Title:  Compositions containing both sedative and non-sedative antihistamines

United States Patent:  6,827,946

Issued:  December 7, 2004

Inventors:  Hirsh; Mark (Wellesley, MA)

Assignee:  Collegium Pharmaceutical, Inc. (Cumberland, RI)

Appl. No.:  012202

Filed:  December 5, 2001

Abstract

Compositions comprising both a sedative and a non-sedative antihistamine are disclosed as well as methods of inhibiting the release of histamines by administration of the compositions to a mammalian subject.

Description of the Invention

FIELD OF THE INVENTION

The present invention relates to compositions comprising both a sedative and a non-sedative antihistamine. More particularly the invention relates to compositions containing the sedating antihistamine in immediate release form and the non-sedating antihistamine in delayed-release form or containing the non-sedating antihistamine in immediate release form and the sedating antihistamine in delayed-release form. The invention further relates to methods of inhibiting the release of histamines by administration of the compositions to a mammalian subject.

BACKGROUND OF THE INVENTION

Hypersensitivity is an immune response after exposure to an antigen. Hypersensitivity usually causes tissue damage. Typical hypersensitivity reactions are allergic rhinitis, allergic conjunctivitis, urticaria, pruritus, sinusitis, angioedema, and anaphylaxis. Antihistamines, normally classified as H₁ receptor antagonists, are used for the prophylaxis and relief of symptoms of hypersensitivity reactions.

The term "antihistamine" is generally applied to Histamine H₁ receptor antagonists. There are two types of antihistamines: the older antihistamines (first generation antihistamines), are associated with troublesome sedative and anti-muscarinic effects and are often called sedating antihistamines. These older antihistamines are distinguished from the newer (second generation) antihistamines which are designated as non-sedating antihistamines.

The older antihistamines are associated with a sedative effect. These antihistamines are often termed "first generation antihistamines" or "sedating antihistamines." The "second generation antihistamines" which are essentially devoid of the sedative effect, are usually termed "non-sedating antihistamines." Both groups of antihistamines are commonly used. Many sedating antihistamines are widely used and are available from the OTC market. Typical first generation antihistamines include brompheniramine, chlorpheniramine, dexbrompheniramine, dexchlorpheniramine, carbinoxamine, clemastine, diphenhydramine, pyrilamine, tripelennamine, tripolidine, methdilazine, bromodiphenhydramine, promethazine, azatadine, cyproheptadine, diphenylpyraline, doxylamine, trimeprazine, phenindamine, and hydroxyzine. Compounds of the second generation antihistamines are fexofenadine, loratadine, descarboethoxyloratadine, norastemizole, desmethylastemizole, cetirizine, acrivastine, ketotifen, temelastine, ebastine, epinastine, mizolastine, and setastine. Cetirizine, in spite of being a second generation antihistamine, has a low to moderate sedative effect.

The sedative effect of the sedating antihistamines can range from slight drowsiness to deep sleep. Daytime sedation can be a problem especially for those who drive or who operate machinery. In view of these problems with sedative antihistamines, non-sedative antihistamines have been developed. This group of compounds has little or no sedative effect and has replaced the first generation antihistamines especially for daytime use. The major disadvantage of the non-sedating antihistamines is the occurrence of drug interactions and hazardous ventricular arrhythmias which has led to the withdrawal of two non-sedating antihistamines from the market.

Although the non-sedating antihistamines have been used widely for daytime control of allergy, the sedative effect of sedating antihistamines may be preferred by patients who suffer from insomnia or by patients who need a good nighttime rest. It may be especially advantageous to administer a sedating antihistamine in combination with a decongestant such as phenylephrine since decongestants such as phenylephrine often stimulate nervousness and anxiety in a patient. Thus distinct advantages can be found for each of the "first generation antihistamines" and "second generation antihistamines."

There are a number of references which disclose the combination of an antihistamine with a decongestant. U.S. Pat. No. 5,314,697 to Kwan et al discloses compositions that contain the non-sedating antihistamine loratadine and the decongestant pseudoephedrine. Such compositions include the loratadine in a film coating for immediate release and pseudoephedrine in a core surrounded by the film coating so that the pseudoephedrine is released over an extended period. There is no mention in this reference of a composition that contains both a sedating antihistamine and a non-sedating antihistamine.

The most common side effects of the sedating antihistamine is CNS depression with effects varying from slight drowsiness to deep sleep. The sedating antihistamines can also cause dizziness and a lack of coordination. These sedative properties of the first generation antihistamines interfere with the normal functioning of patients suffering with allergic manifestations. These patients have to be alert and remain ambulatory throughout the day. Therefore the use of first generation antihistamines in spite of their unique and useful antihistaminic properties has been limited.

U.S. Pat. No. 6,114,346 to Harris et al discloses compositions containing the non-sedating antihistamine desloratadine and which may further contain a decongestant including phenylephrine, pseudoephedrine, and phenylpropanolamine. Such compositions are administered to patients afflicted with upper airway passage allergic inflammation to treat or prevent sleep disorder. Often the upper airway passage allergic inflammation is associated with allergic rhinitis. There is no mention or suggestion in this reference to prepare compositions containing both a sedating antihistamine and a non-sedating antihistamine or to use such a composition to inhibit the release of histamine all through the day and night.

U.S. Pat. No. 6,051,585 to Weinstein et al discloses compositions administered once a day in a single oral dosage containing a decongestant and an antihistamine including a non-sedating antihistamine such as loratadine or fexofenadine. There is no suggestion in this reference to prepare a composition that includes both a sedating antihistamine and a non-sedating antihistamine. Nor is there any suggestion to prepare a composition containing one of the sedating and non-sedating antihistamines in immediate release form and the other in delayed release form.

U.S. Pat. No. 6,086,914 to Weinstein et al discloses antihistamine compositions that contain a non-sedating antihistamine as well as a specific anticholinergic agent. Preferred examples of such a specific anticholinergic agent include belladona extracts such as atropine and scopolamine. The invention claimed in this patent is for "an essentially non-sedating oral formulation containing both an antihistamine limited in sedating and anticholinergic properties and a specific anticholinergic agent.

None of the anticholinergic agents disclosed in this reference in combination with a non-sedating antihistamine is itself a sedating antihistamine. These agents are not also sedating antihistamines. The compositions in the patent are disclosed as "essentially non-sedating." Such is not the case with the compositions according to the present invention which are sedating compositions at certain times following administration of the medication to the patient.

U.S. Pat. No. 5,648,358 to Mitra discloses antihistamine compositions that may contain a mixture of one or more sedating antihistamines including clemastine fumarate as well as an additional sedating antihistamine and a non-sedating antihistamine such as loratidine. The compositions also contain caffeine and including caffeine in the present compositions would be contrary to the purpose of the present invention where a sedating antihistamine is to be released at a certain time. In the reference there is no disclosure of the delayed release of either the sedating antihistamine or the non-sedating antihistamine according to the present invention.

U.S. Pat. No. 5,827,852 to Russell broadly discloses coated pharmaceutical compositions that may include mixtures of active ingredients including sedating and non-sedating antihistamines. Once again there is no disclosure of the delayed release of either the sedating antihistamine or the non-sedating antihistamine according to the present invention.

OBJECTS OF THE INVENTION

It is an object of the invention to provide a once daily oral dosage form which provides both sedating and non-sedating antihistamines for night and daytime histamine control.

It is a further object of the invention to provide a composition for night and daytime histamine control that is free from caffeine.

It is a further object of the invention to provide a composition that is administered to a patient once-a-day so as to improve the ease of administration and thus increase the rate of patient compliance.

It is a further object of the invention to provide a composition that may be designed to be administered once a day, either in the morning or in the evening.

SUMMARY OF THE INVENTION

A first feature of our invention relates to a biphasic antihistamine composition in daily oral uni-dosage or divided dosage form which comprises:

(a) a therapeutically effective amount of a sedating antihistamine to inhibit histamine release for a duration of about 4 to 12 hours, and

(b) a therapeutically effective amount of a non-sedating antihistamine to inhibit histamine release for a duration of 10 to 20 hours, with a delayed release 6 to 10 hours after ingestion.

Alternatively, a second feature of our invention relates to a biphasic antihistamine composition in daily oral uni-dosage or divided dosage form which comprises:

(a) a therapeutically effective amount of a non-sedating antihistamine to inhibit histamine release for a duration of about 10 to 20 hours; and

(b) a therapeutically effective amount of a sedating antihistamine to inhibit histamine release for a duration of 4 to 12 hours, with a delayed release, 8 to 12 hours after ingestion.

According to either of the features disclosed above, there is no utilization of caffeine as it would be contrary to our night-time delivery of the composition right before sleep. One of our approaches is to utilize the properties of sedating antihistamines by administering the same to both provide an antihistaminic effect and to maintain sleep during the night and to use non-sedating antihistamines during the day. When a composition is administered right before bedtime, we utilize the antihistamine properties of a sedating antihistarnine which is immediately released. Six to ten hours or six to eight hours later when the patient needs to be awake, we utilize non-sedating antihistamines which are then released to provide the beneficial effect of an antihistamine thereby permitting the patient to avoid sedation during the time period the patient wishes to remain alert to carry out the normal functions as necessary during the day.

Alternatively when a composition is administered during the day when the patient must remain alert, we utilize non-sedating antihistamines by administering a composition where the non-sedating antihistamines are immediately released and the sedating antihistamines are released several hours later when the patient is ready to sleep.

Thus in our invention we utilize the negative effect of sedation to the advantage of the patient in our administration right before sleep, which allows the patient to have a good night's sleep while at the same time maintains control of the histamine-associated allergic symptoms. Since most patients will want to sleep at night we call the composition where the sedating antihistamine is immediately released our P.M. Medication and the composition where the sedating antihistamine is released several hours after administration our A.M. Medication.

In our once-a-day delivery of the P.M. Medication the sedating antihistamine is released substantially immediately upon ingestion in the night over an extended period of 4 to 12 hours thereby controlling rhinitis and other such allergic symptoms and at the same time inducing drowsiness and sleep in patients so that they can enjoy a good night's sleep. Upon a patient's awakening in the morning or just before that, then the release of non-sedating antihistamines occurs in vivo. The antihistamine effect is still provided but there is no interference with normal function.

In our once-a-day delivery of the A.M. Medication, taken in the morning, we are delaying the release of the sedating antihistamine in vivo such that the sedative effect combined with the antihistaminic effect occurs in the evening whereas the non-sedating antihistamine component is released upon ingestion substantially immediately and is maintained during the day time allowing the patient to function during the day without sedation while having the benefit of the antihistamine. The sedating antihistamine component is released preferably 8 to 12 hours after ingestion, i.e. from 5 to 9 P.M. when the patient is at home and is planning to sleep.

Agents such as analgesics, anti-tussive agents, expectorants, anti-inflammatory agents, anti-pyretic agents, and decongestants can also be included. These agents allow control of symptoms which are common among patients who suffer from allergic rhinitis, common cold, flu, and various other allergic reactions. These agents may be in immediate release form or preferably are in sustained release form. The sustained release is achieved by formulating the particular agent with a sustained-release control polymer selected from the group consisting of methyl cellulose, ethyl cellulose, wax, gums, cellulose acetate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, acrylic acid polymers and copolymers, polymers or copolymers of methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, ethyl methacrylate, hydroxypropyl methyl cellulose acetate succinate, shellac, cellulose acetate trimellitate, vinyl acetate and combinations thereof.

Examples of the sedating antihistamines that may be employed according to our present invention are brompheniramine, chlorpheniramine, dexbrompheniramine, dexchlorpheniramine, carbinoxamine, doxylamine, clemastine, diphenhydramine, pyrilamine, tripelennamine, tripolidine, methdilazine, bromodiphenhydramine, promethazine, azatadine, cyproheptadine, doxylamine, trimeprazine, phenindamine, ketotifen, hydroxyzine, tazifylline, meclizine, acrivastine, setastine, oxatomide, mequitazine, levocabastine, lodoxamide, AHR 11325, phenindamine, azelastine, and ebastine or pharmaceutically acceptable salts thereof.

Examples of the non-sedating antihistamines that may be employed according to our present invention are fexofenadine, loratadine, descarboethoxy loratadine, astemizole, norastemizole, desmethylastemizole, cetirizine, acribastine, and temelastine, or pharmaceutically acceptable salts thereof.

Examples of the decongestants that may be employed include pseudoephedrine, phenylephrine, and pharmaceutically acceptable acid addition salts thereof including the hydrochloride, hydrobromide, bitartrate, and tannate.

Examples of the antitussives that may be employed include caramiphen (edisylate), dextromethorphan (Hbr), codeine (phosphate, sulfate), fominoben, hydromorphone, chlophedianol, carbetapentane, and noscapine.

Examples of expectorants that may be employed include terpin hydrate, guaifenesin (glycerol guaiacolate), bromohexene, potassium guaicolsulfonate, potassium iodide, potassium citrate, ammonium chloride, N-acetyl-cysteine, and ambroxol.

Examples of analgesics and anti-inflammatory agents include acetylsalicylic acid, choline salicylate, magnesium salicylate, diflunisal, acetaminophen, meclofenamate, mefenamic acid, etodolac, diclofenac potassium, ibuprofen, fenoprofen, ketoprofen, naproxen, naproxen sodium, piroxicam, benoxaprofen, flubiprofen, fenbufen, indoprofen, pirprofen, oxaprozin, carpsofen, suprofen, alminoprofen, and tiaprofen.

In the compositions which are the P.M. Medications the sedating antihistamine generally has a duration of activity of about 6 to 10 hours and the non-sedating antihistamine generally has a duration of activity of about 12 to 18 hours. In these compositions the sedating antihistamine is releasable immediately or up to 1 hour following administration. The non-sedating antihistamine is released the next day, 6 to 12 hours following administration.

In the compositions which are the A.M. Medications the sedating antihistamine generally has a duration of activity 6 to 10 hours and the non-sedating antihistamine generally has a duration of activity of about 10 to 20 hours, e.g. 12 to 18 hours. In these compositions the non-sedating antihistamine is releasable immediately or up to 1 hour following administration. The sedating antihistamine is releasable 6 to 12 or 8 to 12 hours following administration.

The rate of delayed release of the non-sedating antihistamine in the P.M. Medication and in the delayed release of the sedating antihistamine in the A.M. Medication is controlled by at least one delayed release control polymer selected from the group consisting of ethyl cellulose, cellulose acetate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, acrylic acid polymers and copolymers, polymers or copolymers of methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, ethyl methacrylate, hydroxypropyl methylcellulose acetate succinate, shellac, cellulose acetate trimellitate, vinyl acetate, azo polymers, pectin, chitosan, amylose, guar gum, and zein or combinations thereof.

The following examples represent preferred features according to the present invention. The present invention is not, however, limited in any way by or to the scope of the specific examples:

EXAMPLE 1

Formulation of Sedating/Nonsedating Antihistamine for Evening Administration

Sedative antihistamine: Dexbrompheniramine

Non-sedative antihistamine: Loratadine

(A) Preparation of loratadine tablets (core): Each dosage form contains the following ingredients:

1. Prepare a granulation including loratadine, lactose, starch 1500 and microcrystalline cellulose.

2. Lubricate the granulation with magnesium stearate.

3. Compress the granulation into tablets about 156.8 mg weight using a suitable tablet compression machine and tooling.

(B) Enteric Coating of Loratadine tablets (core):

1. Prepare an enteric coating solution including Eudragit S, triethyl citrate, glycerol monostearate and ammonia solution in purified water.

2. Coat loratadine tablets (from step (A)) with the enteric coating solution using a conventional coating pan or a fluidized-bed coating apparatus until a desired amount of coating is applied.

(C) Coating of loratadine enteric coated tablets with a film coat containing dexbrompheniramine maleate:

Formulation

1. Dissolve dexbrompheniramine maleate and maleic acid in purified water and disperse Opadry in the solution.

2. Coat loratadine enteric coated tablets from (B) with coating solution containing dexbrompheniramine maleate using a conventional coating pan or a fluid bed coating equipment until a desired amount of dexbrompheniramine maleate is applied.

Each finished tablet contains:

(1) 3 mg dexbrompheniramine maleate in the outer coating for immediate release.

(2) 7 mg loratadine which is enteric coated for a delayed release 4-8 hours after administration.

The film coat may be replaced with a sugar coat or compression coat which contains 3 mg dexbrompheniramine maleate.

Claim 1 of 29 Claims

What is claimed is:

1. A biphasic antihistamine composition in daily oral uni-dosage or divided dosage form which comprises:

(a) a therapeutically effective amount of a sedating antihistamine to inhibit histamine release for a duration of about 4 to 12 hours, and

(b) a therapeuticaily effective amount of non-sedating antihistamine to inhibit histamine release for a duration of 10 to 20 hours with a delayed release 6 to 10 hours after ingestion wherein the delayed release portion is achieved by coating a core or granulations with at least one delayed release control polymer.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.