Double-layer tablet and painkiller tablet with same structure

Abstract

The invention discloses a double-layer tablet, wherein one layer has hole in which the ingredients of the other layer are filled; the number of said hole is 1-3, the diameters of the holes are 1-10 mm. Each layer of the double-layer tablet includes the active ingredients and the adjuvant materials and can be the rapid-release layer or sustained-release layer respectively. The preparation method: Preparing respectively a component I and a component II, both of them containing the active ingredients and the pharmaceutical excipients, and preparing the tablet having holes from component I; Forming the double-layer tablet composed of the component I layer and the component II layer after pressing said tablet having holes with the component II together; and filling the component II into the holes during compressing. It is proved by tests that the double-layer table in the invention is featured with high physical stability, hard breaking during transportation and storage, approximately constant release of medicine and usefulness of keeping stable plasma concentration of the medicine in the patient; thus, the effectiveness and safety of the medicine taken by the patient are improved greatly.

Claims

1. A double-layer tablet comprising an upper layer on top of a lower layer wherein: the upper layer is a sustained-release layer and formed by compressing a first active ingredient and a first pharmaceutically acceptable excipient to have at least one hole with a diameter between about 2-6 mm; and the double-layer tablet comprising an upper layer on top of a lower layer is formed by pressing the upper layer onto a second active ingredient and a second pharmaceutically acceptable excipient so that a part of the second active ingredient and a second pharmaceutically acceptable excipient is under the upper layer as the lower layer and a part of second active ingredient and the second pharmaceutically acceptable excipient fills into the hole(s) of the upper layer.

2. The double-layer tablet according to claim 1, wherein the number of said hole is 1-3.

3. The double-layer tablet according to claim 1, wherein the active ingredients in the two layers are identical or different from each other; and one or more kinds of active ingredients are contained in each layer.

4. The double-layer tablet according to claim 1, wherein said hole penetrates from one side to another side of the upper layer.

5. The double-layer tablet according to claim 1, wherein the lower layer is a rapid-release layer.

6. A double-layer painkiller tablet comprising an upper layer on top of a lower layer, wherein: the upper layer is a sustained-release layer and formed by compressing a first active ingredient and a first pharmaceutically acceptable excipient to have at least one hole with diameter of between about 2-6 mm; and the painkiller double-layer tablet comprising an upper layer on top of a lower layer is formed by pressing the upper layer onto a second active ingredient and a second pharmaceutically acceptable excipient so that a part of the second active ingredient and a second pharmaceutically acceptable excipient is under the first layer as the lower layer and a part of second active ingredient and a second pharmaceutically acceptable excipient fills into the hole(s) of the upper layer, and the active ingredient in one or both layers is selected from group consist of aspirin, magnesium salicylate, sodium salicylate, choline magnesium trisalicylate, diflunisal, bisalicylate, ibuprofen, indomethacin, flurbiprofen, Phenoxy ibuprofen, naproxen, nabumetone, piroxicam, phenylbutazone, diclofenac, fenoprofen, ketoprofen, ketorolac, tetraclofenamic acid, sulindac, tolmetin, and anisodamine.

7. The double-layer painkiller tablet according to claim 6, wherein the number of said hole is 1-3.

8. The double-layer painkiller tablet according to claim 6, wherein the active ingredients in two layers are identical or different from each other; and one or more kinds of active ingredients are contained in each layer.

9. The double-layer painkiller tablet according to claim 6, wherein said hole penetrates from one side to another side of the upper layer.

10. The double-layer painkiller tablet according to claim 6, wherein: the sustained-release layer comprises sustained-release material selected from the group consisting of: hydroxypropyl methylcellulose, ethyl cellulose, hydroxypropyl cellulose, and any combination thereof.

11. The double-layer painkiller tablet according to claim 6, wherein: the pharmaceutically acceptable excipients in both layers are selected from the group consisting of: a filler, a disintegrating agent, a lubricant, a binder, a glidant, and any combination thereof.

12. The double-layer painkiller tablet according to claim 11, wherein: the filler is selected from the group consisting of: lactose monohydrate, lactose, pregelatinized starch, microcrystalline cellulose, and any combination thereof; the disintegrating agent is selected from the group consisting of: sodium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, polyvinylpolypyrrolidone, and any combination thereof; the lubricant is selected from the group consisting of: stearic acid, magnesium stearate, talcum powder, and any combination thereof; the binder is selected from the group consisting of: polyvidone, hydroxy propyl cellulose, hydroxypropyl methylcellulose, and any combination thereof; and the glidant is silicon dioxide.

13. The double-layer painkiller tablet according to claim 6, wherein: the sustained-release layer comprises the following components in weight percentage: the first active ingredient: 40-60%, the sustained-release material: 25-35%, the filler: 13-24%, the lubricant: 0.5% or 1%, the glidant: 0.5% or 1%; and the lower layer comprises the following components in weight percentage: the second active ingredient: 30-60%, the disintegrating agent: 3-6%, the filler: 30-60.5%, the binder: 0-5%, the lubricant: 0.5% or 1%, and the glidant: 0.5% or 1%.

14. The double-layer painkiller tablet according to claim 5, further comprises coating layer with following components in weight percentage, in 80% alcohol in water as a solvent hydroxypropyl methylcellulose E5: 30%, Polysorbate 80: 14%, talcum powder: 5%, and titanium dioxide: 2%.

Description

DESCRIPTION OF FIGURES

(1) FIG. 1 is the structure diagram of a double-layer tablet having one hole.

(2) FIG. 2 is the structure diagram of the double-layer tablet having two holes.

(3) FIG. 3 is the structure diagram of the double-layer tablet having three holes.

(4) In FIG. 1, FIG. 2 and FIG. 3, 1 indicates the tablet I, 2 indicates the tablet II, and 3 indicates the hole.

(5) FIG. 4 is the leaching curve of the double-layer tablet in hypnotic embodiment 1 (wherein four curves indicate the table Ino hole available, table I having holes with diameters 3 mm, tablet I having holes with diameters 4 mm and table I having holes with diameters 6 mm, respectively)

(6) FIG. 5 indicates comparison of three leaching curves of the double-layer tablet having sustained-release layer with holes (diameters 4 mm and 6 mm) and the sustained-release layer with no hole available in hypnotic embodiment 1.

(7) FIG. 6 indicates comparison of three leaching curves of the double-layer tablet having sustained-release layer with holes (diameters 4 mm and 6 mm) and the sustained-release layer with no hole available and only quick release layer in hypnotic embodiment 2.

(8) FIG. 7 indicates comparison of three leaching curves of the double-layer tablet having sustained-release layer with holes (diameters 4 mm and 6 mm) and the sustained-release layer with no hole available in hypnotic embodiment 3.

(9) FIG. 8 indicates comparison of two leaching curves of the double-layer tablet having sustained-release layer with holes (diameters 4 mm and 6 mm) and the sustained-release layer with no hole available in hypnotic embodiment 4.

(10) FIG. 9 is an in vitro release curve of the double-layer controlled-release tablet in analgesic embodiment 1.

(11) FIG. 10 is the in vitro release curve of the double-layer controlled-release tablet in analgesic embodiment 2.

(12) FIG. 11 is the leaching curve of the double-layer controlled-release tablet in analgesic embodiment 3.

(13) FIG. 12 is the leaching curve of the double-layer controlled-release tablet in analgesic embodiment 4.

IMPLEMENTATIONS

(14) The double-layer controlled-release tablet in analgesic embodiments 1-5 is composed of a quick release layer and a sustained-release layer. See Table 1 below for two layers of granules for tabletting the double-layer tablets:

(15) TABLE-US-00009 TABLE 1 Prescriptions of the double-layer controlled-release tablet in all embodiments (1000 tablets, g) Embodiment Embodiment Embodiment Embodiment Embodiment Component 1 2 3 4 5 Sustained-release granules Ibuprofen 250 250 300 200 Ketoprofen Naproxen 300 Hydroxypropyl 50 100 0 25 150 methylcellulose K1001v Hydroxypropyl 100 50 125 100 25 methylcellulose K4M Lactose monohydrate 95 95 65 70 120 Silicon dioxide 2.5 2.5 5 2.5 2.5 Magnesium stearate 2.5 2.5 5 2.5 2.5 Total of sustained-release part 500 500 500 500 500 Sustained-release granules Acetaminophen 150 Ibuprofen 150 Ketoprofen 75 Naproxen 100 150 Lactose 87.5 62.5 50 25 75 Microcrystalline cellulose 63.75 60 40 50 0 Polyvidone 8.75 0 0 0 10 Hydroxypropyl cellulose-HF 0 12.5 0 7.5 0 Croscarmellose sodium 10 10 7.5 15 12.5 Silicon dioxide 2.5 2.5 1.25 1.25 1.25 Magnesium stearate 2.5 2.5 1.25 1.25 1.25 Total of quick release part 250 250 250 250 250

(16) The coating can be applied to said double-layer tablet and the coating comprises following components:

(17) TABLE-US-00010 Hydroxypropyl methylcellulose E5 30 Polysorbate 80 14 Talcum powder 5 Titanium dioxide 2 80% alcohol/aqueous solution Appropriate

(18) The follows explains the preparation method of the double-layer controlled-release tablet of analgesic embodiments 1-5.

Analgesic Embodiment 1

(19) 1. Preparation of sustained-release granules: (1) Weigh ibuprofen sifted by a 60-mesh screen in accordance with the formula, hydroxypropyl methylcellulose K100LV, K4M and lactose, mix them uniformly; then add silicon dioxide and magnesium stearate which are of the dosages in the formula; and transfer the materials mixed to a wet type granulator. (2) Prepare the ethanol solution with concentration of 70% and prepare the soft material for the mixture in the first step. (3) Implement granulation for the soft material prepared by using a 24-mesh screen. (4) Dry and sifting the granules. (5) Acquiring the sustained-release granules for preparing the sustained-release layer.

(20) 2. Preparation of quick release granules: (1) Mix ketoprofen, lactose, microcrystalline cellulose, polyvidone in accordance with the formula and screen the mixture by using the 60-mesh screen; then add silicon dioxide and magnesium stearate, which are of the dosages in the formula; and mix them uniformly in a mixer. (2) Prepare the ethanol solution with concentration of 80% and prepare the soft material for the mixture in the first step (3) Implement granulation for the soft material prepared by using a 24-mesh screen. (4) Dry and sifting the granules. (5) Add croscarmellose sodium in accordance with the extra-addition method and mix croscarmellose sodium and dry granules uniformly. (6) Acquiring the quick release granules, which for forming the quick release layer and filling the holes of the sustained-release layer.

(21) 3. Preparation of double-layer controlled-release tablet: (1) Press the granules of the sustained-release layer, the silicon dioxide and magnesium stearate left into the sustained-release tablets with holes in the middle, wherein the diameters are 3 mm, 4 mm and 6 mm, respectively. Moreover, press the sustained-release tablets without hole. (2) Put the sustained-release tablets into a punching die of a tablet press and fill the granules of quick-release layer; implement the second compressing in the way of shallow concave punching to form the double-layer tablets. (3) Disperse hydroxypropyl methylcellulose E5 in accordance with the formula in the ethanol with concentration of 80%; add polysorbate 80 after swelling; stir the mixture until the materials are dissolved completely and add titanium dioxide and talcum powder; then stir them uniformly and filter the mixture as the coating liquid. (4) Implement coating for the double-layer tablets, increasing the weight of each tablet for 5%, then dry and solidify the tablets.

(22) The sustained-release layer should be pressed into the sustained-release tablets without hole, with holes having diameters 3 mm, with holes having diameters 4 mm and with holes having diameters 6 mm in this embodiment to implement the leaching test, in order to investigate effect of the hole diameter of the sustained-release layer for leaching, wherein the greater the hole diameter of the sustained-release layer is, the faster the leaching speed would be.

(23) The double-layer tablet prepared is applied to leaching test in order to investigate the sustained-release effect after quick release, wherein the quick release layer has been leached completely when sampling and detecting after 0.5 h, see FIG. 9 for the result. The zero-order release effect is shown in the sustained-release layer, that is, the medicine is approximately released at constant speed. Moreover, the in vitro release at constant speed is useful for keeping the stable plasma concentration of the patient; and it is worth mentioning that the greater the diameter of the hole of the sustained-release layer, the faster the release speed would be.

Analgesic Embodiment 2

(24) 1. Preparation of sustained-release granules: (1) Weigh ibuprofen sifted by a 60-mesh screen in accordance with the formula, hydroxypropyl methylcellulose K100LV, K4M and lactose, mix them uniformly; then add silicon dioxide and magnesium stearate which are of the dosages in the formula; and transfer the materials mixed to a wet type granulator. (2) Prepare the ethanol solution with concentration of 75% and prepare the soft material for the mixture in the first step. (3) Implement granulation for the soft material prepared by using a 24-mesh screen. (4) Dry and sifting the granules. (5) Acquiring the sustained-release granules for preparing the sustained-release layer.

(25) 2. Preparation of quick release granules: (1) Mix naproxen, lactose, microcrystalline cellulose and hydroxy propyl cellulose-HF and sodium carboxymethylcellulose in accordance with the formula, screen by using the 60-mesh screen; then add silicon dioxide and magnesium stearate which are of the dosages in the formula; and mix them uniformly in the mixer. (2) Prepare the ethanol solution with concentration of 90% and prepare the soft material for the mixture in the first step (3) Implement granulation for the soft material prepared by using a 24-mesh screen. (4) Dry and sifting the granules. (5) Acquiring the quick release granules, which for forming the quick release layer and filling the holes of the sustained-release layer.

(26) 3. Preparation of double-layer controlled-release tablet: (1) Press the granules of the sustained-release layer, the silicon dioxide and magnesium stearate left into the sustained-release tablets with holes in the middle, wherein the diameters are 4 mm and 6 mm, respectively. (2) Put the sustained-release tablets into a punching die of a tablet press and fill the granules of quick-release layer; implement the second compressing in the way of shallow concave punching to form the double-layer tablets. (3) Disperse hydroxypropyl methylcellulose E5 in accordance with the formula in the ethanol with concentration of 80%; add polysorbate 80 after swelling; stir the mixture until the materials are dissolved completely and add titanium dioxide and talcum powder; then stir them uniformly and filter the mixture as the coating liquid. (4) Implement coating for the double-layer tablets, increasing the weight of each tablet for 5%, then dry and solidify the tablets.

(27) Sampling and detection are implemented within 0.25 h in order to investigate the disintegrating speed of the quick release layer of the double-layer tablet and the sustained-release effect after quick release of the double-layer tablet, wherein the quick release layer is leached more than 85%; and see FIG. 10 for the result. The zero-order release effect is shown in the sustained-release layer, that is, the medicine is approximately released at constant speed. Moreover, the in vitro release at constant speed is useful for keeping the stable plasma concentration of the patient; and it is worth mentioning that the greater the diameter of the hole of the sustained-release layer, the faster the release speed would be.

Analgesic Embodiment 3

(28) 1. Preparation of sustained-release granules: (1) Weigh naproxen sifted by a 60-mesh screen in accordance with the formula, hydroxypropyl methylcellulose K100LV, K4M and lactose, mix them uniformly; then add silicon dioxide and magnesium stearate which are of the dosages in the formula; and transfer the materials mixed to a wet type granulator. (2) Prepare the ethanol solution with concentration of 80% and prepare the soft material for the mixture in the first step. (3) Implement granulation for the soft material prepared by using a 24-mesh screen. (4) Dry and sifting the granules. (5) Acquiring the sustained-release granules for preparing the sustained-release layer.

(29) 2. Preparation of quick release granules: (1) Mix naproxen, lactose, microcrystalline cellulose and hydroxyl propyl cellulose-HF in accordance with the formula and screen the sodium carboxymethylcellulose by using the 60-mesh screen; then add silicon dioxide and magnesium stearate which are of the dosages in the formula; and mix them uniformly in the mixer. (2) Prepare the ethanol solution with concentration of 90% and prepare the soft material for the mixture in the first step (3) Implement granulation for the soft material prepared by using a 24-mesh screen. (4) Dry and sifting the granules. (5) Acquiring the quick release granules, which for forming the quick release layer and filling the holes of the sustained-release layer.

(30) 3. Preparation of double-layer controlled-release tablet: (1) Press the granules of the sustained-release layer, the silicon dioxide and magnesium stearate left into the sustained-release tablets with holes in the middle, wherein the diameters are 4 mm and 6 mm, respectively. Moreover, press the sustained-release tablets without hole. (2) Put the sustained-release tablets into a punching die of a tablet press and fill the granules of quick-release layer; implement the second compressing in the way of shallow concave punching to form the double-layer tablets. (3) Disperse hydroxypropyl methylcellulose E5 in accordance with the formula in the ethanol with concentration of 80%; add polysorbate 80 after swelling; stir the mixture until the materials are dissolved completely and add titanium dioxide and talcum powder; then stir them uniformly and filter the mixture as the coating liquid. (4) Implement coating for the double-layer tablets, increasing the weight of each tablet for 5%, then dry and solidify the tablets.

(31) The leaching tests are implemented for the double-layer tablet prepared in order to investigate the sustained-release effect after quick release of the tablet. Seen from the leaching curve, the quick release effect and sustained-release effect are significant; and see the FIG. 11 for the result.

Analgesic Embodiment 4

(32) 1. Preparation of sustained-release granules: (1) Weigh ibuprofen sifted by a 60-mesh screen in accordance with the formula, hydroxypropyl methylcellulose K100LV, K4M and lactose, mix them uniformly; then add silicon dioxide and magnesium stearate which are of the dosages in the formula; and transfer the materials mixed to a wet type granulator. (2) Prepare the ethanol solution with concentration of 70% and prepare the soft material for the mixture in the first step. (3) Implement granulation for the soft material prepared by using a 24-mesh screen. (4) Dry and sifting the granules. (5) Acquiring the sustained-release granules for preparing the sustained-release layer.

(33) 2. Preparation of quick release granules: (1) Mix ibuprofen, lactose, microcrystalline cellulose and hydroxy propyl cellulose-HF in accordance with the formula and screen the sodium carboxymethylcellulose by using the 60-mesh screen; then add silicon dioxide and magnesium stearate which are of the dosages in the formula; and mix them uniformly in the mixer (2) Prepare the ethanol solution with concentration of 90% and prepare the soft material for the mixture in the first step (3) Implement granulation for the soft material prepared by using a 24-mesh screen. (4) Dry and sifting the granules. (5) Acquiring the quick release granules, which for forming the quick release layer and filling the holes of the sustained-release layer.

(34) 3. Preparation of double-layer controlled-release tablet: (1) Press the granules of the sustained-release layer, the silicon dioxide and magnesium stearate left into the sustained-release tablets with holes in the middle, wherein the diameters are 4 mm and 6 mm, respectively. Moreover, press the sustained-release tablets without hole. (2) Put the sustained-release tablets into a punching die of a tablet press and fill the granules of quick-release layer; implement the second compressing in the way of shallow concave punching to form the double-layer tablets. (3) Disperse hydroxypropyl methylcellulose E5 in accordance with the formula in the ethanol with concentration of 80%; add polysorbate 80 after swelling; stir the mixture until the materials are dissolved completely and add titanium dioxide and talcum powder; then stir them uniformly and filter the mixture as the coating liquid. (4) Implement coating for the double-layer tablets to increase the weight of each tablet for 5%, then dry and solidify the tablets.

(35) The single-layer quick release tablet and the double-layer tablets are prepared to implement the leaching tests in order to investigate the disintegrating speed of the quick release layer of the medicine and the effect of the hole diameter of the sustained-release layer to the sustained-release effect, wherein the quick release layer has been leached more than 90% when sampling and detecting after 0.5 h. Moreover, the linear effect of the in vitro leaching curve of the sustained-release layer having hole diameter of 4 mm is superior to the one of the in vitro leaching curve of the sustained-release layer having hole diameter of 6 mm in this embodiment; and see FIG. 12 for the result.

Analgesic Embodiment 5

(36) The preparation method is the same as that in the embodiment 3, but the ingredients used are different, seeing the Table 1

(37) The following shall explain the stability test of the analgesic double-layer tablet in the invention:

Test 1 Friability Test

(38) The inventor selected 100 double-layer tablets with the sustained-release layers without hole, 100 double-layer tablets with the sustained-release layers having holes with diameters of 3 mm, 4 mm or 6 mm respectively to implement the friability testing and comparison study by using the friability tester, wherein the raw materials, the pharmaceutical excipients and the proportion were implemented in accordance with the embodiment 1; and see Table 2 for the result.

(39) TABLE-US-00011 TABLE 2 Result of friability testing and comparison of double-layer tablet Quantity of tablets subjected to Type of the testing breaking in 100 tablets double-layer tablet Number Number Number Diameter of tablets of tablets of holes of hole broken laminated 0 20 11 1 6 mm 9 0 1 4 mm 1 0 1 3 mm 1 0

(40) It was proved from the result of said friability test that: 1) The occurrence rate of breaking of the double-layer tablets having holes in the invention was reduced greatly, and no lamination occurred. 2) The size of the diameter of the hole plays an active role in preventing lamination; but the degree of breaking of the double-layer tablet would be affected when the diameter of the hole is great.

Test 2 Effect of High Humidity to Stability of Medicine

(41) 20 double-layer tablets were selected from the embodiment 4 respectively, and were placed in the stability testing box to observe after 24 h, wherein the humidity was set at RH95%; and the temperature was set at 25 C. See Table 3 for the result.

(42) TABLE-US-00012 TABLE 3 Effect of high humidity to stability of medicine Type of testing Number of tablets Formula of double-layer tablet subjected to the double- Number Diameter lamination among layer tablet of holes of hole 100 tablets In accordance 0 17 with the 1 6 mm 0 embodiment 4 1 4 mm 0 1 3 mm 0

(43) The result indicated that the double-layer tablet of the invention still had nice stability and was not subjected to lamination under the condition that the ambient humidity was great, the swelling degree of the quick release layer was greater than that of the sustained-release layer and the double-layer tablet could not be separated easily although the quick release layer in the prescription included the super disintegrating agent, and the disintegrating agent had strong hygroscopicity.

Test 3 Effect of Number of Holes in Double-Layer Tablet to Stability

(44) The double-layer tablets with sustained-release layers having no hole and the double-layer tablets having sustained-release layers with one, two and three holes were pressed in accordance with the formula in embodiment 3 (the quick release layer included only the active ingredients and excipient, but did not include the binder); 20 tablets were selected respectively to implement the friability tests in the friability tester and carry out comparison study; and see Table 4 for the result.

(45) TABLE-US-00013 TABLE 4 Effect comparison of number of holes to stability Type of testing Number of tablets subjected double-layer tablet to lamination among 100 tablets Number of holes Number Number in the sustained- of tablets of tablets Formula release layer broken laminated In accordance 0 15 9 with the 1 6 0 embodiment 3 2 2 0 3 1 0

(46) It was proved by said friability test that: 1. The occurrence rate of breaking of the double-layer tablets having holes was reduced greatly, and no lamination occurred. 2. The number of the tablets broken would be reduced along increasing number of the holes.

(47) See Table 5 for the prescription of the double-layer controlled-release tablet in hypnotic embodiments 1-5.

(48) TABLE-US-00014 TABLE 5 Component Embodiment 1 Embodiment 2 Embodiment 3 Embodiment 4 Embodiment 5 Sustained-release granules Zolpidem tartrate 24 24 / / / Zopiclone / / 30 / 36/ Zaleplon / / / 30 Hydroxypropyl 30 60 105 0 90 methylcellulose K1001v Hydroxypropyl 60 30 0 105 15 methylcellulose K4M Lactose monohydrate 183 183 159 159 156 Silicon dioxide 1.5 1.5 3 3 1.5 Magnesium stearate 1.5 1.5 3 3 1.5 Total of sustained-release part 300 300 300 300 300 Quick release granules Zolpidem tartrate 8 8 / / / Zopiclone / / 5 / 10 Zaleplon / / / 5 / Lactose 57 55.5 60 60 55 Microcrystalline cellulose 25.5 25.5 31 25 25.5 Polyvidone 3.5 0 0 0 3.5 Hydroxypropylmethyl-cellose - 0 5 0 3 0 HF Croscarmellose sodium 4 4 2 6 5 Silicon dioxide 1 1 1 0.5 0.5 Magnesium stearate 1 1 1 0.5 0.5 Total of quick release part 100 100 100 100 100

(49) The formula of the coating of the double-layer controlled-release tablet in hypnotic embodiments 1-5 is the same as that in said hypnotic embodiment.

(50) The preparation method comprises steps of:

Hypnotic Embodiment 1

(51) 1. Preparation of sustained-release granules: {circle around (1)} Weigh zolpidem tartrate, hydroxypropylmethyl-cellose K100LV, K4M and lactose monohydrate sifted by the 60-mesh screen in accordance with the formula and mix them uniformly; then add silicon dioxide and magnesium stearate which are of the dosages in the formula; and transfer the materials mixed to the wet type granulator. {circle around (2)} Prepare the ethanol solution with concentration of 70% and prepare the soft material for the mixture in the first step. {circle around (3)} Implement granulation for the soft material prepared by using a 24-mesh screen. {circle around (4)} Dry and sifting the granules. {circle around (5)} Acquiring the sustained-release granules for preparing the sustained-release layer.

(52) 2. Preparation of quick release granules: {circle around (1)} Mix zolpidem tartrate, lactose, microcrystalline cellulose and polyvidone in accordance with the formula and screen the mixture by using the 60-mesh screen; then add silicon dioxide and magnesium stearate which are of the dosages in the formula; and mix them uniformly in the mixer. {circle around (2)} Prepare the ethanol solution with concentration of 80% and prepare the soft material for the mixture in the first step {circle around (3)} Implement granulation for the soft material prepared by using a 24-mesh screen. {circle around (4)} Dry and sifting the granules. {circle around (5)} Add croscarmellose sodium and dry granules in accordance with the extra-addition method and mix them uniformly. {circle around (6)} Acquiring the quick release granules which for forming the quick release layer and filling the holes of the sustained-release layer.

(53) 3. Preparation of double-layer controlled-release tablet: {circle around (1)} Press the granules of the sustained-release layer, the silicon dioxide and magnesium stearate left into the sustained-release tablets with holes in the middle, wherein the diameters are 3 mm, 4 mm and 6 mm, respectively. Moreover, press the sustained-release tablets without hole. {circle around (2)} Put the sustained-release tablets into a punching die of a tablet press and fill the granules of quick-release layer; implement the second compressing in the way of shallow concave punching to form the double-layer tablets. {circle around (3)} Disperse hydroxypropylmethyl-cellose E5 in accordance with the formula in the ethanol with concentration of 80%; add polysorbate 80 after swelling; stir the mixture until the materials are dissolved completely and add titanium dioxide and talcum powder; then stir them uniformly and filter the mixture as the coating liquid. {circle around (4)} Implement coating for the double-layer tablets to increase the weight of each tablet for 5%, then dry and solidify the tablets.

(54) The sustained-release layer should be pressed into the sustained-release tablets without hole, with holes having diameters 3 mm, with holes having diameters 4 mm and with holes having diameters 6 mm in this embodiment to implement the leaching test, in order to investigate effect of the hole diameter of the sustained-release layer to leaching, wherein the greater the hole diameter of the sustained-release layer is, the faster the leaching speed would be. Moreover, see FIG. 4 for the result.

(55) The double-layer tablet prepared is applied to leaching test in order to investigate the sustained-release effect after quick release, wherein the quick release layer has been leached completely when sampling and detecting after 0.5 h, see FIG. 5 for the result. See from the figure, the hole of the sustained-released layer can facilitate release at constant speed.

Hypnotic Embodiment 2

(56) 1. Preparation of sustained-release granules: {circle around (1)} Weigh zolpidem tartrate, hydroxypropylmethyl-cellose K100LV, K4M and lactose monohydrate sifted by the 60-mesh screen in accordance with the formula and mix them uniformly; then add silicon dioxide and magnesium stearate which are of the dosages in the formula; and transfer the materials mixed to the wet type granulator. {circle around (2)} Prepare the ethanol solution with concentration of 75% and prepare the soft material for the mixture in the first step {circle around (3)} Implement granulation for the soft material prepared by using a 24-mesh screen. {circle around (4)} Dry and sifting the granules. {circle around (5)} Acquiring the sustained-release granules for preparing the sustained-release layer.

(57) 2. Preparation of quick release granules: {circle around (1)} Mix zolpidem tartrate, lactose, microcrystalline cellulose and hydroxy propyl cellulose-HF in accordance with the formula and screen the sodium carboxymethylcellulose by using the 60-mesh screen; then add silicon dioxide and magnesium stearate which are of the dosages in the formula; and mix them uniformly in the mixer. {circle around (2)} Prepare the ethanol solution with concentration of 90% and prepare the soft material for the mixture in the first step {circle around (3)} Implement granulation for the soft material prepared by using a 24-mesh screen. {circle around (4)} Dry and sifting the granules. {circle around (5)} Acquiring the quick release granules which for forming the quick release layer and filling the holes of the sustained-release layer.

(58) 3. Preparation of double-layer controlled-release tablet: {circle around (1)} Press the granules of the sustained-release layer, the silicon dioxide and magnesium stearate left into the sustained-release tablets with holes in the middle, wherein the diameters are 4 mm and 6 mm, respectively. Moreover, press the sustained-release tablets without hole. {circle around (2)} Put the sustained-release tablets into a punching die of a tablet press and fill the granules of quick-release layer; implement the second compressing in the way of shallow concave punching to form the double-layer tablets. {circle around (3)} Disperse hydroxypropylmethyl-cellose E5 in accordance with the formula in the ethanol with concentration of 80%; add polysorbate 80 after swelling; stir the mixture until the materials are dissolved completely and add titanium dioxide and talcum powder; then stir them uniformly and filter the mixture as the coating liquid. {circle around (4)} Implement coating for the double-layer tablets to increase the weight of each tablet for 5%, then dry and solidify the tablets.

(59) The single-layer quick release tablet and the double-layer tablets are prepared to implement the leaching tests in order to investigate the disintegrating speed of the quick release layer of the medicine and the sustained-release effect after quick release of the double-layer tablet, wherein the quick release layer has been leached more than 90% when sampling and detecting after 0.25 h. Moreover, see FIG. 6 for the result.

Hypnotic Embodiment 3

(60) 1. Preparation of sustained-release granules: {circle around (1)} Weigh zopiclone, hydroxypropyl methylcellulose K100LV, K4M and lactose sifted by the 60-mesh screen in accordance with the formula and mix them uniformly; then add silicon dioxide and magnesium stearate which are of the dosages in the formula; and transfer the materials mixed to the wet type granulator. {circle around (2)} Prepare the ethanol solution with concentration of 80% and prepare the soft material for the mixture in the first step {circle around (3)} Implement granulation for the soft material prepared by using a 24-mesh screen. {circle around (4)} Dry and sifting the granules. {circle around (5)} (5) Acquiring the sustained-release granules for preparing the sustained-release layer.

(61) 2. Preparation of quick release granules: {circle around (1)} Mix zopiclone, lactose, microcrystalline cellulose and hydroxy propyl cellulose-HF in accordance with the formula and screen the sodium carboxymethylcellulose by using the 60-mesh screen; then add silicon dioxide and magnesium stearate which are of the dosages in the formula; and mix them uniformly in the mixer. {circle around (2)} Prepare the ethanol solution with concentration of 90% and prepare the soft material for the mixture in the first step {circle around (3)} Implement granulation for the soft material prepared by using a 24-mesh screen. {circle around (4)} Dry and sifting the granules. {circle around (5)} Form the quick release layer and fill the holes of the sustained-release layer after acquiring the

(62) 3. Preparation of double-layer controlled-release tablet: {circle around (1)} Press the granules of the sustained-release layer, the silicon dioxide and magnesium stearate left into the sustained-release tablets with holes in the middle, wherein the diameters are 4 mm and 6 mm, respectively. Moreover, press the sustained-release tablets without hole. {circle around (2)} Put the sustained-release tablets into a punching die of a tablet press and fill the granules of quick-release layer; implement the second compressing in the way of shallow concave punching to form the double-layer tablets. {circle around (3)} Disperse hydroxypropyl methylcellulose E5 in accordance with the formula in the ethanol with concentration of 80%; add polysorbate 80 after swelling; stir the mixture until the materials are dissolved completely and add titanium dioxide and talcum powder; then stir them uniformly and filter the mixture as the coating liquid. {circle around (4)} Implement coating for the double-layer tablets to increase the weight of each tablet for 5%, then dry and solidify the tablets.

(63) The double-layer tablets prepared are applied to leaching test in order to investigate the sustained-release effect after quick release of the tablet; the quick release layer has been leached completely when sampling and detecting after 0.5 h. Moreover, see FIG. 7 for the result.

Hypnotic Embodiment 4

(64) 1. Preparation of sustained-release granules: {circle around (1)} Weigh zaleplon, hydroxypropyl methylcellulose K100LV, K4M and lactose sifted by the 60-mesh screen in accordance with the formula and mix them uniformly; then add silicon dioxide and magnesium stearate which are of the dosages in the formula; and transfer the materials mixed to the wet type granulator. {circle around (2)} Prepare the ethanol solution with concentration of 80% and prepare the soft material for the mixture in the first step {circle around (3)} Implement granulation for the soft material prepared by using a 24-mesh screen. {circle around (4)} Dry and sifting the granules. {circle around (5)} (5) Acquiring the sustained-release granules for preparing the sustained-release layer.

(65) 2. Preparation of quick release granules: {circle around (1)} Mix zaleplon, lactose, microcrystalline cellulose and hydroxy propyl cellulose-HF in accordance with the formula and screen the sodium carboxymethylcellulose by using the 60-mesh screen; then add silicon dioxide and magnesium stearate which are of the dosages in the formula; and mix them uniformly in the mixer. {circle around (2)} Prepare the ethanol solution with concentration of 90% and prepare the soft material for the mixture in the first step {circle around (3)} Implement granulation for the soft material prepared by using a 24-mesh screen. {circle around (4)} Dry and sifting the granules. {circle around (5)} Form the quick release layer and fill the holes of the sustained-release layer after acquiring the

(66) 3. Preparation of double-layer controlled-release tablet: {circle around (1)} Press the granules of the sustained-release layer, the silicon dioxide and magnesium stearate left into the sustained-release tablets with holes in the middle, wherein the diameters are 4 mm and 6 mm, respectively. Moreover, press the sustained-release tablets without hole. {circle around (2)} Put the sustained-release tablets into a punching die of a tablet press and fill the granules of quick-release layer; implement the second compressing in the way of shallow concave punching to form the double-layer tablets. {circle around (3)} Disperse hydroxypropyl methylcellulose E5 in accordance with the formula in the ethanol with concentration of 80%; add polysorbate 80 after swelling; stir the mixture until the materials are dissolved completely and add titanium dioxide and talcum powder; then stir them uniformly and filter the mixture as the coating liquid. {circle around (4)} Implement coating for the double-layer tablets to increase the weight of each tablet for 5%, then dry and solidify the tablets.

(67) The single-layer quick release tablet and the double-layer tablets are prepared to implement the leaching tests in order to investigate the disintegrating speed of the quick release layer of the medicine and the sustained-release effect after quick release of the double-layer tablet, wherein the quick release layer has been leached more than 90% when sampling and detecting after 0.25 h. Moreover, see FIG. 8 for the result.

Hypnotic Embodiment 5

(68) The preparation method is the same as that in the embodiment 3, but the ingredients to be used are different, seeing the Table 1

Friability Test and Stability Test of Hypnotic Tablet

(69) 100 double-layer tablets having sustained-release layer without hole and 100 double-layer tablets having sustained-release layer with holes of different diameters are prepared respectively in accordance with the formula and the method in the embodiment 1 in order to implement friability testing and comparison study in the friability tester respectively; and see Table 6 for the result.

(70) TABLE-US-00015 TABLE 6 Testing object Drilling condition Number Number of sustained- of tablets of tablets release layer broken laminated Double-layer tablet Without hole 12 8 in accordance with Hole with diameter 4 0 the formula in of 6 mm embodiment 1 Hole with diameter 1 0 of 4 mm Hole with diameter 1 0 of 3 mm

(71) The result indicates that: 1. The double-layer tablets with sustained-release layer having holes are not subjected to lamination. 2. The tablets having small diameters would less likely to be broken.

(72) 20 double-layer tablets with sustained-release layer having no hole and 20 double-layer tablets with sustained-release layers having holes of different diameters were prepared in accordance with the formula and method in the embodiment 4 respectively, and were placed in the stability testing box, wherein the humidity was set at RH95%; and the temperature was set at 25 C.

(73) Observe the double-layer tablets after 24 h, and see Table 7 for the result.

(74) TABLE-US-00016 TABLE 7 Testing object Number Drilling condition of of tablets sustained-release layer laminated Double-layer tablets Without hole 17 in accordance with Hole with diameter of 6 mm 0 the formula in Hole with diameter of 4 mm 0 embodiment 4 Hole with diameter of 3 mm 0

(75) The quick release layer of the formula includes the super disintegrating agent having strong hygroscopicity; the degree of swelling of the quick release layer is greater than that of the sustained-release layer, and upper layer and the lower layer of the double-layer tablet without hole may be separated from each other when the ambient humidity is great. The quick release granules in the hole may swell after absorbing the moisture when the sustained-release layer has the hole, and the quick release layer may be combined with the sustained-release layer more tightly. Therefore, the double-layer tablet having hole is not subjected to separation during the test.

(76) The result indicated that the double-layer tablet of the invention could keep the stability in the high-temperature and high-humidity environment.

(77) 20 double-layer tablets with sustained-release layer having no hole and 20 double-layer tablets with sustained-release layers having different number of holes were prepared in accordance with the formula and method in the embodiment 3 respectively, and were placed in the friability tester to carry out the friability testing and comparison study, wherein the quick release layer included only the active ingredients and the excipient, but did not include the binder. Moreover, see Table 8 for the result.

(78) TABLE-US-00017 TABLE 8 Testing object Drilling condition Number Number of sustained- of tablets of tablets release layer broken laminated Double-layer tablets 0 15 9 in accordance with 1 6 0 the formula in 2 2 0 embodiment 3 3 1 0

(79) The result indicates that: 1 The double-layer tablets with sustained-release layer having holes are not subjected to lamination. 2. The double-layer tablets having more holes would less likely to be broken.

(80) Seen from the above-mentioned result, the double-layer tablet prepared in the invention has the physical stability superior to the common double-layer tablet, and is more useful for storage and transportation; further, the medicine in the double-layer tablet can be released approximately at constant speed.