Pharmaceutical formulations containing epinastine, belladonna, and pseudoephedrine

Abstract

Oral pharmaceutical compositions comprising as pharmaceutically active compounds a combination of an antihistaminic-effective amount of epinastine or a pharmaceutically acceptable salt thereof, an anticholinergic amount of Belladonna alkaloids (Belladonna) or a pharmaceutically acceptable salt thereof, and of a decongestant-effective amount of pseudoephedrine or a pharmaceutically acceptable salt thereof. Optionally, the formulation includes methylephedrine (methylephrine) or a pharmaceutically acceptable salt thereof in a decongestant-effective amount. The composition further comprises suitable pharmaceutically acceptable carriers or excipients. Another aspect of the present invention relates methods of using such pharmaceutical compositions in the treatment of allergic diseases and/or disorders, in particular, seasonal allergic rhinitis and seasonal allergic conjunctivitis.

Description

FIELD OF THE INVENTION

[0001] The present invention relates to novel oral pharmaceutical compositions comprising as pharmaceutically active compounds a combination of an antihistaminic-effective amount of epinastine or a pharmaceutically acceptable salt thereof, an anticholinergic amount of Belladonna alkaloids (Belladonna) or a pharmaceutically acceptable salt thereof and of a decongestant-effective amount of pseudoephedrine or a pharmaceutically acceptable salt thereof. Optionally, the formulation may comprise methylephedrine (methylephrine) or a pharmaceutically acceptable salt thereof in a decongestant-effective amount. The formulation further comprises suitable pharmaceutically acceptable carriers or excipients. Another aspect of the present invention relates to methods for the preparation of these compositions and methods of using them in the treatment of allergic diseases and/or disorders. In particular, the inventive composition is useful in the treatment of seasonal allergic rhinitis and seasonal allergic conjunctivitis.

BACKGROUND OF THE INVENTION

[0002] Seasonal allergic rhinitis (SAR) and seasonal allergic conjunctivitis (SAC) are allergic-driven diseases with a specific symptomatology. SAR is characterized by sneezing, itching, blocked nose (“congested nose”) and runny nose, while SAC is characterized by eye itching, red eye, and sensation of foreign body. Both allergic reactions may occur separately of each other or at the same time. An adequate systemic symptomatological treatment of SAR and SAC should address all the symptoms. From the state of the art, there is not known any suitable substance able to deal with all these symptoms.

[0003] It is known that H1 antihistamine will deal with the histamine-driven symptoms such as sneezing or itching. H1 antihistamine may also have an effect on runny noses or red eyes but to a lesser grade. Due to this fact they are not the first choice substances to treat the latter. Additionally, H1 antihistamines are unable treat blocked noses.

[0004] From JP-A 10298107 it is known that hyperergasis (hypereregy) of respiratory tract secretion may be suppressed by compositions comprising HI antihistamines and anticholinergics. However, the aforementioned combination is only useful to treat some of the symptoms related to allergic disorders as SAR or SAC. In particular, these formulations or combinations are not suited to treat the issue of blocked noses or red eyes.

[0005] It now was found that the combination of epinastine, an H1antihistaminic agent, Belladonna alkaloids, and pseudoephedrine successfully treat all the aforementioned symptoms of SAR or SAC.

[0006] It is one objective of the present invention to treat the symptoms of seasonal allergic rhinitis, i.e., sneezing, itching, blocked nose, and runny nose.

[0007] It is another objective of the present invention to treat the symptoms of seasonal conjunctivitis, i.e., eye itching, red eyes, and sensation of foreign bodies.

[0008] It is another objective to develop one medication to treat the symptoms of both diseases, SAR and SAC simultaneously.

[0009] Another objective is to develop a suitable pharmaceutical formulation for treating allergic congestion of the Eustachian tubes and/or other diseases from allergic origin deserving the administration of antihistamine and decongestant drugs.

[0010] Another objective of the present invention is the treatment of common cold and in the symptomatic relief associated with cough, cold, and flu symptoms.

[0011] Still another objective of the present invention is to overcome the disadvantages of the medications known in the art in the treatment of SAR and/or SAC.

[0012] Among theses objectives, the developments of medications to treat SAR and/or SAC are preferred.

DETAILED DESCRIPTION OF THE INVENTION

[0013] The present invention solves the problem of insufficient treatment of SAR and/or SAC by providing a pharmaceutical formulation comprising an antihistaminic-effective amount of epinastine or a pharmaceutically acceptable salt thereof, an anticholinergic amount of Belladonna alkaloids or a pharmaceutically acceptable salt thereof and of a decongestant-effective amount of pseudoephedrine or a pharmaceutically acceptable salt thereof Optionally, the formulation may additionally comprise methylephedrine or a pharmaceutically acceptable salt thereof in a decongestant-effective amount. Further ingredients of the formulation of the present invention may be pharmaceutically acceptable carriers or excipients.

[0014] The term Belladonna alkaloids is commonly used in pharmaceutics. The exact method of their winning and the active ingredients of this mixture of alkaloids can be taken from the Deutsches Arzneibuch 9 (DAB 9), Volume 2, pages 932 to 944, Wissenschaftliche Verlagsgesellschaft Stuttgart mbH; Govi-Verlag GmbH, Frankfurt. These pages 932 to 944 are herewith incorporated by reference. Belladonna alkaloids are won as an extract of the plant Atropa Belladonna, i.e., an extract of the leaves and/or the root.

[0015] The main component of the Belladonna alkaloids is atropine. Atropine itself comprises L-(−)-hyoscyamine and its racemate, which develops by drying. Other alkaloids found in Belladonna are L-(−)-hyoscine (L-(−)-scopolamine), N-oxides of hyoscine and/or hyoscamine, atropamine, belladonnine, and optionally nicotine, N-methylpyrroline, N-methylpyrrolidine, pyridine, cuskhygrine and further alkaloids. The names of the alkaloids as written above are taken from the German textbook DAB 9, referred to above. In case of ambiguities, the names shall be taken directly from the textbook, page 934.

[0016] Preferably in the context of the present invention, the mixture of the above named alkaloids are taken. However, the invention is not limited to the use of this exact mixture. In fact, any mixture or any single alkaloid of the designated alkaloids extracted from Atropa Belladonna can be used. In particular, the invention comprises atropine or L-(−)-hyoscyamine alone without the other named alkaloids. In the context of the present invention, the term belladonna alkaloids preferably stands mainly for hyoscyamine and scopolamine as major components in extract of belladonna roots and/or leaves. These anticholinergic alkaloids have analgesic-antispasmodic action and inhibitory action of secretion. Extract of Datura can also be selected as a substitute for belladonna alkaloids.

[0017] Also the above mentioned active ingredients are the preferred ones and as a consequence thereof the formulation preferably does not contain any further active ingredients, the formulation of the present invention is not limited to theses active ingredients alone. As an additional active compound, the compositions according to the invention may optionally contain one or several compounds selected from the group consisting of mucolitic and analgesic-antipyretic compounds and vitamins. Preferred mucolitic ingredients are selected from bromhexine and ambroxol. Preferred analgesic-antipyretic compounds are selected from paracetamol and ibuprofen. Preferred vitamins are selected from vitamins B2, B6, and C. Preferably a leukotriene antagonist is not present.

[0018] In a preferred embodiment, the present invention relates to an oral pharmaceutical composition. Due to the short-lasting effects of pseudoephedrine and Belladonna and, relatively to this, the long-lasting effect of epinastine, it is of advantage to have a sustained release of Belladonna and the decongestant effective amount of pseudoephedrine and/or methylephrine and an immediate release of an antihistaminic effective amount of epinastine.

[0019] The preferred dosage forms are tablets or capsules.

[0020] Concerning the application via a tablet, in the context of the present the invention a bilayer tablet is preferred wherein a first layer A provides for the sustained release of Belladonna and pseudoephedrine, which comprises a decongestant effective amount of pseudoephedrine or a pharmaceutically acceptable salt thereof and a anticholinergic amount of Belladonna or a pharmaceutically acceptable salt thereof. A second layer B provides for the immediate release of epinastine and comprises an antihistaminic effective amount of epinastine or a pharmaceutically acceptable salt thereof. In case the formulation contains additionally methylephedrine or one of its pharmaceutically acceptable salts, the appropriate amount thereof is present in layer A, already comprising pseudoephedrine.

[0021] Both layers A or B may further comprise pharmaceutically acceptable excipients and/or carriers.

[0022] The bilayer tablet according to the invention may additionally contain a tablet coating C consisting of pharmaceutically acceptable excipients, which mask the bitter taste of one of the active compounds.

[0023] In a preferred embodiment of the inventive bilayer tablet, layer A comprises a decongestant effective amount of pseudoephedrine or a pharmaceutically acceptable salt thereof and optionally methylephedrine or a pharmaceutical acceptable salt thereof in a matrix of a swellable hydrophilic polymer which provides a sustained release profile in a period of 3 to 24, preferably 6 to 18, most preferably about 12 hours.

[0024] In another application form, the inventive composition may be formulated as a capsule. Such a capsule can provide the active ingredients either instantly or some of them are provided instantly and others are provided in a sustained manner. As outlined above, it is preferred to formulate the active ingredients pseudoephedrine (or its salts) and Belladonna alkaloids (or its salts thereof) as well as the optionally used methylephrine (or its salts) as a sustained releases form and epinastine or its salts as immediate release form.

[0025] Preferably the capsules are made of materials that at least partially can be digested by humans. Such capsules, e.g., are disclosed in EP 0143524. The latter discloses a two-part capsule of material which is easily digestible by humans.

[0026] EP 0460921 describes capsules of chitosan and starch, grain powder, oligosaccharides, methacrylic acid-methylacrylate, methacrylic acid-ethylacrylate, and hydroxypropylmethylcelluloseacetate, -succinate, or -phthaleate.

[0027] GB 938828 discloses capsules comprising water-soluble gelatine, methylcellulose, polyvinyl alcohol, or water-soluble non-toxic thermoplasts.

[0028] EP 0 606 486 B1 discloses capsules being composed of hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, starch, hydroxypropyl starch, and sodium alginate.

[0029] JP 2002-525412A discloses capsules being composed of pullulan.

[0030] Principally all these capsules can be take for the present invention, preferred are gelatine-capsules, in particular hard-gelatine capsules. Other preferred capsules are made of starch or of a cellulose-derivative like hydroxypropylmethylcellulose and pullulan. Pullulan is a neutral simple polysaccharide produced from cultured Aureobasidium pullulans. It has a structure of chains of repeated α-1,6 bondage of maltotriose composed of three glucoses in α-1,4 bondage. It is listed in Japanese Pharmaceutical Excipients (JPE). Preferred standard capsules have the following physical characteristics:

Size	5	4	3	2	1	0
Body-Volume [mL]	0.13	0.21	0.28	0.37	0.49	0.68

[0031] Among them, capsule-sizes of 1 or 2 are preferred.

[0032] According to the invention, the term pharmaceutically acceptable salts stands for acid addition salts of the active compounds pseudoephedrine, epinastine, Belladonna alkaloids, and/or methylephedrine. These acid addition salts can be formed with inorganic acids like hydrochloric acid, hydrobromic acid, or sulfuric acid or with organic acids, as for instance, oxalic acid, fumaric acid, or methanesulfonic acid. Epinastine is preferably used as its hydrochloric acid addition salt. Pseudoephedrine and also methylephedrine are preferably used as the hydrochlorides or the sulfates. Within the present invention, the hydrochloride salts for the latter two compounds are most preferred.

[0033] The release of pseudoephedrine and optionally methylephedrine takes place over 3 to 24, preferably 6 to 24, most preferably about 12 to 24 hours. The preferred dose regimen is a “once a day application”, regardless of how the formulation is applied.

[0034] The concentration range of pseudoephedrine salt plus methylephedrine salt in the compositions according to the invention is between 5 mg and 240 mg daily, preferably 10 mg to 200 mg daily, more preferably 20 mg to 150 mg daily.

[0035] If methylephedrine or a salt thereof is present, what is preferred, both compounds pseudoephedrine and methylephedrine are preferably present in the formulation in the same amount, i.e., amount w/w. Thus, to reach a total amount of pseudoephedrine plus methylephedrine (their salts respectively) of, e.g., 78 mg daily, each of the two compounds is present in an amount of 39 mg daily; and for a total amount of 60 mg daily, each compound is present in an amount of 30 mg daily.

[0036] The concentration range of epinastine salt in the compositions according to the invention is between 2 mg and 20 mg daily, preferably 5 mg to 15 mg daily, more preferably 7.5 mg to 12.5 mg daily.

[0037] The concentration range of Belladonna alkaloids in the compositions according to the invention is between 0.05 mg and 4.0 mg daily, preferably between 0.05 mg and 2.0 mg daily, more preferably 0.1 mg to 1.5 mg daily, most preferably between 0.2 mg and 0.6 mg daily.

[0038] In case of a bilayer tablet, each layer is in contact with each other in a portion of their surface, but provides independent release profiles for both active substances mentioned before.

[0039] The sustained release layer A comprises, beside the active ingredient(s), a swellable hydrophilic polymer. Typical swellable hydrophilic polymers include cellulose ethers such as methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, and carboxyethylcellulose or mixtures thereof. The use of hydroxypropylmethylcellulose (HPMC) is preferred. Particularly useful are the HPMC polymers HPMC USP2910 and USP2208, like for instance, METHOCEL® E5, E4M, E15M, K15M, and K100M supplied by the Dow Chemical Company. In the aforementioned abbreviations, the designation “E” refers to USP2910 whereas “K” refers to USP2208. The number designation refers to the viscosity in a 2% aqueous solution (e.g., 5 designates a viscosity of 5 cps; 15M designates a viscosity of 15000 cps).

[0040] The excipients that could be optionally used in the sustained release layer A are insoluble polymers, soluble or insoluble fillers, antiadherents, coloring agents, lubricants, and additional binders. Typical fillers are, for example, lactose, microcrystalline cellulose, dibasic calcium phosphate, and cornstarch. Examples of antiadherents, which are used to prevent tablets from sticking to the tablet press, are colloidal silicon dioxide and talc. Magnesium stearate, talc, and stearic acid are typical lubricants. Typical binders are povidone, and cornstarch.

[0041] The immediate release matrix layer B comprises, beside the active ingredient, different combinations of excipients. The excipients that could be optionally used in the immediate release layer B are insoluble polymers, soluble or insoluble fillers, antiadherents, lubricants, coloring agents, disintegrants, and additional binders. Typical fillers are, for example, lactose, microcrystalline cellulose, dibasic calcium phosphate, and cornstarch. Examples of antiadherents, which are used to prevent tablets from sticking to the tablet press, are colloidal silicon dioxide and talc. Typical disintegrants are crospovidone, sodium starch glycolate, and crosscarmellose sodium. Typical coloring agents are selected from FD&C red 40 HT 2aluminum lake, 2-hydroxy-1,1′-azonaphthalene-3,6,4′-trisulfonic acid trisodium salt, erythrosine, iron oxides, 1-(4-sulfo-1-naphthylazo)-2-naphthol-6,8-disulfonic acid trisodium salt, 2′,4′,5′,7′-tetrabromo-4,5,6,7-tetrachlorofluorescein disodium salt, 2,4,5,7-tetraiodo-3,6-dihydroxyxanthene-9-spiro-1′-(4′,5′,6′,7′-tetrachloro-3′H-isobenzofuran-3′-one dipotassium salt, trisodium 3-carboxy-5-hydroxy-1-p-sulfophenyl-4-p-sulfophenylazopyrazole, 6-hydroxy-5-((4-sulfonphenyl)azo-2-naphthalenesulfonic acid disodium salt, and optionally aluminum lakes thereof. Magnesium stearate, talc, and stearic acid are typical lubricants. Typical binders are povidone and cornstarch.

[0042] Water and ethanol are examples of volatile components which can be used in the manufacture process of both layers to granulate powders. These volatile components are removed during processing and therefore do not appear in the finished product.

[0043] The tablet coating is optional since the presence of it does not significantly modify the release rates of the active substances present in the core layers. The presence of the coating is preferred because it masks the bitter taste of one of the active substances and enhances the properties of dosage form. Because of that, a lot of different coatings with different polymers, plasticizers, and other excipients could be used without significantly modifying the release profile of the active substances present in the core tablet. A typical coating comprises a polymer, such as hydroxypropylmethylcellulose, and a plasticizer, such as polyethylene glycol. Optional excipients could be added to the coating, such as antifoaming agents and opacifying agents. An example of an antifoaming agent is silicone. Examples of opacifying agents are titanium dioxide, talc, and aluminum lake dyes.

[0044] The inventive formulation also can be applied via a tablet comprising sustained release and non-sustained release granules or a capsule comprising the same.

[0045] In case of such a tablet, non-sustained release granules and sustained release granules, which are coated with a sustained release film, are mixed with suitable excipients and then they are compressed as a tablet.

[0046] Similarly, non-sustained release granules and sustained release granules, which are coated with sustained release film, are mixed 1:9 to 9:1, preferably 3:7 to 7:3, and are filled into a capsule or are compressed into tablet.

[0047] A non-sustained release granule comprises an amount of epinastine or a pharmaceutically acceptable salt thereof. Optionally it may comprises a portion of the total amount of belladonna alkaloids or a pharmaceutically acceptable salt thereof and a portion of the total amount of pseudoephedrine or a pharmaceutically acceptable salt thereof and optionally a portion of the total amount of methylephedrine or a pharmaceutically acceptable salt thereof, if necessary.

[0048] A sustained release granule comprises either a portion or the total amount of belladonna alkaloids or a pharmaceutically acceptable salt thereof, pseudoephedrine or a pharmaceutically acceptable salt thereof, and optionally methylephedrine or a pharmaceutically acceptable salt thereof.

[0049] Preferably the non-sustained release granules contain only epinastine or a pharmaceutically acceptable salt thereof as active ingredient while the sustained release granules comprise the remaining active ingredients.

[0050] Any compounds conventionally used as a sustained-release coat can be used for the purpose of this invention. Specific examples which can be given include water insoluble polymers such as ethyl cellulose, aminoalkyl methacrylate copolymer polyvinyl acetate, polyvinyl chloride, polyethylene, and the like; intestinally soluble polymers such as cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, styrene acrylic acid copolymer, methacrylic acid copolymer, maleic anhydrous acid copolymer, shellac, and the like; paraffin waxes such as paraffin, microcrystalline wax, and the like; higher alcohols, preferably saturated and unsaturated C6-C26-alcohols, preferably unbranched and unsubstituted, such as stearyl alcohol, cetyl alcohol, and the like; esters of higher fatty acids, preferably saturated and unsaturated C6-C26-acids, preferably unbranched and unsubstituted, such as glycerol esters of fatty acids, hydrogenated oils, carnauba wax, beeswax, Japan (haze) wax, and the like; and higher fatty acids as defined above, such as stearic acid, palmitic acid, myristic acid, behenic acid, and the like (or the sodium, calcium, or magnesium salts of these higher fatty acids).

[0051] These excipients may be used alone or mixed. The coating amount is preferably 10% to 50% for granules.

[0052] Furthermore, the excipients that could be optionally used in sustained release film are water soluble polymers, sugar alcohols, plasticizers, titanium oxide, talc, coloring agents, and so on. Typical water soluble polymers and sugar alcohols are hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone, and polyethylene glycol. Typical plasticizers are glycerin fatty acid ester, triethyl citrate, propylene glycol, and triacetin.

[0053] For any of the inventive application forms, bilayer tablet, tablet or capsule any of the aforementioned ingredients can be taken, if appropriate.

[0054] In the context of the present invention capsules and tablets comprising sustained release and non-sustained release granules are preferred.

[0055] The invention will be further described by the following examples. These examples disclose certain preferred embodiments of the invention. The methods of manufacturing the compositions according to the invention like for instance granulation, tablet compression, tablet-coating, etc., are well known to the person skilled in the art. Those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit of the invention. Accordingly, it is intended that the invention be not limited to the following explicitly disclosed examples.

                                 EXAMPLE 1
                                 mg per 2 tablets
                                 (daily)
Core
A. First Layer: Pseudoephedrine, Belladonna, and
Methylephedrine Layer
pseudoephedrine hydrochloride    60
methylephedrine hydrochloride    60
Belladonna                       0.3
METHOCEL ® K15M PRCR*            198
lactose monohydrate              104.8
microcrystalline cellulose       106
colloidal silicon dioxide        1.65
magnesium stearate               2.75
povidone                         16.5
Total First Layer                550
B. Second Layer: Epinastine Layer
epinastine HCl                   10
FD&C red 40 HT aluminum lake (allura red AC) 0.38
microcrystalline cellulose       70
lactose monohydrate              154.62
povidone                         12.5
magnesium stearate               2.5
Total Second Layer               250
Total Core                       800
Coating
C. Film Coating
METHOCEL ® E5                    15
polyethylene glycol 6000         1.97
silicone antifoam S184           0.03
Total Film Coating               1.7
Total Film Coated Tablets        817
*PR means Premium grade and CR means Controlled Released grade.

[0056] Method of Manufacture

[0057] A. First Layer

[0058] A1. Dissolve povidone in a hydroalcoholic mixture;

[0059] A2. Blend pseudoephedrine hydrochloride, methylephedrine hydrochloride, Belladonna alkaloids, a portion of the microcrystalline cellulose, lactose, and METHOCEL® K15M for 5 to 30 minutes in a suitable mixer.

[0060] A3. Use alcoholic or hydroalcoholic solution prepared previously in step A1 to granulate the powder mix of step A2.

[0061] A4. Dry and mill the granulation from step A3, using suitable size screen.

[0062] A5. Blend the screened granulation with a portion of the microcrystalline cellulose and colloidal silicon dioxide for 3 to 15 minutes.

[0063] A6. Add magnesium stearate and blend for 3 to 15 minutes.

[0064] B. Second Layer

[0065] B1. Pass through a suitable screen epinastine HCl, Allura red AC (FD&C red 40 HT) aluminum lake, and microcrystalline cellulose. Blend for 5 to 30 minutes in a suitable mixer.

[0066] B2. Add lactose and povidone. Blend for 15 to 120 minutes in a suitable mixer.

[0067] B3. Add magnesium stearate. Blend for 3 to 20 minutes in a suitable mixer.

[0068] C. Compression:

[0069] Compress A and B into a suitable bilayer tableting machine in suitable size tablets.

[0070] D. Coating

[0071] D1. Dissolve METHOCEL® E5 and Polyethylene Glycol in suitable amount of water.

[0072] D2. Dissolve silicone antifoam in suitable amount of isopropyl alcohol.

[0073] D3. Add D2 to D1 and mix.

[0074] D4. Coat tablets with the METHOCEL® E5/polyethylene glycol solution from step D3 in a suitable coater.

[0075]

EXAMPLE 2
mg per 2 tablets (daily)
Core
A. First Layer: Pseudoephedrine, Belladonna, and
Methylephedrine Layer
pseudoephedrine hydrochloride 60
methylephedrine hydrochloride 60
Belladonna                    0.3
METHOCEL ® K15M PRCR*         198
lactose monohydrate           126.2
microcrystalline cellulose    100
colloidal silicon dioxide     2.75
magnesium stearate            2.75
Total First Layer             450
B. Second Layer: Epinastine Layer
epinastine HCl                10
lactose monohydrate           168.4
microcrystalline cellulose    70
Punceau 4R red aluminum lake  0.35
magnesium stearate            1.25
Total Second Layer            250
Total Core                    700
Coating
C. Film Coating
METHOCEL ® E5                 4.42
polyethylene glycol 6000      2.72
talc                          8.76
titanium dioxide              1.1
Total Film Coating            17
Total Film Coated Tablets     717
*PR means Premium grade and CR means Controlled Released grade.

[0076] Method of Manufacture

[0077] A. First layer

[0078] A1. Blend pseudoephedrine hydrochloride, methylephedrine hydrochloride, Belladonna alkaloids, microcrystalline cellulose, lactose, colloidal silicon dioxide and HPMC K15M for 5 to 30 minutes in a suitable mixer.

[0079] A2. Add magnesium stearate and blend for 3 to 15 minutes.

[0080] B. Second layer

[0081] B1. Pass through a suitable screen epinastine HCl and microcrystalline cellulose. Blend for 5 to 30 minutes in a suitable mixer.

[0082] B2. Add lactose. Blend for 15 to 120 minutes in a suitable mixer.

[0083] B3. Add magnesium stearate. Blend for 3 to 20 minutes in a suitable mixer.

[0084] C. Compression

[0085] Compress A and B into a suitable bilayer tableting machine in suitable size tablets.

[0086]

[0087] D. Coating

[0088] D1. Dissolve METHOCEL® E5 and polyethylene glycol in suitable amount of water.

[0089] D2. Add titanium dioxide and talc in suitable amount of water and mix.

[0090] D3. Add D2 to D1 and mix.

[0091] D4. Coat tablets with the METHOCEL® E5/polyethylene glycol solution from step D3 in a suitable coater.

[0092]

EXAMPLE 3
Core
A. First Layer: Pseudoephedrine, Belladonna, and
Methylephedrine Layer
mg per 2 tablets (daily)
pseudoephedrine hydrochloride 60
methylephedrine hydrochloride 60
Belladonna                    0.3
METHOCEL ® K15M PRCR*         247.5
lactose monohydrate           165.7
talc                          11
magnesium stearate            5.5
Total First Layer             550
*PR means Premium grade and CR means Controlled Released grade.

[0093] In Example 3, the second layer and coating are identical to that of Example 2 and the manufacture method was conducted analogously to the method outlined in Example 2.

EXAMPLE 4
Core
A. First Layer: Pseudoephedrine, Belladonna, and
Methylephedrine Layer
mg per 2 tablets (daily)
pseudoephedrine hydrochloride 60
methylephedrine hydrochloride 60
Belladonna                    0.3
METHOCEL ® K15M PRCR*         198
lactose monohydrate           99.2
microcrystalline cellulose    99.5
colloidal silicon dioxide     2.75
povidone                      27.5
magnesium stearate            2.75
Total First Layer             550
*PR means Premium grade and CR means Controlled Released grade.

[0094] In Example 4, the second layer and coating are identical to that of Example 1 and the manufacture method was conducted analogously to the method outlined in Example 1.

EXAMPLE 5
Core
A. First Layer: Pseudoephedrine, Belladonna, and
Methylephedrine Layer
mg per 2 tablets (daily)
pseudoephedrine hydrochloride 60
methylephedrine hydrochloride 60
Belladonna                    0.3
METHOCEL ® K15M CR*           330
lactose                       83.2
talc                          11
magnesium stearate            5.5
Total First Layer             550
*CR means Controlled Released grade.

[0095] In Example 5, the second layer and coating are identical to that of Example 1 and the manufacture method was conducted analogously to the method outlined in Example 1.

EXAMPLE 6
Core
A. First Layer: Pseudoephedrine, Belladonna, and
Methylephedrine Layer
mg per 2 tablets (daily)
pseudoephedrine hydrochloride 60
methylephedrine hydrochloride 60
Belladonna                    0.3
METHOCEL ® K15M CR*           275
microcrystalline cellulose    138.2
talc                          11
magnesium stearate            5.5
ethanol                       sq.
Total First Layer             550
*CR means Controlled Released grade.

[0096] In Example 6, the second layer and coating are identical to that of Example 1 and the manufacture method was conducted analogously to the method outlined in Example 1.

EXAMPLE 7
Core
A. First Layer: Pseudoephedrine, Belladonna, and
Methylephedrine Layer
mg per 2 tablets (daily)
pseudoephedrine hydrochloride 60
methylephedrine hydrochloride 60
Belladonna                    0.3
METHOCEL ® K15M CR*           215
dibasic calcium phosphate     108.2
ethyl cellulose               40
talc                          11
magnesium stearate            5.5
ethanol                       sq.
Total First Layer             500
*CR means Controlled Released grade.

[0097] In Example 7, the second layer and coating are identical to that of Example 1 and the manufacture method was conducted analogously to the method outlined in Example 1.

EXAMPLE 8
Core
A. First Layer: Pseudoephedrine, Belladonna, and
Methylephedrine Layer
mg per 2 tablets (daily)
pseudoephedrine hydrochloride 60
methylephedrine hydrochloride 60
Belladonna                    0.3
METHOCEL ® K15M CR*           137.5
METHOCEL ® K100M CR*          137.5
lactose                       138.2
talc                          11
magnesium stearate            5.5
ethanol                       sq.
Total First Layer             550
*CR means Controlled Released grade.

[0098] In Example 8, the second layer and coating are identical to that of Example 1 and the manufacture method was conducted analogously to the method outlined in Example 1.

EXAMPLE 9
Core
A. First Layer: Pseudoephedrine, Belladonna, and
Methylephedrine Layer
mg per 2 tablets (daily)
pseudoephedrine hydrochloride 60
methylephedrine hydrochloride 60
Belladonna                    0.3
METHOCEL ® K15M CR*           275
lactose                       138.2
talc                          11
magnesium stearate            5.5
ethanol                       sq.
Total First Layer             550
*CR means Controlled Released grade.

[0099] In Example 9, the second layer and coating are identical to that of Example 1 and the manufacture method was conducted analogously to the method outlined in Example 1.

EXAMPLE 10
Core
A. First Layer: Pseudoephedrine, Belladonna, and
Methylephedrine Layer
mg per 2 tablets (daily)
pseudoephedrine hydrochloride 60
methylephedrine hydrochloride 60
Belladonna                    0.3
METHOCEL ® K15M CR*           206.2
METHOCEL ® K100M CR*          68.8
lactose                       138.2
talc                          11
magnesium stearate            5.5
ethanol                       s.q.
Total First Layer             550
*CR means Controlled Released grade.

[0100] In Example 10, the second layer and coating are identical to that of Example 1 and the manufacture method was conducted analogously to the method outlined in Example 1.

EXAMPLE 11
Core
A. First Layer: Pseudoephedrine, Belladonna, and
Methylephedrine Layer
mg per 2 tablets (daily)
pseudoephedrine hydrochloride 60
methylephedrine hydrochloride 60
Belladonna                    0.3
METHOCEL ® K15M CR*           235
dibasic calcium phosphate     108.2
ethyl cellulose               20
talc                          11
magnesium stearate            5.5
ethanol                       sq.
Total First Layer             500
*CR means Controlled Released grade.

[0101] In Example 11, the second layer and coating are identical to that of Example 1 and the manufacture method was conducted analogously to the method outlined in Example 1.

EXAMPLE 12
Core
A. First Layer: Pseudoephedrine, Belladonna, and
Methylephedrine Layer
mg per 2 tablets (daily)
pseudoephedrine hydrochloride 60
methylephedrine hydrochloride 60
Belladonna                    0.3
METHOCEL ® K15M CR*           255
lactose                       39.7
microcrystalline cellulose    68.5
talc                          11
magnesium stearate            5.5
ethanol                       s.q.
Total First Layer             500
*CR means Controlled Released grade.

[0102] In Example 12, the second layer and coating are identical to that of Example 1 and the manufacture method was conducted analogously to the method outlined in Example 1.

EXAMPLE 13
Core
A. First Layer: Pseudoephedrine, Belladonna, and
Methylephedrine Layer
mg per 2 tablets (daily)
pseudoephedrine hydrochloride 60
methylephedrine hydrochloride 60
Belladonna                    0.3
METHOCEL ® K15M CR*           255
dibasic calcium phosphate     108.2
talc                          11
magnesium stearate            5.5
ethanol                       s.q.
Total First Layer             500
*CR means Controlled Released grade.

[0103] In Example 13, the second layer and coating are identical to that of Example 1 and the manufacture method was conducted analogously to the method outlined in Example 1.

                                 EXAMPLE 14
                                 mg per 2 capsules (daily)
(a) Non-Sustained Release Granules
epinastine hydrochloride         10
pseudoephedrine hydrochloride    30
methylephedrine hydrochloride    30
Belladonna                       0.15
hydroxypropylcellulose           3.5
sucrose                          475.35
Non-Sustained Release Granules Total 549
(b) Sustained Release Granules
pseudoephedrine hydrochloride    30
methylephedrine hydrochloride    30
Belladonna                       0.15
hydroxypropylcellulose           4
sucrose                          90.85
methacrylic acid copolymer, type B 40.6
glycerol esters of fatty acids   3.1
talc                             1.3
Sustained Release Granules Total 200
Encapsulation Mixture
non-sustained release granules   549
sustained release granules       200
talc                             1
Total Capsules                   750

[0104] Method of Manufacture

[0105] A. Non-sustained Release Granules

[0106] A1. Dissolve hydroxypropylcellulose in ethanol.

[0107] A2. Blend epinastine hydrochloride, pseudoephedrine hydrochloride, methylephedrine hydrochloride, and belladonna in a suitable mixer and pulverize the powder mix.

[0108] A3. Produce spherical granules by spraying the solution prepared previously in step A1 over sucrose, introducing the powder mix obtained from step A2.

[0109] A4. Dry and pass through granules from step A3 with suitable size screen to produce non-sustained release granules.

[0110] B. Sustained Release Granules

[0111] B1. Dissolve hydroxypropylcellulose in ethanol.

[0112] B2. Blend pseudoephedrine hydrochloride, methylephedrine hydrochloride and belladonna in a suitable mixer.

[0113] B3. Produce spherical granules by spraying the solution prepared previously in step B1 over sucrose introducing the powder mix obtained from step B2.

[0114] B4. Dry and pass through granules from step B3 with suitable size screen

[0115] B5. Dissolve Methacrylic acid copolymer, type B in ethanol and mix with glycerol esters of fatty acids and talc.

[0116] B6. Coat the granules obtained from step B4 with the solution prepared previously in step B5 to produce sustained release granules.

[0117] C. Encapsulation Mixture

[0118] C1. Mix non-sustained release granules and sustained release granules with talc.

[0119] C2. Fill the mixture obtained from step C1 into capsules.

[0120]

                                 EXAMPLE 15
                                 mg per 2 capsules (daily)
(a) Non-Sustained Release Granules
epinastine hydrochloride         10
pseudoephedrine hydrochloride    30
methylephedrine hydrochloride    30
Belladonna                       0.15
hydroxypropylcellulose           3.5
sucrose                          475.35
Non-Sustained Release Granules Total 549
(b) Sustained Release Granules
pseudoephedrine hydrochloride    30
methylephedrine hydrochloride    30
Belladonna                       0.15
hydroxypropylcellulose           4
sucrose                          90.85
ethyl cellulose                  38.75
hydroxypropylmethylcellulose 2910 1
glycerol esters of fatty acids   2.25
talc                             3
Sustained Release Granules Total 200
Encapsulation Mixture
non-sustained release granules   549
sustained release granules       200
talc                             1
Total Capsules                   750

[0121] In Example 15, the manufacture method was conducted analogously to the method outlined in Example 14.

                                 EXAMPLE 16
                                 mg per 2 capsules (daily)
(a) Non-Sustained Release Granules
epinastine hydrochloride         10
pseudoephedrine hydrochloride    30
methylephedrine hydrochloride    30
Belladonna                       0.15
sucrose                          310.1
epinastine hydrochloride         10
Non-Sustained Release Granules Total 380.25
(b) Sustained Release Granules
pseudoephedrine hydrochloride    30
methylephedrine hydrochloride    30
Belladonna                       0.15
sucrose                          114.85
ammonio methacrylate copolymer   31.5
ethyl cellulose                  7.875
glycerol esters of fatty acids   1.641
talc                             2.734
Sustained Release Granules Total 218.75
Encapsulation Mixture
non-sustained release granules   380.25
sustained release granules       218.75
talc                             1
Total Capsules                   600

[0122] In Example 16, the manufacture method was conducted analogously to the method outlined in Example 14.

                                 EXAMPLE 17
                                 mg per 2 capsules (daily)
(a) Non-Sustained Release Granules
epinastine hydrochloride         10
pseudoephedrine hydrochloride    30
methylephedrine hydrochloride    30
Belladonna                       0.15
sucrose                          310.1
epinastine hydrochloride         10
Non-Sustained Release Granules Total 380.25
(b) Sustained Release Granules
pseudoephedrine hydrochloride    30
methylephedrine hydrochloride    30
Belladonna                       0.15
sucrose                          114.86
ammonio methacrylate copolymer   35.83
ethyl cellulose                  3.54
glycerol esters of fatty acids   1.64
talc                             2.73
Sustained Release Granules Total 218.75
Encapsulation Mixture
non-sustained release granules   380.25
sustained release granules       218.75
talc                             1
Total Capsules                   600

[0123] In Example 17, the manufacture method was conducted analogously to the method outlined in Example 14.

                                 EXAMPLE 18
                                 mg per 2 tablets (daily)
(a) Non-Sustained Release Granules
epinastine hydrochloride         10
pseudoephedrine hydrochloride    30
methylephedrine hydrochloride    30
Belladonna                       0.15
hydroxypropylcellulose           12.5
microcrystalline cellulose       154.85
lactose                          12.5
Non-Sustained Release Granules Total 250
(b) Sustained Release Granules
pseudoephedrine hydrochloride    30
methylephedrine hydrochloride    30
Belladonna                       0.15
hydroxypropylcellulose           4
sucrose                          90.85
methacrylic acid copolymer, type b 30.45
magnesium stearate               10.15
glycerol esters of fatty acids   3.1
talc                             1.3
Sustained Release Granules Total 200
Compression Mixture
non-sustained release granules   250
sustained release granules       200
microcrystalline cellulose       126
crosscarmellose sodium           12
talc                             6
magnesium stearate               6
Total Tablets                    600

[0124] Method of Manufacture

[0125] A. Non-Sustained Release Granules

[0126] A1. Dissolve hydroxypropylcellulose in ethanol.

[0127] A2. Blend epinastine hydrochloride, pseudoephedrine hydrochloride, methylephedrine hydrochloride, belladonna, microcrystalline cellulose, and lactose in a suitable mixer and knead the mixture with the solution from step A1.

[0128] A3. Dry and pass through granules obtained from step A2 with suitable size screen to produce non-sustained release granules.

[0129] B. Sustained Release Granules

[0130] B1. Dissolve hydroxypropylcellulose in ethanol.

[0131] B2. Blend pseudoephedrine hydrochloride, methylephedrine hydrochloride, and belladonna in a suitable mixer.

[0132] B3. Produce spherical granules by spraying the solution prepared previously in step B1 over sucrose, introducing the powder mix obtained from step B2.

[0133] B4. Dry and pass through granules from step B3 with suitable size screen.

[0134] B5. Dissolve methacrylic acid copolymer, type B in ethanol and mix with glycerol esters of fatty acids, magnesium stearate, and talc.

[0135] B6. Coat the granules obtained from step B4 with the solution prepared previously in step B5 to produce sustained release granules.

[0136] C. Compression

[0137] C1. Mix non-sustained release granules and sustained release granules with microcrystalline cellulose, crosscarmellose sodium, talc, and magnesium stearate.

[0138] C2. Compress the mixture into a suitable tableting machine in suitable size tablets.

[0139]

                                 EXAMPLE 19
                                 mg per 2 tablets (daily)
(a) Non-Sustained Release Granules
epinastine hydrochloride         10
pseudoephedrine hydrochloride    30
methylephedrine hydrochloride    30
Belladonna                       0.15
sucrose                          161.1
Non-Sustained Release Granules Total 231.25
(b) Sustained Release Granules
pseudoephedrine hydrochloride    30
methylephedrine hydrochloride    30
Belladonna                       0.15
sucrose                          114.85
ammonio methacrylate copolymer   31.5
ethyl cellulose                  7.875
glycerol esters of fatty acids   1.641
talc                             2.734
Sustained Release Granules Total 218.75
Compression Mixture
non-sustained release granules   231.25
sustained release granules       218.75
microcrystalline cellulose       126
crosscarmellose sodium           12
talc                             6
magnesium stearate               6
Total Tablets                    600

[0140] In Example 19, the manufacture method was conducted analogously to the method outlined in Example 18.

                                 EXAMPLE 20
                                 mg per 2 tablets (daily)
(a) Non-Sustained Release Granules
epinastine hydrochloride         10
pseudoephedrine hydrochloride    30
methylephedrine hydrochloride    30
Belladonna                       0.15
sucrose                          161.1
Non-Sustained Release Granules Total 231.25
(b) Sustained Release Granules
pseudoephedrine hydrochloride    30
methylephedrine hydrochloride    30
Belladonna                       0.15
sucrose                          114.86
ammonio methacrylate copolymer   35.83
ethyl cellulose                  3.54
glycerol esters of fatty acids   1.64
talc                             2.73
Sustained Release Granules Total 218.75
Compression Mixture
non-sustained release granules   231.25
sustained release granules       218.75
Microcrystalline cellulose       126
Crosscarmellose sodium           12
Talc                             6
Magnesium stearate               6
Total Tablets                    600

[0141] In Example 20, the manufacture method was conducted analogously to the method outlined in Example 18.

EXAMPLES 20 to 40

[0142] The same as Examples 1 to 20, but the methylephrine is replaced by the same amount of pseudoephedrine, i.e., the amount of pseudoephedrine is doubled.

Claims

1. A pharmaceutical composition comprising: (a) an antihistaminically-effective amount of epinastine or a pharmaceutically acceptable salt thereof; (b) an anticholinergically-effective amount of a Belladonna alkaloid or a pharmaceutically acceptable salt thereof; (c) a decongestant-effective amount of pseudoephedrine or a pharmaceutically acceptable salt thereof; and (d) a pharmaceutically acceptable carrier or excipient.

2. The pharmaceutical composition of claim 1, further comprising: methylephrine or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition according to claim 1, wherein the Belladonna alkaloid is selected from the group consisting of atropine, L-(−)-hyoscyamine, L-(−)-hyoscine, N-oxides of hyoscine and/or hyoscamine, atropamine, belladonnine, nicotine, N-methylpyrroline, N-methylpyrrolidine, pyridine, and cuskhygrine.

4. The pharmaceutical composition according to one of claims 1 to 3, wherein the active ingredients (a), (b), and (c) are formulated for instant release.

5. The pharmaceutical composition according to claim 1 or 3, wherein epinastine or a pharmaceutically acceptable salt thereof is formulated for instant release and at least a portion of the Belladonna alkaloids or a pharmaceutically acceptable salt thereof or the pseudoephedrine or a pharmaceutically acceptable salt thereof is formulated for sustained release.

6. The pharmaceutical composition according to claim 2, wherein epinastine or a pharmaceutically acceptable salt thereof is formulated for instant release and at least a portion of the Belladonna alkaloids or a pharmaceutically acceptable salt thereof, the pseudoephedrine or a pharmaceutically acceptable salt thereof, or the methylephrine is formulated for sustained release.

7. The pharmaceutical composition according to claim 5, wherein the total amounts of the Belladonna alkaloids or a pharmaceutically acceptable salt thereof and the pseudoephedrine or a pharmaceutically acceptable salt thereof are formulated for sustained release.

8. The pharmaceutical composition according to claim 6, wherein the total amounts of the Belladonna alkaloids or a pharmaceutically acceptable salt thereof, the pseudoephedrine or a pharmaceutically acceptable salt thereof, and the methylephrine are formulated for sustained release.

9. The pharmaceutical composition according to one of claims 1 to 3, wherein the amounts of epinastine or a pharmaceutically acceptable salt thereof is between 2 mg and 20 mg, the amounts of the Belladonna alkaloids or salt pharmaceutically acceptable salt thereof is between 0.05 mg and 4.0 mg, and the amounts of pseudoephedrine plus methylephrine or the corresponding pharmaceutically acceptable salts thereof is between 5 mg and 240 mg.

10. The pharmaceutical composition according to claim 9, wherein the amounts of pseudoephedrine and methylephrine are the same.

11. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a bilayer tablet.

12. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition is a bilayer tablet.

13. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is a bilayer tablet.

14. The bilayer tablet according to claim 11, comprising: (a) a first layer A, providing for the sustained release of Belladonna alkaloids, pseudoephedrine, and optionally methylephrine or the corresponding pharmaceutical salts thereof; and (b) a second layer B, providing for the immediate release of epinastine, comprises an antihistaminically-effective amount of epinastine or a pharmaceutically acceptable salt thereof.

15. The bilayer tablet according to claim 14, wherein: the first layer A comprises 60 mg pseudoephedrine hydrochloride, 60 mg methylephrine hydrochloride, and 0.3 mg Belladonna alkaloids; and the second layer B comprises 10 mg epinastine hydrochloride.

16. The bilayer tablet according to claim 11, further comprising a tablet coating C consisting of pharmaceutically acceptable excipients.

17. The bilayer tablet according to claim 12, further comprising a tablet coating C consisting of pharmaceutically acceptable excipients.

18. The bilayer tablet according to claim 13, further comprising a tablet coating C consisting of pharmaceutically acceptable excipients.

19. The bilayer tablet according to claim 14, wherein the first layer A comprises a decongestant-effective amount of pseudoephedrine or a pharmaceutically acceptable salt thereof, and methylephrine or a pharmaceutically acceptable salt thereof, and an anticholinergically-effective amount of the Belladonna alkaloids or a salt thereof, in a matrix of a swellable hydrophilic polymer.

20. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a capsule.

21. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition is a capsule.

22. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is a capsule.

23. The capsule according to one of claims 20 or 22, wherein the capsule material comprises a compound selected from the group of chitosan and starch, grain powder, oligosaccharides, methacrylic acid-methylacrylate, methacrylic acid-ethylacrylate, hydroxypropylmethylcelluloseacetate, -succinate, or -phthalate, polyvinyl alcohol, water-soluble non-toxic thermoplasts, hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropyl starch, sodium alginate, gelatine, hard gelatine, and pullulan.

24. The capsule according to one of claims 20 or 22, wherein the ingredients are formulated as sustained release and non-sustained release granules.

25. The capsule according to claim 24, wherein the non-sustained granules are coated with a coating comprising a water insoluble polymer, intestinally soluble polymer, paraffin wax, higher alcohol, higher fatty acid, or higher fatty acid ester.

26. The pharmaceutical composition according to claim 1, wherein the ingredients are formulated as granules which are compressed to a tablet.

27. The pharmaceutical composition according to claim 2, wherein the ingredients are formulated as granules which are compressed to a tablet.

28. The pharmaceutical composition according to claim 3, wherein the ingredients are formulated as granules which are compressed to a tablet.

29. The pharmaceutical composition according to one of claims 26 to 28, wherein the ingredients are formulated as sustained release and non-sustained release granules which are compressed to a tablet.

30. The pharmaceutical composition according to claim 29, wherein the non-sustained release granules are coated with a coating comprising a water insoluble polymer, intestinally soluble polymer, paraffin wax, higher alcohol, higher fatty acid, or higher fatty acid ester.

31. A method of treating seasonal allergic rhinitis, seasonal allergic conjunctivitis, allergic rhinitis, allergic congestion of the Eustachian tubes, other allergic origin diseases treated using antihistamine and decongestant drugs, or cough, cold and flu symptoms in a patient in need of such treatment, the method comprising administering to a patient the pharmaceutical composition according to one of claims 1 to 3, the bilayer tablet according to one of claims 11 to 19, the capsule according to any of claims 20 to 22, or the tablet according to one of claims 26 to 28.