SA98190484B1 - Pharmaceutical formulations for controlled release of active substances - Google Patents

Abstract

The present invention relates to oral drug formulations that allow controlled release of at least one active substance. The composition includes at least one active substance, between 5 and 60% by weight, in relation to the total weight of the concentrate, of at least one excipient selected from inert intermediates, water-absorbent intermediates, lipid interfaces, mixtures of inert intermediates and lipid interfaces , mixtures of water-absorbent interlayers and inert interlayers, except for mixtures comprising polyacrylic acid and at least one hydrophilic interlayer of the cellulose type; and between 5 and 50% by weight, for the total weight of the composition, of at least one aqueous-soluble alkaline agent under physiological pH conditions, selected from alkali or alkaline earth or alkali metal hydroxides, bicarbonates, carbonates, sodium borate and bases membership. The invention further includes a process for preparing the composition, multi-layered drug formulations incorporating at least one layer of the invented composition, and processes for producing such formulations.

Description

L Drug formulations for the controlled release of active substances Full Description BACKGROUND THE INVENTION The present invention relates to drug formulations that can be administered orally that allow the controlled release of active substances (Li ga) and methods for preparing these formulations. Oral administration is 0 Controlled release of pharmacologically active substances so that they can be administered in daily doses ALE Ideally in a single daily dose The release of active substances during oral administration can be controlled by interlayer type drug formulations Depending on the excipient It is possible to specify? Types of interlayers which are interlayers (Alla) hydrophobic and lipophilic. Mixed interstitials can also be generated by the combination of 0 justifying materials for these different types of matrix Matrix Inert interlayers include materials Excipient mainly belongs to the class of thermoplastic polymers. It is inert to biological tissues; other excipients in the formulation and the active substance. It is insoluble and indigestible in the fluids of the gastrointestinal tract. Among these substances may be mentioned “polyethylene “polyvinyl” chloride “polyamides” polymethylmethacrylates “vinyl acetate/vinyl chloride copolymers ve polystyrene “ethyl cellulose” silicones etc. It generally uses a concentration ranging from 010 to 0. Water-absorbing interfacial materials include gelatinizing agents that can be divided into ? Classes: derivates <hydroxyethylcellulose chydroxypropyl methylcellulose ( cellulose noncellulose polysaccharides ((7- “methylcellulose <hydroxypropyl cellulose 00” “galactomannans) gum (guar carob gum”); gum arabic “agar” sterculia ga—a “alginates etc.) 974P 5 carbopols 934P) acrylic acid polymers s etc.). It is generally used at a concentration of 010 to Ver. Interfacial materials include € types of fatty excipients: glycerides «<palmitin «stearin' mono-, di- or triglycerides] 0 emyristin emyristin castor oils v-seed or palmitic esteric (etc.) fatty acids, alcohols (precirol <hydrogenated cotton) fatty acid esters (cetostearyl alcohols or cetyl stearyl ¢lauric acids etc.) and waxes sucrose distearate (sucrose and propylene glycol from monostearates) .75 6 to 01 white wax”; amber wax etc.). It is generally used when a concentration of (

° The presence of excipients of the type-interstitial substance in the pharmaceutical formulations makes it possible; in a number of cases; slowing the release of the active substances in the stomach; However, these justified intermediate-type substances do not always make it possible to sufficiently slow the release of an active substance or obtain the optimal release patterns required.

For example; Laie Interstitial-type drug formulations contain ale that must be released 0 compulsorily into the stomach; The release of the active substance over sufficiently long periods of time depends not only on the type of excipient used in the formulation; But also on the time the drug combination stays in the stomach. accordingly; Several documents mention the use of floating inter-sale opportunities. particulary. EC Patent 7,065,777 describes drug formulations for the controlled release of active substances. Jedi is a mixed substrate derived from a mixture of cellulose ethers, polyacrylic acids eo, and one of its pharmaceutically acceptable derivatives or salts comprising; add to that; From 1: to 750 by weight in relation to the total weight of the excipients. Substance dain of an effervescent foaming agent. The effervescent foaming agent makes it possible to cause the drug composition to float in the gastric fluid; This increases the residence time in the stomach. The effervescent foaming agent is bicarbonate, an alkaline or alkaline earth metal preferably used in combination with an organic acid. However, the flotation of the gastric fluid in the gastric fluid does not permit the resolution of other problems noted in the context of controlling the release of active substances from drug formulations and the interstitial substance. In reality; The amounts of interstitial excipients necessary for ALS' long-term release of the active ingredient can prove to be very large and could make production of the dosage form Jaa ve impossible or costly furthermore; The release of some active substances is highly pH dependent. Z For example JB some of the active substances are not released at all in the stomach; But in other areas

¢ From the gastrointestinal tract. Addition of (lI) to the same area of the gastrointestinal tract the release pattern will differ depending on whether the formulation is administered with a meal or not. For active substances whose release depends on the pH, it is therefore desirable to find new matrix formulations that make It is possible to regulate the release rate so that the active substance© can be released at the same rate regardless of the pH of the medium Finally it is very common for the release pattern of an active ingredient from an intermediate form to be erratic over time i.e. the release kinetics are not zero but A function of the square root of time Zero kinetics of release corresponds to a uniform and constant release over time which is much needed in order to assure a regular and long lasting therapeutic effect. Oral simultaneous administration of an active substance released immediately after administration The same substance or a secondary active substance is released gradually and regularly after administration In Alla simultaneous administration of the same active substance z for instantaneous release and for prolonged release (cael) this makes It is possible to release, Ae yu, a sufficient dose of an active substance to elicit the desired effect and to maintain this effect by gradual 1 and prolonged release of the same active substance. If an active substance is released immediately and another active sale is released gradually, this makes it possible to obtain combined therapeutic effects by ¥ of active substances that have very different pharmacokinetic patterns. in this context;. alls World Patent 94/09761 describes WO slow-release oral formulation comprising: Y.0) Interstitial core comprising: pseudoephedrine sulfate hydroxypropylmethylcellulose ethylcellulose calcium phosphate dibasic povidone Yo silicon dioxide “magnesium stearate” and o on the core Interstitial material includes: cde (oy) loratadine hydroxypropylmethylcellulose polyethylene glycol 400 polyethylene glycol 3350 ° Slow release formulation for oral administration EP-A-0396404 prescribe application The European patent includes: (a) The core of the interstitial material includes:

Ibuprofen pseudoephedrine 1 hydroxypropylmethylcellulose Swellable water absorbent as 85 dibasic Lubricant as calcium phosphate Excipients as and magnesium stearate (b) Coating on the core includes: Other excipients. cell absorbent polymer <Loratadine vo In this context; Solid oral drug formulations have been described in combination; In one unit; a section showing instantaneous firing and a section showing delayed firing. However, these formulations require technically very complex preparation methods and/or do not allow obtaining the required release patterns for all the active substances. pharmacologically active such that a sufficient therapeutic effect is observed over appropriately long time periods of gal in controlled release, eg only in one dose or even two doses per day. In particular, formulations conforming to the present invention do not require excessive amounts In addition, we have now also discovered that these controlled-release formulations can be used in combination with an immediate-release formulation. For the same substance or for another active substance; Yo in one unit intended for oral administration

1 General Description of the Invention The present invention relates to pharmaceutical formulations that can be administered orally. allow the controlled release of at least one active substance comprising: (a) at least one such active substance;

0 - (b) between 0 and 7210 by weight for the total weight of the formulation; at least one explanatory material; selected from inert metamaterials; water absorbent interlayers; Grease Interlayers Mixtures of inert interlayers and inert interlayers Grease mixtures of water-absorbent interlayers and fatty interlayers Mixtures of water-absorbent interlayers and inert interlayers; except mixtures including polyacrylic acid and at least one waterproof dala interlayer of type 661101086;

6 > (c) between * and 17 of the weight; For the total weight of the formulation; One alkaline agent on JE is soluble in an aqueous state under physiological pH conditions; It is selected from chydroxides, bicarbonates, and phosphates > 18 alkaline and c-alkali earths; sodium borate, in addition to the basic salts of organic acids.

BRIEF EXPLANATION OF DRAWINGS VO The present invention is particularly illustrated by Figures 1 through *: Figure 1: Bioavailability patterns of pseudoephedrine produced with bilayer tablets cetirizine (instant release)/pseudoephedrine ( controlled release); Figure ?: In vitro release kinetics of ctrapidil inter-sale tablets without alkalizing agent; 7 Figure*: In vitro release kinetics of 08010:1; interstitial tablets with alkaline agent; Figure: In vitro release kinetics of ¢hydrocodones interstitial tablets with and without alkalizing agent; Figure #: Trapidil bioavailability patterns obtained with inter-coated tablets. vo Detailed description of the invention Pharmaceutical formulations conforming to the present invention include excipients an interstitial selected from inert interlinings; Water absorbent and lipophilic.

Examples of inert interfaces that can be used according to the present invention are: “vinyl acetate/vinyl chloride copolymers” “polyethylene” “polyvinyl chloride” “polystyrene” ethyl cellulose “silicones” polyamides “polymethylmethacrylates” etc. ° Examples of water-absorbing interlayers that can be used according to the present invention are: <hydroxyethyl cellulose chydroxypropyl methylcellulose ) cellulose Noncellulose polysaccharides «(7- - methylcellulose hydroxypropyl cellulose cgalactomannans) Gum (guar carob gum) Arabic gum Gum “agar” sterculia 8 p etc.) 974P 5 carbopols 934P) acrylic acid polymers s etc.). The preferred water absorbent interfacial 0 for use according to the present invention is J— hydroxypropyl celluloses K METHOCEL or 8. The content of the excipients of the type hydroxypropyl methylcellulose in the compositions conforming to the present invention is preferably between © and 7710 in terms of total weight for combination. Examples of interfacial materials that can be used according to the present invention are: glycerides (¢mono-, di- or triglycerides) palmitin labeled emyristin hydrogenated castor or cottonseed oils etc) “stearic acid” “cetosteary alcohols sf cetyl alcohol “ stearyl alcohol ¢lauric acid “palmitic acid etc) monostearates) fatty acid esters from propylene glycol and from “sucrose” csucrose distearate, etc.) and wax materials (pad white amber wax, etc.). Y. The excipient may also be an interstitial substance in the form of a mixture. However, the pharmaceutical formulations of the invention do not include mixtures comprising cpolyacrylic acid and at least one hydrophobic interlayer of the type cellulose. Physiological pH so that it produces the desired effect. The alkaline vo factor can be chosen from bicarbonates “carbonates <hydroxides” and 0108018168 alkaline or alkaline earth metals sodium borate in addition to basic salts of organic acids (for example, sodium citrate). On the other hand, salts that are insoluble in water under conditions physiological pH;

A

The lida of the invention is dibasic; The calcium phosphate of magnesium stearate Jie present is not suitable. The amount of alkaline agent present in pharmaceutical formulations conforming to the present invention is optimal from weight to weight of the total formulation. 780 © to For active substances that can present in compositions identical to the present invention; ° There can be a wide variety of types. Anti-allergic; Painkillers; dy sell can be selected from vasoconstrictors, antitussives, etc. In particular, the applicant has noted that the invention is particularly suitable for active substances whose free base is less soluble in water than their pharmaceutically acceptable salts. Examples of non-specific “phenylephrine” ephedrine “pseudoephedrine” for these active substances are 0 < hydroxyzine cefletirizine “cetirizine hydrocodone to phenylpropanolamine

Ly all its isomers cmorphine “codeine” pentoxyverine “buclizine” meclozine or its pharmaceutically acceptable salts. Very large limits depending on the active substance mentioned. Yo In addition to the above ingredients; Pharmaceutical formulations conforming to the present invention may, etc.); hydrolyzed materials (cavicel starch materials (talc binders) etc.); calginic lubricants; modified cellulose derivatives; colloidal “o-cyclodextrin” derivatives etc.); Taste masking agents silica ¢magnesium stearate 0 Flavorings or coloring agents o(alkylated and alkylated derivatives y-cyclodextrin “B-cyclodextrin” methacrylic (example: © and 11010e derivatives; alas resins as well as agents etc. “nylons” polyvinyl chloride The pharmaceutical formulations conforming to the present invention are generally available in solid form. ) Galenos. Pharmaceutical formulations identical to the invention are available as small granules. etc; These forms are encapsulated or otherwise

Controlled-release drug compositions conforming to the present invention may be prepared by several conventional methods known to persons skilled in the art. As dale the pharmaceutical compositions of the present invention are prepared by a process comprising the following successive steps: -1 ° preparation of a homogeneous mixture containing components of (b); and (c) other excipients that are optional; “- Manufacture tablets from the homogeneous mixture obtained in Step 1; optionally after granulation. Tablets can be formed into many types, ideally with direct tableting. Optional granulation can be done in step? either wet or dry; Alternatively, 0 granulation-molten. According to a particular application of the invention; The controlled-release drug formulations identical to the invention are used in combination with one or more drug formulations that allow a momentary release of the active substances. When these two types of fixtures are present in the same unit; This Jang is possible (sand) in giving candy on both the immediate release of a primary active substance and the long-term release of the same substance or sold ve a secondary active substance. According to cl the present invention “Lind relates to drug formulations that can be administered orally” comprising: (0) at least one layer comprising Bale active and excipients allowing instantaneous release of said active substance after administration; and (b) at least a second layer permitting the release of said active substance after administration; controlled for the same substance or a second active substance; 7 includes the same said substance or a second said active substance; » at least one excipient of an intermediate type and at least one alkaline agent. For class 0 » excipients that allow a momentary release of the active substance can selection of diluents (x lactose cemcompress) binders (cavicel starch 001707100011006 etc.); hydrolyzed materials (starch materials modified starch; derivatives “cellulose [Yo] cpectins alginic cracks” mola (dale) Ale silica colloidal “magnesium stearate etc.); flavor masking agents (a-cyclodextrin).

Ye flavorings or substances o(alkylated) and alkyl derivatives ¢y-cyclodextrin “B-cyclodextrin colouring. These combined medicinal formulations can be prepared according to various methods known to those skilled in the art. These combined medicinal formulations can be provided In the form of a tablet in which at least one “AST” layer is attached to at least one “B” layer. In this case, these () medicinal compositions can be prepared by a process that includes the following successive steps: Preparation of homogeneous mixtures Separate from the components of layers (A) and (B); and (1) in a multi-tablet machine (1) form tablets from the resulting homogeneous mixtures in (Y) layer. May be preceded by a granulation step for homogeneous mixtures It is possible to prepare this type of dead disc (1) optional, then the step of forming tablets Ve (1) is possible in step Manufacture of multilayer tablets such as “Killian Fette” etc. The multilayer tablets are particularly suitable for cases of combinations of active substances from which newly produced vo “pseudoephedrine/cetirizine” for example Jaw on daa especially sade Therapeutic effects Long-acting hydrocodone immediate-release/hydrocodone <hydrocodone/acetaminophen immediate-release. Adal Specifies. In examples (dla A) the following examples show the present invention without; on by weight relative to the total weight of the formulations. (c) containing doses of controlled-release pseudoephedrine tablets prepared sequentially; Compositions presented in dled mg tablets are manufactured directly from homogeneous mixtures 0 1. Table ve Tablets (a) contain 7136 of an interlayer excipient and 714,765 of an alkalinity agent. N.01 mg and hardness 180007; has an average weight

11

Tov and 740 do not contain discs B and C; As for its two parts containing an alkalinity factor and containing 01.7 mg of an interstitial substance, respectively. It has an average weight of 767 mg N and 71 N. 118 and its special hardness grades are coal 1 tablet composition table (a); (b) and (c) mg/tablet © 0 Ingredients YY. 1 YY Pseudoephedrine. HC1 - 10 fo Methocel K15M CR

You - - Methocel K100M CR - = 6 (se No «Na,CO;s

Ve 00.0 Ola Avicel pH 102 7 L 1 Aerosil 200 ¢ 7 Y.A Magnesium stearate These three tablet types can be identified in oe pseudoephedrine The kinetics of release ° - American pharmacopoeia (77th edition of No. 1 USP 23 Lab Assisted Melt Apparatus

Onn The tablets are placed in the basket which undergoes fifty revolutions per minute. The melting medium consists of an hour – a sample is taken from the melting medium for 11 hours; For JS A AOTY milliliters of distilled water kept at .7 by 1101.0. The results of these tests are presented in table pseudoephedrine and table 1 tests Ve pseudoephedrine for release 7 () (=) () time (hours) 61 1.7 1 ach 1 1.4 74 5/7.06 ¥ which is 7.6 4.46 Y

YY. ¥AY. EY ¢

AY. oY a..¢¢ Yo.40 1

Ao YY 7.61 no no but F 217 v4.1 A ava 1.71 AY.AY 1 7.4.2.5 m YY The results of Table ¥ show that the release patterns are quite similar in 7 cases; Slower release is observed for discs (A). This shows that very good release control can be obtained with less interstitial excipient when an alkaline agent is present in the formulation.

b will also subject disks (a); (b) and (c) for a human bioavailability test over the YY period | hour. in this test; Comparison of bioavailability patterns obtained with tablets “(f) (b) and (c) is made with the bioavailability pattern obtained by administering instant-release gelatin capsules to pseudoephedrine containing doses of 01 mg; Given after an interval of 1 hour. ° This crossover study is conducted in A healthy subjects (men 0 to 18 years of age) –; each one gives; Forms with a "removal" period of 7 days between administrations. Blood samples are taken from individuals over the course of YY hours according to the following programs: Interstitial discs: Sunfit (1.0 TcKT LHN) every three YY hours; Ve igelatin capsules Sun Dip Fit Qasal cf (FY Fact Late GLA cA agent PY YE 1 ay hour. Estimation of pseudoephedrine levels by a validated HPLC method (UV determination) The results of this bioavailability study are presented in Figure 1 and in Table oF in which AUC represents the area under the curve; Yds Bioavailability pseudoephedrine in humans Gelatin capsules Tablets (1 VY mg) (eee xY) | )( (2) (@)

FIAY (μg.hr/mL) 4 977 µg AUC »m (µg/mL) Yao 17 Yay µm °£.0 (hr) m Tmax Results from this bioavailability study show regular release patterns Significantly more with drug combinations including interstitial excipients containing doses of anal Yo than with two administrations of immediate-release tablets containing doses of 10 mg. 7 moreover; The active substance is released in a similar manner for tablets (a)» (b) and (c). This example illustrates the fact that; To obtain sufficient long-term release of the active substance, a much smaller amount of the excipient (717 instead of 7400 or 0 75) is sufficient when this excipient is combined with an alkaline agent.

VY

1 example als - the effect of aaa) Yo controlled release containing doses of pseudoephedrine prepared tablets prepared with sodium carbonate 117 and / a Methocel K1SM CR 715.4 and containing direct tablets of a homogeneous mixture having the composition presented in a table; (Tablets D). Table 0; Tablets D 00 Pseudoephedrine. HC1 M Methocel K15M CR $a anhydrous «(Na,CO;

AY.o Avicel pH 102 m Aerosil 200

Y.A Magnesium stearate Tablets (3) have an average weight of 797.5 mg. Part of these tablets are coated with “xanthan gaa decithin (polyvinyl alcohol) Opadry | OY-B-28920 from pseudoephedrine tablets. Release kinetics determined in the laboratory. Dioxide 0 (talc cm) The results are presented in Table 1. CKD coated or uncoated in the same way as in example 00 © pseudoephedrine table 7 Release time (hours) uncoated coated

Yo. B1 8.1 £v.0 Y 8.6 87.4 v 87 8. ¢

YY. 7.4 ° to Hekla Yv.\ 1

ALY AY Y

AYA AY. ¢ A The results presented in Table © show that encapsulation does not affect the release kinetics of the active substance

1 Example? Effect of different alkalizing agents 081 mg controlled release containing doses of pseudoephedrine Tablets prepared (they) sodium bicarbonate 10 s Methocel KISM CR ZY: and contain (g) Manufacture direct tablets potassium hydrogen phosphate (and) or sodium bicarbonate 0

A of homogeneous mixtures having the compositions presented in Table 1 Table | Tablets E, F and G Components E and G

VA YA YA Pseudoephedrine. HC1

Ya Ya. Ya. Methocel K15M CR - - YA Anhydrous Na,COs - M - NaHCO;

Ya. - - K,HPO4 511 0) 51 Avicel pH 102 7 7 7 Aerosil 200 1 1 1 Magnesium stearate for tablets (e); (5) and (g) resulting pseudoephedrine The release kinetics in the laboratory rpm are in table 001 with the baskets rotated at 1 in the same way as in example for 1

Yd pseudoephedrine to release 7

Geo

YA.4Q 8.7 1/1 1 . |. 71 Y 2.7 ov.Y YA.Q yen ya.a 7.0 lb 7.7 7.4 va.) ° for both AY. 5.1 4 .ATA £4.% No The results of Table 7 show that prolonged release is produced with the three alkaline agents used; Sodium carbonate The effect is more intense with yo ¢ eg pseudoephedrine/alkalininzing A bilayer controlled-release pseudoephedrine 071 mg Bilayer tablets containing release doses are prepared in the following way (tablets (h)). Jas] cetirizine in its release © mg

A from the compositions in Table (Has Ha) from separate homogeneous mixtures GUS 8 and Table 9 are prepared in a multi-layer tablet manufacturing machine to give Hp Ha. Bi-layer tablets are made in the mixture tablets. The layers are stuck together. These tablets are then coated with titanium dioxide “xanthan gum, lecithin “polyvinyl alcohol) Opadry OY-B-28920 (tale. extended-release layer contains 7171.1 excipients interlayer cal SY) in this. sodium carbonate 715.7 and Table A Hy mixture of ° Cetirizine. 2HC1 A Tablettose 7.5 Avicel pH 102 ..Yo Aerosil 200 Magnesium stearate Table 1:

Hp 10 Pseudoephedrine Mixture. HC1 ¢o Methocel K15M CR 4 Anhydrous «Na,CO3 6 Aerosil 200

Y.A Magnesium stearate For tablets cetirizine 3 Pseudoephedrine In vitro release kinetics for drug Vo at 001 rpm in advance with baskets rotating at 1 (h); Resulting in the same way as in example .01 in the table

Table 01 7 Release cetirizine s pseudoephedrine Time (hours) Cetirizine pseudoephedrine : 107 +.Yo Done AY.Y 56 +0 Aw YY. “Yo 1 AK AT. A OA.0 av./ AY.Y ¢ .79 av.oe 7.4 | YeV.$ A 4.0 0101 01 Ye (Yo) A 01 A 1" Example *: Effect of pH Controlled release trapidil tablets (I) and (E) containing Yoo 0 mg doses are prepared by direct tablet manufacturing from homogeneous mixtures having the compositions presented in Table AY Tablets (I) and (Z) contain 777.7 excipients as an interstitial substance; Tablets (I) do not contain an alkali factor and tablets (Z) contain 7717.8 of an alkali factor. Table 11 Compositions of tablets (I) and ( j) mg/tablet Ingredients (i) (j) Veo AI Trapidil Yoo Yoo Methocel K15M CR “(Na,COs3) Anhydrous — vo Avicel pH 102 91 11 Aerosil 200 7 3 Magnesium stearate 1 1 The average weights and degrees of hardness of the disks (i) and (j) are 1005.7 mg yyo 5 newton yo (i nor ,9e mg and Ya nyuthan (j) 3 respectively. The kinetics In vitro release to trapidil was determined according to the method described in Example 1 using two solubility media: a standard oN solution of hydrochloric acid and a phosphate buffer solution at pH .7.

VY

Plus OY rpm. The results of this study are presented in Table 100 of the rotational speed of the baskets

XX to Figures 11 Table: As a function of ambient pH trapidil release 1

Veo pH of Stabilizer Meter +.) HCI Time (h) = ( Y ) = ( ( Y ) 6 L A M 1 1.74 Yo A 7,” M Y

YA.£1". A 18 1 A M B 8.7 3

YAY ¥o.q £Y.Y 16.4 ° 71 621 £V.A The 1 £1.4 EY. ov. YX VLA 7 8.6 and 89.1 AYN A ov.Y m Tv. 4..¢ 1

TY. oq.) Ve 41. “1” load b l 0.8 yo km 74 each Yoo VY These discs show the kinetics (da) of the 11 discs and the results presented in Table 1. Figure shows Very different release depending on the pH.These results show that a controlled release of 0 and prolonged release cannot be obtained in a strongly acidic medium when there is no alkalinity factor in the formulation.For tablets (J) the release is prolonged. The duration of the substance 11 Figure ¥ and the results presented in the table show that it is obtained very well in a strongly acidic medium when there is an agent in the (Say Adal) pharmaceutical composition. At doses of 10 mg (J) controlled release (k); hydrocodone tablets containing AY are prepared by manufacturing tablets directly from homogeneous mixtures having the compositions in the tablet table (k) on 7207.7 excipients interstitial It does not contain an alkaline factor: the tablets ve contain an excipient interlayer of 747.7 and an alkaline factor 717.8. (J)

: YA 11 Tablet Composition Table (K) and (L (J) (¢) Ingredients Vo Vo Hydrocodone bitartrate no Ao Methocel K100M CR 70 - Se No (Na,COs3 m ¢A Avicel pH 102 mM Aerosil 200 \.o 0. Magnesium stearate From tablets (K) and (L) with the help of hydrocodone Release kinetics are determined in the laboratory for the drug Tablets are placed in the dissolving container The speed of rotation of the paddles is LY No. USP 23 Hydrogen melting device of milliliters of stabilized solution at 0000 revolutions per minute The melting medium consists of 0 at pH 3355.04 Samples over an 11 hour period of melting medium are estimated at 0.4 phosphate and fig. 16 The results of this study are presented in the table (HPLC by hydrocodone

VE schedule of hydrocodone Release 7 (J) (<4) Time (hr) 8 4 1 4.7 A ¥

WY. 10, ¢ 1. AY 1 £0.A 4.6 A ov.1 aV.A Ye 7.1 and VY that the presence of an alkaline agent in the formulation slows the release of substance 14 The results presented in the active table show. In addition to that; As shown in Figure 4; The release kinetics are linear; In other words, the rate of release remains constant over time. 0 By spectral microscopic examination hydrocodone is carried out under similar conditions and by the DAL test, the test shows

YA hour. In addition to that; The release of the material is completed after VA at a constant rate of release over the Lad UV hour.

Example Vv bilayer tablets hydrocodone [hydrocodone] bilayer tablets prepared with VO mg doses of hydrocodone consisting of a controlled release layer containing a dose of 01 mg hydrocodone and an instantaneous release © layer containing Dosage of 10 mg hydrocodone in the following manner (tablets 6) Two separate homogeneous mixtures (Mas Ma) are prepared from the compositions given in Table Vo and Table 1" 3. Tablets are then made from the mixtures Mp. 14 Mp in Multilayer tablet making machine to produce bilayer tablets in which the two layers are bonded together.In this Coal BY) Long Release Layer 0 contains 747.7 methocel 1100/4 CR and 17.7 sodium carbonate Vo Table. Hp mixture Ingredients mg/tablet Hydrocodone bitartrate ° YAY Tablettose Avicel pH 2 16.1 LY Aerosil 200 of Magnesium stearate Table 11 Hp hia Ingredients mg/tablet 01 Hydrocodone bitartrate Methocel K100M CR 7 “Na,CO;3 No Mane 7} 7.1 Avicel pH 102 Aerosil 200 A 1 Magnesium stearate The release kinetics of hydrocodone are determined in vitro of ual AY (m) with the aid of melter 23 USP No. 1. The rotational speed of the baskets is 100 rpm. The dissolution medium consists of 1.060 milliliters of a buffer solution pH 0.A testing for hydrocodone as in Example 6. The results are presented in Table AY

ml Table 117 / Release Hydrocodone Time Hydrocodone (Rely) 0 0/mh Y 1.0 : ¢ .1 AY. 1 Ad A ey Ye 011 VY The results presented in Table 17 show that exactly 772% of hydrocodone is released after 1 hour; This corresponds to the hydrocodone content in the instantaneous-release layer (777.9 of the total dose). after that; Hydrocodone release continues gradually and regularly according to A gall kinetics similar to oo observed in Example 6. Example A sale inactive inter-hydrocodone tablets Prepare controlled-release hydrocodone tablets (N ) and (o) contain doses of V0 mg and contain cellulose acetate as an excipient as an inert intermediate substance for the manufacture of tablets directly from 0 homogeneous mixtures having the compositions in Table VA The tablets (n) contain 754 substances Excipient inert interlayer and 717.7 alkalinity factor The tablets (Q) contain 754 excipient inert interlayer and do not contain alkalinity factor. YA Table of Compositions of Tablets (n) and (o) mg/a Al Ingredients (N ( ( o ) yo \o Hydrocodone bitartrate AN A Cellulose acetate CA398-10NF oY TY Emcompass 0 Sodium carbonate Zero Aerosil 200 m 0..: \.o 0. Magnesium stearate The release kinetics of Hydrocodone of these two types of the tablet are determined in the laboratory with the help of a melting apparatus vo 118823 No. 1. The tablets are placed in a basket It is rotated at a speed of 100 revolutions per minute

In the dissolution medium of 00000 milliliters of a phosphate buffer solution at pH .0.A test hydrocodone as in example +. The results are presented in Table A Table 19 / Release Hydrocodone Hydrocodone Time (hr) )©( (h) \ 1 through YA.Y¢ YY.eg ¥¢ .a : 47.5 1 7.5 46 ...+ A 1.7 No A10 OA.

EE Ye 40.1 AY.YY 11 44.1¢ The results presented in Table 19 show that the presence of an alkaline agent in the formulation slows the release of the active substance oo. In addition to that; As in the example; The release kinetics are linear. Example 0 Interventional Tablets — Hydrocodone Hydrocodone Release Controlled Tablets (P) and (V) are prepared containing VO mg doses and contain CUTINAHR as excipient. Homogeneous 0 mixtures having the compositions found in Table Ye. Tablets (P) contain 77007 sake interfacial fats and 717.7 alkalinity factors, and tablets (F) contain 72707 sake interfacial fats and do not contain an alkalinity factor. Table 01 Compositions of tablets (p) and (p) mg/ga All ingredients (&( )=( yo eo Hydrocodone bitartrate Cutina HR Avicel pH 102 You AY.Y Sodium carbonate 9 zero Aerosil 200 0.. 0.. \.o 0. Magnesium stearate The release kinetics of Hydrocodone of these two types of the tablet are determined in the laboratory with the help of a melting apparatus ve 1158023 No. 1 placed The tablets in a basket are rotated at a speed of 100 rpm yy at pH phosphate mL of a buffer solution pH 000 of the dissolution medium is made up of

YY as in the + example. The results are presented in the table. Hydrocodone is tested 0.A

YY hydrocodone release table 7 ÷ Hydrocodone time (hours)© (q) 8. 0.4} \

AE. ET 1.6 8.15 YV..0 Y 1.6 Ya...) ¢ 0164 D VY 01. 7 m A

Varory Av .aY Ve 017 for VY that the presence of an alkaline agent in the composition slows down the release of substance 71. The results presented in the table show. active. In addition to that, as in the example - the release kinetics acquires the linear characteristic 01 °, for example, hydrocodone mixed interstitial tablets -

Vo controlled release (r) and (s) containing doses of hydrocodone Tablets are prepared as EUDRAGIT and 1/1 t 15 METHOCEL K100M CR mg and contain a mixture of interstitial excipients by direct manufacture of tablets from homogeneous mixtures It has the compositions listed in Table 0. Tablets (R) contain 757.7 excipients intersubstance and 717.7 alkalinity factor. 0 Tablets (s) contain “747.7 exogenous intersubstance and do not contain alkalinity factor.

YY Tablet formulations table (y) and (s) mg/tablet (©) Ingredients (y) yo yo Hydrocodone bitartrate eY.o oY.o Methocel K100M CR 1.5 1.68 Eudragit RSPM

TA Dr Avicel pH 2 0 Ye. Sodium carbonate MM Aerosil 200 6 \.o Magnesium stearate

yy The release kinetics of Hydrocodone of these two tablet types are determined in the laboratory with the aid of a USP 23 No. 1 melter. The tablets are placed in a basket and rotated at 100 rpm. The dissolution medium consists of 5000 milliliters of a buffer solution of phosphate at pH 4. Test hydrocodone as in example >. The results are presented in Table AY o Table YY 7 Release Hydrocodone Hydrocodone Time (hr) (AM) 8 1.1 9.1 1 EY.

A YAY ¥ 7 Aja £4.v1 YAY ¢ 8.7 1 651 .A 1 ALA YAY AY.

YR A AY.YY AAYY Ye 014 1 No The results presented in Table 77 show that the presence of the alkaline agent in the formulation Ung releases the active substance. add cella as in the example; The release kinetics are linear. Example 11 Interstitial Coated Efletirizine Tablets Ye Prepared Release Controlled Efletirizine Tablets (T); (u) and (v) contain doses of 01 mg wet granulation of the active ingredient with -emcompress their composition specified in Schedule YE Table YE Tablet Compositions (T); (u) and (v) mg/tablet Ingredients (t (u) v) Ye Ye.

Ye Efletirizine. 2HCI Ye Methocel K15M CR 2 77.7 Yo 55.7 vv Emcompress VY Y.

Sodium bicarbonate zero VY LY 1 Aerosil 200 1 1 y Magnesium stearate Opadry Y1-7000 1 Be 7

Y¢ from the tablet in the laboratory with the help of EDEN of these types efletirizine Release kinetics are determined in 001 cycle The tablets are placed in a basket subjected to rotation at a rate of 1. USP No. 23 per minute melting device. test? Dissolution media: water and solutions pH stabilized at pH 6.0 and for a buffered solution pH at HPLC by efletirizine test V.0.

Yo for other solutions. Results are given in pH 0.UV table and spectroscopic microscopy©

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The results presented in Table Yo show that for disk (v); which does not contain alkaline agent; Release kinetics are strongly pH dependent. For the other two disc types; This difference is reduced by a Cows degree, for example, 11 h. A coated interfacial material of 1011" 1181 prepares water-absorbing interfacial materials (z); (and (g) containing doses of Yao mg of trapidil containing On a wet granulation alkaline agent for the ingredients, lactose » sodium bicarbonate 00701076 Their composition is specified in Table XT Table 716 Tablet Compositions (Z)» (V) and (G) mg/tablet Components (Z) 5 2 ‎ 0*0.0.Trapidil a y LI} Methocel K15M CR zero zero zero Yo.

Methocel K4M CR Zero Zero Natrosol 250 HHX Zero Vou Zero Ta Te Te Sodium bicarbonate 001 84 Avicel PH 101 Zero TY 79 9 Lactose 100 mesh Aerosil standard 7 Radan 3 05 7 Magnesium stearate 7 Y y Y Povidone K30 YA Yo YA Opadry Y1-7000 “The tablets (=) (4) and (g) are subjected to a bioavailability test in a human over the course of del VE. Each volunteer is given two tablets at time zero. The patterns of bioavailability obtained with tablets (z); (v) and (g) are compared with the pattern produced by “administrations at TAL ald hour intervals for 100 mg instant-release gelatin capsules (reference). The pattern is also determined After a single administration of a (Se) solution containing Yoo mg Trapidil vo. This cross-sectional study A included healthy subjects (men aged 18 to £0 (Bie) each subject given the five forms With a period of "removal from the body" V days between two administrations Blood samples were collected from individuals over the course of YE hours according to the following programs: Oral solution: Sun YY Dave Active AY in 0 #.oY 4 and 1 hours;

yy; And 1 hour later? 7 oY 59 6.737 yellow gelatin capsule and 14 hours. 01 YT a1 cA cf oY interstitial tablets: row 0.0) – the area AUC le representing the YY results This study is presented in Figure 0, and in the table it represents the time necessary to reach max.

Cmax©

YY Table Human bioavailability of trapidil tablets (Z) & ( (g gelatin capsule (µg/mL) l (008m) AUC (µg/mL) 0.0 fda Cpa HE™D a Yo £ \ (h) Tmax The results of this study show that interstitial tablets provide prolonged release of the active substance. Rapid release; Tablets (V) give gelatin results compared to multiple administration of capsules, thus avoiding peaks of Ya / C by about Cmax, less dae tmax, particularly useful with an hour of equal absorption of VY over a period In excess of diay, a stable stable level of PEN appears in the blood, practically Ye, of the active rectifier.

Claims (1)

YA security_items 01 1- An oral drug formulation that allows the controlled release of at least one active substance 7 that includes: v (a) at least one active substance mentioned; (b) between 0 and 70 by weight; For the total weight of the formulation; from at least one excipient; selected from the group consisting of inert metamaterials; Absorbent interlayers celal interlayers (a0 1 mixtures of inert interlayers and fat interlayers; mixtures of el all 7 sorbent interlayers and inert interlayers; with the exception of mixtures containing polyacrylic acid and an absorbent interlayer A For water, at least one type of cellulose and: a c) between 0 and 005 pounds of weight; For the total weight of the formulation; of at least one alkaline agent Ve, soluble in an aqueous state under physiological pH conditions; It is selected from group 11 consisting of phosphates ¢bicarbonate “carbonate hydroxides” 31 alkaline or earth sodium borate “ss VY” and basic salts of organic acids. 0 *- The pharmacological composition is according to Claim 1, in which the active substance of group Y consisting of hydrocodone “trapidil efletirizine” pseudoephedrine is selected, its optical isomers 1 5 and its pharmaceutically acceptable salts. 1?- Composition gall 4 according to claim 1 in which the excipient excipient the interlayer Y is -hydroxypropyl methylcellulose 1?- The medicinal composition according to claim 1 includes; In addition, one or more excipients ¥ are additionally acceptable medicinally. a 01©- The medicinal composition according to the claim of where one or more of the additional pharmaceutically acceptable X excipients mentioned is selected from the group consisting of diluents; binders; clad y lubricants; taste masking agents; flavoring agents; Coloring and coating agents. 1 +- Process for preparing a medicinal composition according to claim 1; comprising the following successive steps: 1 (b); and (c) pursuant to the off claim) prepare a homogeneous mixture containing (1) x components and optionally present additional excipients; and ¥ (Y) Manufacture tablets from the homogeneous mixture obtained in step (1); optionally after granulation. Yq 7- A drug combination that can be administered orally allows immediate release of a first active substance and long-term release 3 It includes: Ail for the same substance or for an active substance Y At least one layer includes an active substance and an excipient that allows for a momentary release of the active substance (00 ¥ stated after administration; and ¢ e (b) at least one second layer allowing controlled release of the same substance or a second active substance; 1. This layer is a drug composition under Claim 1 where The instantaneous release layer (A) is in contact with the oF of the drug composition of claim - + 01 l of the long-acting release layer (B). The sequence of steps includes: oF of the preparation of a drug of the claim Adee - 4 01 Prepare separate homogeneous mixtures of the components of layers (a) and (b); and (1) Y. Make tablets from the mixture obtained in step (1) in a multi-layer tablet making machine. (7) 0 Preparation process According to Claim 9, where the tableting step (7) is preceded (1-01-01) by a granulation step for the homogeneous mixtures produced in step Y