepared by coating the immediate release pellets in the same manner as described for tablets. Coating may be carried out, for example, in a coating pan or in a solution phase coater-dryer. The amount and composition of the coating is adjusted from that used in the tablets to reduce the permeability of the coating to account for a much larger surface for diffusion in the pellets.
    [54] Delayed release pellets may contain a pharmaceutically acceptable organic acid to maintain the internal micro-pH of the pellets while solpidem is a basic medicament while eluting at neutral pH conditions of the small intestine.
    [55] Optionally, because zolpidem is a basic medication, delayed release pellets are eudragit It can be coated with a pH sensitive membrane that contains a polymer soluble at neutral pH, such as S, and is impermeable at acid pH, which increases drug permeability above pH 5 to compensate for the decreased solubility of the drug at higher pH. Do it.
    [56] Optionally, sustained release pellets and immediate release powder.
    [57] (3) tablets comprising a number of delayed release coated pellets comprising a medicament contained in a matrix also comprising a medicament:
    [58] Optionally, the tablet may consist of a mixture of delayed release coated pellets and immediate release uncoated pellets containing the medicament, contained within the unmedicated matrix.
    [59] Optionally, the delayed release coating pellet can be further coated with a layer comprising the medicament and other excipients allowing immediate release from the layer, included in the medicament-free matrix.
    [60] The matrix surrounding the pellets should preferably be formulated such that compression into the tablet does not interfere with the warmth of the membrane surrounding the pellets. In contact with the solution, the tablet disintegrates to rapidly release the medicament from the matrix, or from the immediate release pellet, or from the immediate release pellet coating, after which the drug is slowly released from the delayed release pellet. The pellets may be formulated with pharmaceutically acceptable organic acids to maintain the micro-pH of the pellets while eluting at neutral pH conditions of the small intestine.
    [61] (4) the multilayer tablet includes:
    [62] (i) one or two delayed release layers, comprising a medicament and a hydrophilic polymer (preferably a cellulose derivative),
    [63] (ii) at least one immediate release layer comprising a medicament, and possibly
    [64] (iii) hydroxypropylcellulose, hydroxyethylcellulose or soluble diluents such as lactose, sorbitol, mannitol, or another layer comprising a hydrophilic polymer and a soluble excipient, which do not include a medicament, the layer being from a delayed release layer Regulate the release of medication.
    [65] Although well known to those skilled in the art, each layer contains other excipients to provide suitable properties for pressing, lubrication, and bonding. Examples of such two-layer and multilayer tablets are shown in FIGS. 7A-D, where the immediate release layer is denoted by i, the delayed release layer is denoted by p and the layer controlling the emission profile is denoted by m.
    [66] (5) Multi-coated tablets include:
    [67] (i) Since the medicament and zolpidem are basic medicaments, a core comprising an optionally pharmaceutically acceptable organic acid to maintain a constant pH,
    [68] (ii) a composite coating that provides slow release of the medicament from the core,
    [69] (iii) a coating layer comprising a medicament in which the formulation is released quickly or immediately in contact with the solution.
    [70] Although well known to those skilled in the art, each part of the tablet, in particular the inner core, may contain other excipients to provide properties suitable for pressing, lubrication, and bonding. Methods for making both multilayer and multi-coated tablets are described in W. C. Gunsel, Compression coated and layer tablets in Pharmaceutical Dosage Forms: Tablets, Vol 1. edited by H. A. Lieberman and L. Lachamn, Dekker N.Y. (1980).
    [71] As other specific embodiments within the scope of the present invention, mention may be made of pharmaceutical compositions designed to prevent abuse. Indeed it is known that some medicines and especially sleeping pills designed for legal oral use have the potential for abuse. One method of substantially reducing or even eliminating this possibility for drug abuse of a pharmaceutical agent for the purpose of the present invention is to release the active ingredient according to the in vitro profile of phase 2 as described above after normal administration. , And, if mixed with a beverage, to provide a pharmaceutical composition for oral administration comprising zolpidem, which may simultaneously produce visual changes or changes in the appearance of the beverage, whether or not containing alcohol. These visual changes or changes are designed to prevent the active ingredient from being administered to the person in the beverage without the knowledge of the user.
    [72] These visual changes include, according to the invention, all means for indicating the presence of the composition in the beverage. The following may be referred to as a method of introducing visual changes: containing colored excipients, floating the composition on the surface of the beverage, on the surface of the beverage, on the edge of the glass, on the beverage and / or bottom of the glass Forming insoluble particles in the phase or a combination thereof. Virtually alcoholic beverages include, for example, coffee, tea, wine, fortified wines, spirits, liquors, hot or cold chocolate beverages, all gaseous or nonalcoholic beverages, all cocktails or fruit juices, milk, creams, etc. It may consist of a mixture of.
    [73] Floating the composition can be accomplished by foaming, which can be obtained by a foamer, as described below. In addition to these foaming properties, the composition may exhibit a viscosity increasing property that appears in contact with the beverage. Therefore, when bubbles form, they are "trapped" and the composition swells. Lowering the density may keep the pharmaceutical composition on the beverage surface. Such viscosity may be obtained by one or more gelling materials. Hydrophilic excipients are particularly suitable as well as the gel forming materials specified below.
    [74] The particles can be obtained by combining lipophilic excipients and hydrophilic excipients as described above. A list of suitable lipophilic excipients is specified below.
    [75] The composition of the present invention according to this specific embodiment may liberate the particles even if the composition does not float or immediately floats.
    [76] The foamer may be a carbon dioxide generator system. This may include suitable carbon dioxide generators and pharmaceutically acceptable acids.
    [77] Carbon dioxide generators are typically carbonates or bicarbonates of alkali or alkaline earth metals or amino acids. Calcium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, L-lysine carbonate, arginine carbonate or sodium seskicarbonate may be mentioned as carbon dioxide generators. The acid can be an acid anhydride, monocarboxylic acid, polycarboxylic acid or partial salt of polycarboxylic acid. More specifically citric acid, tartaric acid, ascorbic acid, fumaric acid, nicotinic acid, acetylsalicylic acid, maleic acid, adipic acid, succinic acid, malic acid, malonic acid may be selected or glutaric anhydride, citric anhydride, monosodium citrate and succinic acid It may be anhydride.
    [78] The carbon dioxide generator may be constituted by a mixture of the carbon dioxide generators mentioned above.
    [79] In such carbon dioxide generators, the acidic compound content is generally selected such that the ratio between the number of moles in the acidic compound to the number of moles in the carbon dioxide generator is between one and two.
    [80] The gel forming material may consist of one or more hydrophilic excipients that inflate the composition and trap the generated gas. To form insoluble particles, one or more lipophilic excipients are added to the hydrophilic excipients.
    [81] Foaming and particle formation processes create viscous masses that float and adhere to the glass. This process can take from 0.5 to 25 minutes depending on the type of beverage.
    [82] Among the lipophilic excipients may be mentioned: glycerol stearate, palmitostearate and behenate; Hydrogenated vegetable oils and derivatives thereof; Plant and animal waxes and derivatives thereof; Hydrogenated castor oil and derivatives thereof and cetyl esters and alcohols.
    [83] Among the hydrophilic excipients, mention may be made of: cellulose derivatives, hydroxyethylcellulose, hydroxypropylcellulose (50 to 1250 kDa molecular weight), hydroxypropylmethylcellulose (10 to 1500 kDa molecular weight), carboxymethylcellulose and sodium carboxymethyl Cellulose; Vegetable gums and derivatives thereof; Alginic acid derivatives; Polyethylene glycol and derivatives thereof; Starch and its derivatives; Silica, polymethacrylate and acrylic acid and methacrylate copolymers.
    [84] One of the components of the gel forming material may be chosen to be less soluble in alcohol.
    [85] Coloring excipients may conveniently be added to cause a visual change that prevents abuse. It can color liquids or particles simultaneously or can be colored separately. Among the suitable coloring excipients the following may be mentioned: indigotin, cokinyl carminic acid, yellow orange S, allura red AC, iron oxide, coucurmin, riboflavin, tarrazine, quinoline yellow, azorubin, amaranth, carr Min, erytocin, red 2G, patented blue V, shiny blue FCF, chlorophyll, cupper complex of chlorophyll, green S, caramel, shiny black BN, carbo medicinelis begetavibilis, brown FK and HT , Carotenoids, anato extracts, paprika extracts, lycopene, lutein, canthaxanthin, beetruk red, athocyanin, calcium carbonate, titanium dioxide, aluminum, silver, gold or ritrubin BK or other suitable for oral administration Coloring excipients.
    [86] These visual means of preventing abuse may include characteristic pharmaceutical entities, containing no active substance, together with immediate and sustained release entities comprising pharmaceutical forms, which may be incorporated into one of these two entities. Can be. However, the third method is to incorporate all or certain of them into separate entities and at the same time add certain to immediate or sustained release entities.
    [87] As described above, the method of incorporating abuse resistance will depend on the type of formulation. In the case of tablets described above, including tablets contained within capsules, substances that exhibit abuse resistance (colored materials, foamed couples ...) may be included in the immediate release entity of the formulation. Optionally in the case of multi-layer tablets and immediate tablets in capsules, they may be incorporated into separate layers containing no active substance, but have substances which exhibit abuse resistance. This layer can be added to sustained release tablets or tablets in capsules, provided the tablets are formulated as a matrix and not coated with a coating that exhibits sustained release properties. In the case of capsules containing sustained release pellets and immediate release pellets or granules, the abuse resistant material may be incorporated into the immediate release entity or added separately, except for the foamed couple.
    [88] The invention is illustrated by the following examples. However, the present invention is not limited by the following examples:
    [89] Example 1 Delayed-Release Tablets Containing 10 mg of Zolpidem Hemitartrate
    [90] The first four of the following materials were mixed together, granulated with water, dried and measured. The granulate was then mixed with magnesium stearate and pressed using a rotary tablet at a weight of 120 mg per tablet.
    [91] Zolpidem hemitartrate 8.3%
    [92] Lactose 86.6%
    [93] Citric acid 2.5%
    [94] Hydroxypropylmethylcellulose 606 1 2.1%
    [95] Magnesium Stearate 0.5%
    [96] 1 Parmacoat 606, sold by Shin-Etsu Co.
    [97] The tablets were coated with a sufficient amount of the following mixture to obtain the desired elution profile in an Acelacotta pan coater.
    [98] Ethylcellulose1 2.0%
    [99] Diethylphthalate 0.4%
    [100] Hydroxypropylmethylcellulose 606 2.0%
    [101] Isopropanol 47.8%
    [102] Dichloromethane 47.8%
    [103] 1 Etocell, sold by Dow Chemical Co.
    [104] In vitro dissolution profiles of the tablets were obtained using US Pharmacopoeia Apparatus II. Two elution media were used: 900 ml 0.01 M hydrochloric acid and 900 ml pH 6.8 potassium phosphate 0.05 M buffer, stored at 37 ± 0.5 ° C. Elution percentage was determined by measuring UV absorption at 270 nm (continuous sampling by peristaltic pump in closed system). Results are shown in FIG. 3.
    [105] Comparative Example 1 Acid-Free Delayed-Release Tablet Containing 10 mg of Zolpidem Hemitartrate
    [106] Tablets were prepared according to the same method as Example 1 and having the following composition:
    [107] Zolpidem hemitartrate 8.3%
    [108] Lactose 89.1%
    [109] Hydroxypropylmethylcellulose 606 2.1%
    [110] Magnesium Stearate 0.5%
    [111] These were coated with a polymer mixture comprising 50% hydroxypropylmethylcellulose and 50% ethylcellulose. The in vitro dissolution profile of the tablets was obtained by the method of Example 1. The results are shown in FIG. These show that delayed release tablets containing acid exhibit an elution profile independent of pH.
    [112] Example 2 Immediate Release Tablets Containing 10 mg of Zolpidem Hemitartrate
    [113] A tablet containing 10 mg of zolpidem hemitartrate was prepared in the same manner as in Example 1 to have a single weight of 120 mg, and has the following composition:
    [114] Zolpidem hemitartrate 8.3%
    [115] Lactose 75.8%
    [116] Microcrystalline Cellulose 1 10.0%
    [117] Hydroxypropylmethylcellulose 606 2.1%
    [118] Sodium Carboxymethylcellulose 2 3.2%
    [119] Magnesium Stearate 0.6%
    [120] 1 Avicel, sold by FMC.
    [121] 2 Primogel, sold by Abebe.
    [122] Elution of the tablets was tested according to the method described in Example 1, in a 0.01 M hydrochloric acid medium. 90% of the amount of zolpidem contained in the immediate release tablet was released in less than 30 minutes.
    [123] The immediate release tablets obtained were administered orally to six healthy volunteers in pharmacokinetic studies. Two tablets were administered orally to each volunteer in a single dosing study. Blood samples were taken at 30 minutes, 1, 2, 3, 4, 6, 8, 10 hours and analyzed for zolpidem. The results (average zolpidem plasma concentration) are plotted in FIG. 5 (closed squares).
    [124] Example 3 A formulation consisting of an immediate release tablet comprising 10 mg of zolpidem hemitartrate according to Example 2 in a gelatin capsule and a delayed release tablet comprising 10 mg of zolpidem hemitartrate according to Example 1.
    [125] Pharmacokinetic studies were performed on simultaneous administration of delayed release tablets and immediate release tablets. As described above, one immediate release tablet and one delayed release tablet each containing 10 mg of zolpidem were administered to the same six volunteers as in the study described in Example 2. The results (average zolpidem plasma concentration) are plotted in FIG. 5 (open squares). The results show a rapid increase in zolpidem concentration to give the same peak as in immediate release at 30 minutes, but this is 3-6 hours after dosing more than those obtained with the same dosage (20 mg) of immediate release formulation. It is a plasma concentration obtained in. The total amount of zolpidem is released in up to about 8 hours. The elution profile is the same as the addition of the elution profiles of Examples 1 and 2. Therefore, the immediate and delayed release pharmaceutical entity contained 10 mg of zolpidem hemitartrate (50%), respectively, and the immediate release phase was 12.2 mg (61%) and the delayed release phase was 7.8 mg (39%). The complete elution time (90% released) was 2 hours. Profile parameters were T 3 = 2.12 hours; T 2 = 1.19 hours; (T 2 -T 1 ) = 0.43 (T 3 -T 1 ) and the profile is close to zero order.
    [126] Example 4 Capsules Comprising a Mixture of Immediate Release Pellets and Coated Delayed Release Pellets
    [127] A suspension comprising 100 g zolpidem hemitartrate in 670 g of ethanol and 100 g of povidone sold as Plasdon K29 / 32 by BASF was prepared. 750 g of this suspension were sprayed onto 1060 g of 16-18 mesh microgranules in a solution phase dryer. Zolpidem elution was tested in 0.01 M hydrochloric acid according to the method of Example 1. 80% eluted in 2 minutes and 100% eluted in 30 minutes.
    [128] Methacrylate copolymer Eudragit RL100 25 g, methacrylate copolymer Eudragit 143 g of RS100 (both sold by Lom Parma) and trade name Eudrapex by Lom Parma as a plasticizer A solution comprising 18.7 g of ethyl citrate sold as was prepared in 1180 g of a 60:40 m / m isopropanol / acetone mixture. Pellets containing zolpidem were coated with this polymer mixture by spraying in a solution phase dryer and the final amount of coating was 20% by weight of the uncoated pellet weight. After maturing the pellets at 35 ° C. for 24 hours, a mixture of these coated pellets and the uncoated pellets described above was prepared 1: 1 for the zolpidem content and filled into gelatin capsules to zolpidem hemi per capsule The total content of tartrate was 15 mg (12 mg zolpidem base). Elution on the capsules was tested by the method of Example 1 and the resulting profile is shown in FIG. 6.
    [129] The immediate and delayed release pharmaceutical entities therefore contained 7.5 mg of zolpidem hemitartrate (50%), respectively. Because of the lag-time of about 1 hour before release from the delayed release entity, the immediate release phase (60%) and delayed release phase (40%) corresponded exactly to the entity. The complete elution time (90% released) was 3.17 hours. Profile parameters are: T 3 = 3.17 hours; T 2 = 1.68 hours; (T 2 -T 1 ) = 0.44 (T 3 -T 1 ) and the profile was S-shaped.
    [130] Example 5 Tablets comprising coated delayed release pellets comprising 5 mg zolpidem hemitartrate in a quick-disintegrating matrix comprising 7.5 mg zolpidem hemitartrate.
    [131] Delayed release coated pellets were prepared as described in Example 4. Pellets were then prepared using the same method with 20% by weight of microcrystalline cellulose. Granules of the following composition were then prepared by wet granulation:
    [132] Zolpidem hemitartrate 8.4%
    [133] Lactose 20.0%
    [134] Microcrystalline Cellulose 1 62.9%
    [135] Hydroxypropylmethylcellulose 606 3.0%
    [136] Crospovidone 2 5.0%
    [137] Magnesium Stearate 0.7%
    [138] 1 Avicel, sold by FMC.
    [139] 2 Collidone CL, sold by BASF.
    [140] It was mixed with the coated pellets at a ratio of 3 parts of granules to 2 parts of coated pellets (based on zolpidem content) and the mixture was compressed into tablets containing 12.5 mg of zolpidem hemitartrate (equivalent to 10 mg of zolpidem base). .
    [141] Example 6 : Two-layer immediate / delayed release tablet comprising 12.5 mg of zolpidem hemitartrate.
    [142] Granules were prepared by granulation according to the following composition. The granulation process is that described in Example 1:
    [143] Granule 1 (immediate release)
    [144] Zolpidem hemitartrate 4.4%
    [145] Lactose 150 Mesh 68.3%
    [146] Microcrystalline Cellulose 20.0%
    [147] Hydroxypropylmethylcellulose 606 2.5%
    [148] Sodium Carboxymethylcellulose 3.8%
    [149] Magnesium Stearate 1.0%
    [150] Granule 2 (Delayed Release)
    [151] Zolpidem hemitartrate 5.6%
    [152] Lactose 150 Mesh 40.0%
    [153] Microcrystalline Cellulose 20.0%
    [154] Tartaric Acid 8.4%
    [155] Hydroxypropylmethylcellulose 1 25.0%
    [156] Magnesium Stearate 1.0%
    [157] 1 Metoroz 90SH400, sold by Shin-Etsu.
    [158] The mixture was then compressed into bilayer tablets of the type shown in FIG. 7 (a) using an alternative tablet press. Each tablet contained 12.5 mg of zolpidem hemitartrate, the first immediate release layer had 125 mg of granule 1 comprising 5.5 mg of zolpidem hemitartrate, and the delayed release layer was 7 mg of zolpidem hemitartrate Grind 2 granules containing 125 mg. In vitro dissolution profiles of the tablets were obtained using the US Pharmacopeia Apparatus 2. Three elution media were used: 0.01 M hydrochloric acid, pH 6.8 potassium phosphate 0.025 M buffer, and pH 7.5 potassium phosphate 0.015 M buffer. Elution medium capacity was 500 ml and stored at 37 ± 0.5 ° C. It stirred by the paddle method (75 rpm). To prevent tablets from adhering to the glass surface, the grill was placed at the bottom of each container. Elution percentage was determined by measuring UV absorption at 310 nm (continuous sampling by peristaltic pump in closed system). The results are shown in FIG. The dissolution profile is almost independent of the pH of pH 1 to 6.8. Zolpidem continued to release at a significantly reduced rate at pH 7.5. The immediate release entity contained 5.5 mg of zolpidem hemitartrate (44%) and the delayed release entity contained 7.5 mg of zolpidem hemitartrate (56%). The complete elution time (90% released) was 2.14 hours. Because of the release from the delayed release pharmaceutical entity between 0 and 0.5 hours, the corresponding immediate release phase was 7.5 mg (60%) and the delayed release phase was 5 mg (40%). Profile parameters are: T 3 = 2.23 hours; T 2 = 1.38 h; (T 2 -T 1 ) = 0.51 (T 3 -T 1 ), and the profile is order 0.
    [159] Comparative Example 2 : Comparison of the Elution Profile of a Two-Layer Immediate / Delayed-Release Tablet Containing 12.5 mg of Zolpidem Hemitartrate with the Elution Profile of Immediate Release and Delayed-Release Tablets of the Same Composition
    [160] Granules were prepared by wet granulation according to the following composition. The granulation process was as described in Example 1:
    [161] Granule 1 (immediate release)
    [162] Zolpidem hemitartrate 6.0%
    [163] Lactose 150 Mesh 66.7%
    [164] Microcrystalline Cellulose 20.0%
    [165] Hydroxypropylmethylcellulose 606 2.5%
    [166] Sodium Carboxymethylcellulose 3.8%
    [167] Magnesium Stearate 1.0%
    [168] Granule 2 (Delayed Release)
    [169] Zolpidem hemitartrate 4.0%
    [170] Lactose 150 Mesh 55.4%
    [171] Microcrystalline Cellulose 20.0%
    [172] Hydroxypropylmethylcellulose 1 20.0%
    [173] Magnesium Stearate 1.0%
    [174] 1 Metoroz 90SH400, sold by Shin-Etsu.
    [175] A portion of each granule was compressed into bilayer tablets of the type shown in FIG. 7 (a) using an alternative tablet press. Each tablet contained 12.5 mg of zolpidem hemitartrate, the first immediate release layer had 125 mg of granule 1 comprising 6.5 mg of zolpidem hemitartrate, and the delayed release layer contained 6 mg of zolpidem hemitartrate. It contains 125 mg of granules 2 containing. Elution profiles were tested using US Pharmacopoeia Apparatus 2. Elution medium was 0.01 M hydrochloric acid, preserved at 37 ± 0.5 ° C. The volume was 500 ml and stirred by paddle method (75 rpm). Elution percentage was determined by measuring UV absorption at 310 nm (continuous sampling by peristaltic pump in closed system). The results are shown in FIG. The pH of the dissolution medium had a significant effect on the profile, and the increased pH inhibited the dissolution rate.
    [176] The remaining portions of each granule of Comparative Example 2 were each compressed into 125 mg weight tablets, the immediate release tablet (granule 1) contained 7.5 mg of zolpidem hemitartrate and the delayed release tablet was zolpidem hemitart 5 mg of rate was included. The in vitro dissolution profile of the tablets was obtained by the method of Example 1.
    [177] The resulting profile is shown in FIG. 9. Surprisingly, the presence of the immediate release layer had a significant effect on the dissolution of the hydrophilic matrix delayed release layer in the two-layer tablet, but the dissolution profile of the separated tablet was the sum of the profiles of the separated tablets, and the delayed release layer of the two-layer tablet It was considerably slower than in the case of isolated tablets.
    [178] Comparative Example 3 : pH Dependence of the Elution Profile of a Two-Layered Tablet Comprising 12.5 mg of Zolpidem Hemitartrate Without Acid in a Delayed-Release Layer
    [179] Granules similar to the granules of Example 6 were prepared, with the only difference being that tartaric acid was lost and lactose (48.8%) was used instead for granule 2 (delayed release). The mixture was then compressed into bilayer tablets of the type shown in FIG. 7 (a) using an alternative tablet press, as in Example 6. In vitro dissolution profiles of the tablets were obtained as in Example 6, using two elution media: 0.01 M hydrochloric acid and pH 6.8 potassium phosphate 0.025 M buffer. The results are shown in FIG. The dissolution profile in 0.01 M hydrochloric acid was almost similar to that of the formulation with acid (Example 6), but the rate at pH 6.8 was much lower.
    [180] Example 7 Three Layer Immediate / Delayed Release Tablets Containing 12.5 mg of Zolpidem Hemitatrate
    [181] Granules were prepared by the Example 1 method according to the following composition:
    [182] Layer 1 (Instant Release)
    [183] Zolpidem hemitartrate 5.0%
    [184] Lactose 150 Mesh 67.7%
    [185] Microcrystalline Cellulose 20.0%
    [186] Hydroxypropylmethylcellulose 606 2.5%
    [187] Sodium Carboxymethylcellulose 3.8%
    [188] Magnesium Stearate 1.0%
    [189] Layer 2 (inactive)
    [190] Lactose (spray dried) 60.0%
    [191] Microcrystalline Cellulose 24.0%
    [192] Tartaric Acid 10.0%
    [193] Hydroxyethylcellulose 5.0%
    [194] Magnesium Stearate 1.0%
    [195] Layer 3 (Delayed Release)
    [196] Zolpidem hemitartrate 6.0%
    [197] Lactose 150 Mesh 40.0%
    [198] Microcrystalline Cellulose 19.0%
    [199] Tartaric Acid 9.0%
    [200] Hydroxypropylmethylcellulose 1 25.0%
    [201] Magnesium Stearate 1.0%
    [202] 1 Metoroz 90SH4000, sold by Shin-Etsu.
    [203] They were compressed into a three layer tablet, in the form shown in FIG. 7 (d) as described in Example 6, and layer 1 comprising 100 mg of granule 1 had 5 mg of zolpidem hemitartrate and layer 2 ( The extra layer) contained 100 mg of granule 2 and layer 3 comprised 125 mg of granule 3 and 7.5 mg of zolpidem hemitartrate.
    [204] Example 8 Coated Two-Layer Immediate / Delayed-Release Tablets Containing 10 mg of Zolpidem Hemitartrate and Containing Foamed Couples and Dye in Immediate Release Layer
    [205] The mixture was prepared according to the composition shown below. Powder mixture 1 for the immediate layer was prepared by dry mixing the first eight components. The remaining three ingredients were then added. Granule 2 for the delayed release layer was prepared by granulating the first five components with water, and the remaining two components were dried, sieved and mixed with the granules.
    [206] Powder Mixture 1 (Instant Release)
    [207] Zolpidem hemitartrate 3.6%
    [208] Anhydrous lactose 11.3%
    [209] Microcrystalline Cellulose 24.3%
    [210] Povidone K30 5.0%
    [211] Tartaric Acid 23.0%
    [212] Sodium bicarbonate 25.0%
    [213] Sodium Carboxymethylcellulose 3.0%
    [214] Indigotin W6004 0.8%
    [215] Sodium Dodecyl Sulfate 2.0%
    [216] Colloidal Silica 1.0%
    [217] Magnesium Stearate 1.0%
    [218] Granule 2 (Delayed Release)
    [219] Zolpidem hemitartrate 4.4%
    [220] Lactose 150 Mesh 36.0%
    [221] Tartaric Acid 8.4%
    [222] Microcrystalline Cellulose 20.0%
    [223] Hydroxypropylmethylcellulose 1 30.0%
    [224] Colloidal Silica 0.2%
    [225] Magnesium Stearate 1.0%
    [226] 1 Metoroz 90SH4000, sold by Shin-Etsu.
    [227] The mixture was then compressed into bilayer tablets of the type shown in FIG. 7 (a) using a Manesti BL tablet press. Each tablet contained 10 mg of zolpidem hemitartrate, the first immediate release layer with 125 mg of powder mixture included 4.5 mg of zolpidem hemitartrate, and the delayed release layer with 125 mg of granule 2 5.5 mg pydem hemitartrate was included.
    [228] The film coating (4% by weight of tablet) of the following composition was applied as a 20% dispersion in anhydrous alcohol using a coating turbine (Grat GC300).
    [229] Copovidone 1 12%
    [230] Ethylcellulose 12%
    [231] Titanium Dioxide 46%
    [232] Talc 30%
    [233] 1 Collidone VA64, sold by BASF.
    [234] The elution profile of the tablets was determined in 0.01 M hydrochloric acid using the apparatus and method described in Example 6. The results are shown in FIG.
    [235] Example 9 Coated Three-Layer Immediate / Delayed-Release Tablets Containing 10 mg of Zolpidem Hemitartrate and Containing Foamed Couples and Dyestuffs
    [236] The mixture was prepared according to the composition shown below. Powder mixture 1 for the immediate layer was prepared by dry mixing the first eight components. The remaining three ingredients were then added. Granule 2 for the delayed release layer was prepared by granulating the first five components with water, and the remaining two components were dried, sieved and mixed with the granules.
    [237] Powder Mixture 1 (Instant Release)
    [238] Zolpidem hemitartrate 4.0%
    [239] Microcrystalline Cellulose 36.4%
    [240] Povidone K30 5.0%
    [241] Tartaric Acid 23.0%
    [242] Sodium bicarbonate 25.0%
    [243] Sodium Carboxymethylcellulose 3.0%
    [244] Black Iron Oxide 0.3%
    [245] Indigotin 0.8%
    [246] Sodium Dodecyl Sulfate 1.0%
    [247] Colloidal Silica 1.0%
    [248] Magnesium Stearate 0.5%
    [249] Powder mixture 2 (anti-abuse)
    [250] Microcrystalline Cellulose 40.4%
    [251] Povidone K30 5.0%
    [252] Tartaric Acid 23.0%
    [253] Sodium bicarbonate 25.0%
    [254] Sodium Carboxymethylcellulose 3.0%
    [255] Black Iron Oxide 0.3%
    [256] Indigotin 0.8%
    [257] Sodium Dodecyl Sulfate 1.0%
    [258] Colloidal Silica 1.0%
    [259] Magnesium Stearate 0.5%
    [260] Granule 3 (Delayed Release)
    [261] Zolpidem hemitartrate 4.0%
    [262] Lactose 150 Mesh 36.0%
    [263] Tartaric Acid 8.4%
    [264] Microcrystalline Cellulose 20.4%
    [265] Hydroxypropylmethylcellulose 1 30.0%
    [266] Colloidal Silica 0.2%
    [267] Magnesium Stearate 1.0%
    [268] 1 Metoroz 90SH4000, sold by Shin-Etsu.
    [269] The mixture was then compressed into three layer tablets of the type shown in FIG. 7 (d)-The zolpidem-free layer of granule 2 was denoted in m using a Manesti BL tablet press. Each tablet contained 10 mg of zolpidem hemitartrate. Each tablet contained 125 mg of granule or powder mixture, and both immediate release and delayed release layers contained 5 mg of zolpidem hemitartrate.
    [270] Tablets were film coated as described in Example 8.
    [271] Example 10 Dry Coated Delayed-Release Tablets Containing 15 mg of zolpidem hemitartrate
    [272] Granules were prepared with the following compositions using the method described in Example 1.
    [273] Granule 1 (immediate release)
    [274] Zolpidem hemitartrate 4.0%
    [275] Lactose 150 Mesh 48.7%
    [276] Microcrystalline Cellulose 40.0%
    [277] Hydroxypropylmethylcellulose 606 2.5%
    [278] Sodium Carboxymethylcellulose 3.8%
    [279] Magnesium Stearate 1.0%
    [280] Granule 2 (Delayed Release)
    [281] Zolpidem hemitartrate 7.2%
    [282] Lactose 150 Mesh 38.4%
    [283] Microcrystalline Cellulose 20.0%
    [284] Tartaric Acid 8.4%
    [285] Hydroxypropylmethylcellulose 1 25.0%
    [286] Magnesium Stearate 1.0%
    [287] 1 Metoroz 90SH4000, sold by Shin-Etsu.
    [288] Granule 2 was compressed using an alternative tablet press to give a 125 mg weighted delayed release tablet comprising 9 mg of zolpidem hemitartrate. The tablets were dry coated with Granule 1, the dry coating weight was 150 mg and the dose of zolpidem hemitartrate in the coout was 6 mg.
    权利要求:
    Claims (21)
    [1" claim-type="Currently amended] 37 o C, in an aqueous buffer, by a two-phase in vitro dissolution profile measured with a Type II elution instrument according to the US Pharmacopeia, where the first phase is an immediate release layer and the second phase is a delayed release layer, and then zolpidem or its A pharmaceutical composition comprising zolpidem or a salt thereof, comprising a sustained release formulation adapted to release the salt.
    [2" claim-type="Currently amended] The pharmaceutical composition of claim 1, wherein the first phase has a maximum duration of 30 minutes.
    [3" claim-type="Currently amended] The pharmaceutical composition according to claim 1 or 2, wherein the second phase has a zero order release profile.
    [4" claim-type="Currently amended] The pharmaceutical composition according to claim 1 or 2, wherein the second phase has a profile in which the release is proportional to the square root of time.
    [5" claim-type="Currently amended] The pharmaceutical composition according to claim 1 or 2, wherein the second phase has a primary release profile.
    [6" claim-type="Currently amended] The pharmaceutical composition according to claim 1 or 2, wherein the second phase has an S-type release profile.
    [7" claim-type="Currently amended] The pharmaceutical composition according to any one of claims 1 to 6, wherein 40 to 70% of the total amount of zolpidem is released in the immediate release phase.
    [8" claim-type="Currently amended] The pharmaceutical composition according to any one of claims 1 to 7, wherein the time for 90% release of the total zolpidem is 2 to 6 hours.
    [9" claim-type="Currently amended] A pharmaceutical composition comprising zolpidem or a salt thereof, characterized in that there are two kinds of pharmaceutical entities: one is an immediate release entity and the other comprises a delayed release entity.
    [10" claim-type="Currently amended] The pharmaceutical composition of claim 9 having a dosage form in capsules, tablets, multilayer tablets, multi-coated tablets.
    [11" claim-type="Currently amended] The pharmaceutical composition of claim 9 or 10, wherein the pharmaceutical composition consists of at least one immediate release tablet and at least one delayed release tablet.
    [12" claim-type="Currently amended] The pharmaceutical composition according to claim 9 or 10, consisting of delayed release pellets and immediate release pellets.
    [13" claim-type="Currently amended] The pharmaceutical composition according to claim 9 or 10, consisting of a tablet comprising a number of delayed release coated pellets comprising a medicament contained in a matrix comprising a medicament.
    [14" claim-type="Currently amended] The method of claim 9 or 10,
    (i) one or two delayed release layers, comprising a medicament and a hydrophilic polymer (preferably a cellulose derivative),
    (ii) at least one immediate release layer comprising said medicament, and possibly
    (iii) another layer that does not include a medicament but comprises a hydrophilic polymer
    Pharmaceutical composition comprising a multilayer tablet comprising a.
    [15" claim-type="Currently amended] The method of claim 9 or 10,
    (i) a core comprising a medicament and optionally a pharmaceutically acceptable organic acid for maintaining a constant pH,
    (ii) a polymer coating layer that slowly releases the medicament from the core,
    (iii) a coating layer comprising a medicament which is released quickly or immediately by contacting the formulation with a solution.
    Pharmaceutical composition comprising a multi-coated tablet comprising a.
    [16" claim-type="Currently amended] The pharmaceutical composition of claim 9, wherein the immediate release entity and the delayed release entity are administered simultaneously but separately.
    [17" claim-type="Currently amended] The method of claim 1, wherein the delayed release entity can be selected from tartaric acid, malic acid, fumaric acid, lactic acid, citric acid, adipic acid or succinic acid and acid salts thereof in racemic or isomeric form. A pharmaceutical composition comprising a pharmaceutically acceptable organic acid.
    [18" claim-type="Currently amended] 18. A pharmaceutical composition according to any one of claims 1 to 17, which can cause a visual change when participating in a beverage containing or without alcohol.
    [19" claim-type="Currently amended] The method of claim 18, wherein the visual change is due to the release of the included excipient, or the composition floating on the beverage surface, or the formation of insoluble particles on the glass edge, at the beverage, and / or at the glass bottom, or a combination thereof. Pharmaceutical composition, characterized in that configured.
    [20" claim-type="Currently amended] 20. A foaming machine, hydrophilic excipient and optionally lipophilic excipient and colored excipient, optionally in the form of a capsule containing tablets, multilayer tablets or controlled release pellets and immediate release pellets or granules. Pharmaceutical composition.
    [21" claim-type="Currently amended] The pharmaceutical composition according to any one of claims 1 to 20, wherein zolpidem is in zolpidem hemitartrate form.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1998-12-04|Priority to EP98403037.9
    1998-12-04|Priority to EP98403037A
    1999-12-01|Application filed by 고든 라이트, 사노피-신델라보
    1999-12-01|First worldwide family litigation filed
    1999-12-01|Priority to PCT/EP1999/010454
    2001-08-22|Publication of KR20010080640A
    2011-02-08|Publication of KR101013272B1
    2011-02-08|Application granted
    优先权:
    申请号 | 申请日 | 专利标题
    EP98403037.9|1998-12-04|
    EP98403037A|EP1005863A1|1998-12-04|1998-12-04|Controlled-release dosage forms comprising a short acting hypnotic or a salt thereof|
    PCT/EP1999/010454|WO2000033835A1|1998-12-04|1999-12-01|Controlled-release dosage forms comprising zolpidem or a salt thereof|
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