Buccal, non-polar spray or capsule

Description of equivalent WO 9738663 A2

TITLE OF THE INVENTION BUCCAL, NON-POLAR SPRAY OR CAPSULE

BACKGROUND OF THE INVENTION It is known that certain biologically active compounds are better absorbed through the oral mucosa than through other routes of administration, such as through the stomach or intestine. However, formulations suitable for such administration by these latter routes present their own problems. For example, the biologically active compound must be compatible with the other components of the composition such as propellents, solvents, etc. Many such formulations have been proposed. For example, U.S. P. 4,689,233, Dvorsky et a]-, describes a soft gelatin capsule for the administration of the anti-coronary drug nifedipine dissolved in a mixture of polyether alcohols. U.S. P. 4,755,389, Jones et aj., describes a hard gelatin chewable capsule containing nifedipine. A chewable gelatin capsule containing a solution or dispersion of a drug is described in U.S. P. 4,935,243, Borkan et aj. U.S. P. 4,919,919, Aouda el ai, and U.S. P. 5,370,862, Klokkers-Bethke, describe a nitroglycerin spray for administration to the oral mucosa comprising nitroglycerin, ethanol, and other components. An orally administered pump spray is described by Cholcha in U.S. P. 5,186,925. Aerosol compositions containing a hydrocarbon propellant and a drug for administration to a mucosal surface are described in U.K. 2,082,457, Su, U.S. P. 3, 155,574, Silson ej al., U.S. P. 5,01 1 ,678, Wang gl al-, and by Parnell in U.S. P. 5, 128, 132. It should be noted that these references discuss bioavailability of solutions by inhalation rather than through the membranes to which they are administered.

SUMMARY OF THE INVENTION A buccal aerosol spray or soft bite gelatin capsule using a non-polar solvent has now been developed which provides biologically active com- pounds for rapid absorption through the oral mucosa, resulting in fast onset of effect.

The buccal aerosol spray compositions of the present invention, for transmucosal administration of a pharmacologically active compound soluble in a pharmacologically acceptable non-polar solvent comprising in weight % of total composition: pharmaceutically acceptable propellant 50-95%, non- polar solvent 5-50%, active compound 0.0025-40%, suitably additionally comprising, by weight of total composition a flavoring agent 0.05-5%. Preferably the composition comprises: propellant 55-85 %, non-polar solvent 15-45%, active compound 0.025-20%, flavoring agent 0.1 -2.5%; most suitably propellant 60-80%, non-polar solvent 19-32%, active compound 0.125-12.5%, flavoring agent 0.1-3.0%.

The soft bite gelatin capsules of the present invention for transmucosal administration of a pharmacologically active compound, at least partially soluble in a pharmacologically acceptable non-polar solvent, having charged thereto a fill composition comprising in weight % of total composition: non-polar solvent 30-99.8%, emulsifier 0-20%, active compound 0.0003-32%, provided that said fill composition contains less than 10% of water, suitably additionally comprising, by weight of the composition: flavoring agent 0.05-60%. Preferably, the soft bite gelatin capsule comprises: non-polar solvent 40-99.8%, emulsifier 0-15%, active compound 0.004-26%, flavoring agent 0.1-55%; most suitably: non-polar solvent 40-99.5%, emulsifier 0-10%, active compound 0.015-24.0%, flavoring agent 0.1 -50%.

It is an object of the invention to coat the mucosal membranes either with extremely fine droplets of spray containing the active compounds or a βoiϋtion or paste thereof from bite capsules. It is also an object of the invention to administer to a mammalian in need of same preferably man, a predetermined amount of a biologically active compound by this method or from a soft gelatin bite capsule.

A further object is a sealed aerosol spray container containing a composition of the spray formulation, and a metered valve suitable for releasing from said container a predetermined amount of said composition.

As the propellant evaporates after activation of the aerosol valve, a mist of fine droplets is formed which contains solvent and active compound .

The propellant is a non-Freon material, preferably a C₃.._θ hydrocarbon of a linear or branched configuration. The propellant should be substantially non-aqueous. The propellant produces a pressure in the aerosol container such that under expected normal usage it will produce sufficient pressure to expel the solvent from the container when the valve is activated but not excessive pressure such as to damage the container or valve seals.

The solvent is a non-polar hydrocarbon, preferably a C₇.₁₈ hydrocarbon of a linear or branched configuration, its alcohols, fatty acid esters, and triglycerides, such as miglyol. The solvent must dissolve the active compound and be miscible with the propellant, i.e., solvent and propellant must form a single phase at 0-40 ^*C at a pressure range of 1 -3 atm.

A further object is a soft gelatin bite capsule containing a composition of as set forth above. The formulation may be in the form of a viscous solution or paste containing the active compounds. Although solutions are preferred, paste fills may also be used where the active compound is not soluble or only partially soluble in the solvent of choice. Where water is -used to form part of the paste composition, it should not exceed 10% thereof. (All percentages herein are by weight unless otherwise indicated.) The non-polar solvent is chosen such that it is compatible with the gelatin shell and the active compound. The solvent preferably dissolves the active compound. However, other components wherein the active compound is not soluble or only slightly soluble may be used and will form a paste fill.

Soft gelatin capsules are well known in the art. See, for example, U.S. P. 4,935,243, Borkan et al., which is incorporated herein by reference for its teaching of such capsules. The capsules of the present invention are intended to be bitten into to release the low viscosity solution or paste therein, which will then coat the buccal mucosa with the active compounds. Typical capsules, which are swallowed whole or bitten and then swallowed, deliver the active compounds the stomach, which results in significant lag time before maximum blood levels can be achieved or subject the compound to a large first pass effect. Because of the enhanced absorption of the compounds through the oral mucosa and no chance of a first pass effect, use of the bite capsules of the invention will eliminate much of the lag time, resulting in hastened onset of biological effect. The shell of a soft gelatin capsule of the invention may comprise, for example: gelatine 50-75%, glycerine 20-30%, colorants 0.5-1 .5%, water 5-10%, and sorbitol 2-10%.

The spray compositions of the invention are intended to be administered from a sealed, pressurized container. Unlike a pump spray, which allows the entry of air into the container after every activation, the aerosol container of the invention is sealed at the time of manufacture. The contents of the container are released by activation of a metered valve, will does not allow entry of atmospheric gasses with each activation. Such containers are commercially available. BRIEF DESCRIPTION OF THE DRAWING The figure is a schematic diagram showing routes of absorption and processing of pharmacologically active substances in a mammalian system.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The preferred active compounds of the present invention are nicotine, clemastine, testosterone, estradiol, progesterone, flύoxetine, and piroxicam in their nonionized form or as the free base of the pharmaceutically acceptable salts thereof (provided, for the aerosol or spray compositions, they are soluble in the spray solvent), as well as, where appropriate the esters or triglycerides thereof. These compounds are soluble in the non-polar solvents of the invention at useful concentrations or can be prepared as pastes at useful concentrations. These concentrations may be less than the standard accepted dose for these compounds since there is enhanced absorption of the compounds through the oral mucosa. This aspect of the invention is especially important when there is a large (40-99.99%) First pass effect.

As propellants for the sprays, propane, N-butane, iso-butane, N-pentane, iso-pentane, and neo-pentane, and mixtures thereof may be used. N-butane and iso-butane, as single gases, are the preferred propellants. It is permissible for the propellant to have a water content of no more than 0.2%, typically 0.1-0.2%. (All percentages herein are by weight unless otherwise indicated.) It is also preferable that the propellant be synthetically produced to minimize the presence of contaminants which are harmful to the active compounds. These contaminants include oxidizing agents, reducing agents, Lewis acids or bases, and water. The concen¬ tration of each of these should be less than 0.1 %, except that water may be as high as 0.2%. Suitable solvents for the capsules include the spray solvents listed above, as well as [C₂-C₂₄] fatty acid C₂-C_β esters, including the triglycerides. Similarly, water is not a suitable solvent component in the spray compositions. When the capsule fill is a paste, other liquid components may be used instead of the above low molecular weight solvents. These include soya oil, corn oil, other vegetable oils, and C₇.₁₈ hydrocarbons of a linear or branched configuration, and their alcohols and their fatty acid esters and triglycerides.

It is expected that some glycerin and water used to make the gelatin shell will migrate from the shell to the fill during the curing of the shell. Likewise, there may be some migration of components from the fill to the shell during curing and even throughout the shelf-life of the capsule. Therefore, the values given herein are for the compositions as prepared, it being within the scope of the invention that minor variations will occur.

The preferred flavoring agents are synthetic or natural oil of pepper¬ mint, oil of spearmint, citrus oil, fruit flavors, sweeteners (sugars, aspartame, saccharin, etc.), and combinations thereof.

The active substances include the active compounds selected from the group consisting of alkaloids, anti histamines, steroid hormones, non- steroidal anti-inflammatories, analgesics and anti-depressants, benzo- diazepines, such as tamezepam.

Clemastine hydrogen fumarate is a known (Tavist^®, Sandoz) anti- histamine. Both the spray and capsule of the invention advantageously coat the oral mucosa with an immediately available dose of clemastine which can be rapidly absorbed. This is highly desirable, as during an acute asthma attack. Nicotine is a component of tobacco products which is considered addictive. Smokers wishing to stop smoking have a dual problem. First, is the addictive properties of nicotine itself. Second, is that the habit is associated with smoking activities, i.e., puffing, inhaling, etc. Both the spray and capsule of the invention dissociate these two problems. By presenting nicotine in a form which can be readily absorbed, the spray and capsule allow the smoker to temporarily continue nicotine use but terminate smoking. Once the habit of smoking is stopped, the former smoker can then be weaned off nicotine use, as by less frequent use and/or by use of a lower concentration spray or capsule. Advantageously, during this regimen, the user is exposed to none of the carcinogens present in tobacco smoke.

Testosterone is a hormone produced by gonadal cells. Testosterone, especially the esters thereof (e.g., acetate, propionate, enanthate, and cypionate), is used in the treatment of hypogonadism.

Estradiol is an estrogen steroid secreted from the ovaries. Estradiol, especially the esters thereof (e.g., diacetate, and benzoate), is used as estrogen replacement therapy, especially in post-menopausal women.

Progesterone is a hormone produced by the corpus luteum. Fluo- xetine is an antidepressant also known as Prozac. Piroxicam is a known (Feldene^®, Pfizer) anti-inflammatory.

The formulations of the present invention comprise an active compound or a pharmaceutically acceptable salt thereof. The term

"pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including organic and inorganic acids or bases. When an active compound of the present invention is acidic, salts may be prepared from pharmaceutically acceptable non-toxic bases. Salts derived from all stable forms of inorganic bases include aluminum, ammonium, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, zinc, etc. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion- exchange resins such as arginine, betaine, caffeine, choline, N,N'- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethyl¬ aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethγl- piperidine, glucamine, glucosamine, histidine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, etc.

When an active compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethane- sulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, mandelic, methanesulfonic, mucic, nitric, pamoic, panto- thenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, etc. Particularly preferred are citric, hydrobromic, maleic, phosphoric, sulfuric, and tartaric acids.

In the discussion of methods of treatment herein, reference to the active compounds is meant to also include the pharmaceutically acceptable salts thereof. While certain formulations are set forth herein, the actual amounts to be administered to the mammal or man in need of same are to be determined by the treating physician. The invention is further defined by reference to the following examples, which are intended to be illustrative and not limiting.

EXAMPLE 1 Clemastine Spray

A spray of the invention comprises the following formulation:

Amount Preferred Amount Most-Preferred Amount Propellant 50-95% 55-85% 65-80%

Non-polar solvent 5-50% 15-45% 20-35% Clemastine Base 0.12-10% 0.25-6.25% 0.25-5%

Flavoring agent 0.05-3% 0.1 -2.5% 0.2-2%

It is particularly preferred to formulate the spray delivering 1 .Omg/ activation formulation: Amount

Butane 67%

Miglyol 29.5%

Clemastine Base 3.1 %

Peppermint 0.4% For delivery of 0.5mg active substance, Clemastine Base 1.6%

EXAMPLE 2 Nicotine Spray

A spray of the invention comprises the following formulation: Amount Preferred Amount Most-Preferred Amount

Propellant 50-95% 55-85% 65-80%

Non-polar solvent 5-50% 15-45% 20-35%

Nicotine 0.125-2.5% 0.25-1.75% 0.25-1.25%

Flavoring agent 0.05-3% 0.1-2.5% 0.1 -2.5% It is particularly preferred to formulate the spray delivering 0.5mg/ activation:

Amount Butane 67% Miglyol 31.25%

Nicotine 1.5% for 0.5mg.

Peppermint 0.25%

For delivery of 0.4mg active substance, Nicotine 1.25%.

EXAMPLE 3

Testosterone Spray

A spray of the invention comprises the following formulation:

Amount Preferred Amount Most-Preferred Amount Propellant 50-95% 55-85% 65-80% Non-polar solvent 5-50% 15-45% 20-35%

Testosterone* 0.125-25% 2.5-20% 5-12.5%

Flavoring agent 0.05-3% 0.1 -2.5% 0.1 -2.5%

*or esters thereof, preferably, the acetate, propionate, and enenthate esters

It is particularly preferred to formulate the spray delivering 4mg/ activation:

Amount

Butane 67%

Miglyol 20.25% Testosterone 12.5%

Peppermint 0.25% O 97/38663 PC17US97/02795

1 1

EXAMPLE 4 Estradiol Spray

A spray of the invention comprises the following formulation:

Amount Preferred Amount Most-Preferred Amount Propellant 50-75% 55-85% 75-99%

Non-polar solvent 25-50% 15-45% 20-35%

Estradiol* 0.0025-2.5% 0.025-1.5% 0.125-1.0%

Flavoring agent 0.05-3% 0.1 -2.5% 0.1 -2.5%

*or esters thereof, preferably, the diacetate and benzoate esters

It is particularly preferred to formulate the spray: Amount Butane 67%

Miglyol 32.4% Estradiol 0.31 %

Peppermint 0.25%

EXAMPLE 5 Progesterone Spray A spray of the invention comprises the following formulation:

Amount Preferred Amount Most-Preferred Amount Propellant 50-75% 55-85% 65-80%

Non-polar solvent 25-50% 15-45% 20-35%

Progesterone 0.0025-2.5% 0.025-2.0% 0.125-0.5% Flavoring agent 0.05-3% 0.1 -2.5% 0.1 -2.5% It is particularly preferred to formulate the spray delivering 0.32mg/ activation:

Amount Butane 67% Miglyol 31.2%

Progesterone 1.0%

Spearmint 0.5%

EXAMPLE 6 Clemastine Bite Capsule

A paste containing bite capsule of the invention comprises the following fill formulation:

Amount Preferred Amount Most-Preferred Amount Non-polar solvent 75-99% 90-98% 85-99.5% Emulsifier 0-20% 0-15% 0-10%

Clemastine fumarate" 0.0003-1.85% 0.003-0.74% 0.018-0.185%

Flavoring agent 0.05-5% 0.1 -2.5% 0.1-2.5%

'as paste

It is particularly preferred to formulate the fill for the 1.34mg capsule: Amount

Soya Oil 91.4%

Lecithin 5.88%

Clemastine fumarate 0.50% for 1.34mg. Orange Aroma 1 .04% Citron Oil 0.81 %

Na-Saccharine 0.37%

For delivery of 0.68m active substance, Clemastine fumarate 0.25%. EXAMPLE 7 Testosterone Bite Capsule

A bite capsule of the invention comprises the following fill formulation:

Amount Pr eferred Amount Mc ist-Preferred Amount

Non-polar solvent 55-99% 66-97% 85-99.5%

Emulsifier/wetting 0-20% 0-15% 0-10% agents

Testosterone* 0.01-3.7% 0.37-2.96% 0.7-1.85%

Flavoring agent 0.05-5% 0.1-2.5% 0.1-2.5%

*or esters thereof, preferably, the acetate, propionate, and enenthate esters

It is particularly preferred to formulate the fill for 5mg capsule: Amount Miglyol 90.1 %

Lecithin 5.88%

Testosterone 1 .8%

Orange Aroma 1.04% Citron Oil 0.81 % Na-Saccharine 0.37%

EXAMPLE 8 Estradiol Bite Capsule

A bite capsule of the invention comprises the following fill formulation:

Amount Preferred Amount Most-Preferred Amount

Non-polar solvent 65-99% 85-98% 85-99.5%

Emulsifier/wetting 0-20% 0-15% 0-10% agents

Estradiol* 0.0003-1.85% 0.003-0.74% 0.018-0.185%

Flavoring agent 0.05-5% 0.1-2.5% 0.1 -2.5% *or esters thereof, preferably, the diacetate and benzoate esters

It is particularly preferred to formulate the fill for 0.5mg capsule: Amount Miglyol 91 .71 %

Lecithin 5.88%

Estradiol 0.18 for 0.5mg capsules

Orange Aroma 1.04% Citron Oil 0.81 % Na Saccharine 0.37%

EXAMPLE 9 Progesterone Bite Capsule

A bite capsule of the invention comprises the following fill formulation:

Amount Preferred Amount Most-Preferred Amount Non-polar solvent 55-99% 75-98% 85-99.5%

Emulsifier/wetting 0-20% 0-15% 0-10% agents Progesterone 0.0003-3.7% 0.0003-2.7% 0.74-1 .85%

Flavoring agent 0.05-5% 0.1-2.5% 0.1 -2.5%

It is particularly preferred to formulate the fill for a 3mg capsule: Amount Miglyol 91.83%

Lecithin 5.88%

Progesterone 1.1 1 %

Oil of Citron 0.81 %

Na-Saccharine 0.37% EXAMPLE 10 Fluoxetine Bite Capsule

A bite capsule of the invention comprises the following fill formulation: Amount Preferred Amount Most-Preferred Amount

Non-polar solvent 75-99.8% 75-99.8% 85-99.5%

Emulsifier/wetting 0-20% 0-15% 0-10% agents Fluoxetine* HCI* * 0.018-9.25% 0.37-3.7% 0.74-3.7%* * Flavoring agent 0.05-5% 0.1-3% 0.5-2.5%

*lf used as the free base, it will be a solution, at least in part * * As a paste.

It is particularly preferred to formulate the fill for a 5mg capsule:

Amount

Soya Oil 91.07%

Lecithin 5.88%

Fluoxetine HCI 1.85%

Peppermint 1.2%

EXAMPLE 1 1 Piroxicam Bite Capsule

A bite capsule of the invention comprises the following fill formulation: Amount Preferred Amount Most-Preferred Amount

Non-polar solvent 75-99.8% 75-99.8% 85-99.5%

Emulsifier/wetting 0-20% 0-15% 0-10% agents Piroxicam 0.018-9.25% 0.37-3.7% 0.74-3.7% Flavoring agent 0.05-5% 0.1-3% 0.5-2.5% It is particularly preferred to formulate the fill for a 5mg capsule: Amount Soya Oil 91 .07%

Lecithin 5.88% Piroxicam 1 .85%

Oil of Citron 0.81 %

Na Saccharine 0.37%

EXAMPLE 12 Nicotine 0.5mg Bite Capsule

A bite capsule of the invention comprises the following fill formulation:

Amount Preferred Amount Most-Preferred Amount Non-polar solvent 30-99.8% 35-99.8% 40-99.5% Emulsifier/wetting 0-20% 0-15% 0-10% agents Nicotine^" 0.018-0.74% 0.037-0.37% 0.37-0.20%

Flavoring agent 0.05-60% 0.1 -55% 0.5-50%

^" or as nicotine sulfate It is particularly preferred to formulate the fill for a 0.5mg capsule:

Amount Soya Oil 46.67%

Chocolate powder 46.67% Lecithin 6.105% Peppermint Oil 0.185% Na Saccharine 0.185% Nicotine 0.185% EXAMPLE 13

Clemastine Fumarate with Phenylpropanolamine Hydrochloride Bite Capsule

A bite capsule of the invention comprises the following fill formulation: Amount Preferred Amount Most-Preferred Amount

Non-Polar solvent 65-99% 50-98% 70-98%

Clemastine fumarate* 0-01 -1 .85% 0.03-0.74% 0.018-0.185%

Phenylpropanolamine

HCI* 1 -30% 1.5-20% 1 .8-10%

Flavoring agent 0.05-5% 0.1 -2.5% 0.1 -2.5%

Emulsifier/Wetting

Agent 0-20% 0-15% 0-10% *Present as paste.

It is particularly preferred to formulate the composition fill for a clemastine fumarate 1.34mg/25mg phenylpropanolamine hydrochloride bite capsule:

Amount Non-Polar Solvent: Soya 82.20%

Lecithin 5.88% Clemastine fumarate 0.50% Phenylpropanolamine HCI 9.20% Orange aroma 1 .04%

Oil of Citrus 0.81 %

Na Saccharine 0.37%

EXAMPLE 14 Clemastine Fumarate/Pseudoephedrine Hydrochloride Bite Capsule

A bite capsule of the invention comprises the following fill formulation: Amount Preferred Amount Most-Preferred Amount

Non-Polar solvent 50-95% 55-90% 60-85%

Emulsifier/wetting agent 0-20% 0-15% 0-10%

Clemastine fumarate* 0.01-1.85% 0.03-0.74% 0.05-0.185%

Pseudoephedrine HCI* 3-30% 5-25% 10-23%

Flavoring agent 0.05-5% 0.1-2.5% 0.1-2.5% * Present as paste.

It is particularly preferred to formulate the composition fill for a 1.34mg clemastine fumarate/60mg pseudoephedrine HCI capsule:

Amount

Non-Polar Solvent:

Soya 69.18%

Lecithin 5.88%

Clemastine fumarate 0.50%

Phenylpropanolamine HCI 22.22%

Orange aroma 1.04%

Oil of Citrus 0.81 %

Na Saccharine 0.37%