Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
  • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Definitions

• the present invention relates to stable liquid and solid pharmaceutical compositions containing loratadine and a nasal decongestant and optionally containing an expectorant and their use in the treatment of allergic and inflammatory conditions with cough and/or nasal congestion.
• Loratadine is a long-acting, non-sedating antihistamine with selective peripheral histamines H1 reception approved for treatment of the symptoms of allergic reaction, for example, for the relief of nasal and non-nasal symptoms associated with seasonal allergic rhinitis or for treatment of chronic idopathic urticaria in human patients.
• Nasal decongestants such as phenylpropanolamine, pseudoephedrine and their pharmaceutically acceptable salt such as the hydrogen chloride or hydrogen sulfate acid addition salts are useful for treating symptoms associated with allergic conditions such as seasonal allergic rhinitis or perennial allergic rhinitis as well as symptoms associated with the common cold including nasal congestion.
• Mucolytic expectorants have been known in the art for some time. See
• Syrup formulations are commonly used for delivery of drugs particularly where the drugs are to be delivered to pediatric patients.
• Loratadine syrup formulations have been found to be chemically and physically unstable and to have a proliferation of microbial agents such as molds, yeasts and bacteria.
• liquid and solid pharmaceutical compositions containing loratadine and a nasal decongestant and optionally containing an expectorant which are chemically and physically stable and resistant to microbial contamination. It would also be desirable to provide liquid pharmaceutical compositions which contain loratadine and a nasal decongestant and optionally contain an expectorant which are free of sugar, for example, glucose or sucrose, and ethanol and thus suitable for pediatric use.
• the present invention provides liquid pharmaceutical composition which are chemically and physically stable and protected from microbial contamination after storage at room temperature for up to 36 months.
• the liquid pharmaceutical compositions of the present invention are suitable for pediatric use.
• the present invention provides a stable pharmaceutical composition
• a stable pharmaceutical composition comprising an effective amount of loratadine or a pharmaceutically acceptable salt thereof and an effective amount of nasal decongestant or a pharmaceutically acceptable salt thereof and optionally an effective amount of an expectorant or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.
• the present invention provides a stable liquid pharmaceutical composition comprising an effective amount of loratadine or a pharmaceutically acceptable salt thereof and an effective amount of nasal decongestant or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable liquid carrier.
• the present invention provides the present invention also provides a stable liquid pharmaceutical composition comprising an effective amount of loratadine or a pharmaceutically acceptable salt thereof and an effective amount of pseudoephedrine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable liquid carrier.
• the present invention provides a stable liquid pharmaceutical composition
• a stable liquid pharmaceutical composition comprising an effective amount of loratadine or a pharmaceutically acceptable salt thereof an effective amount of pseudoephedrine or phenylpropanolamine or a pharmaceutically acceptable salt thereof, at least one pharmaceutically acceptable liquid carrier, and a combination of (1 ) a sweetener, (2) at least one pharmaceutically acceptable solvent, and (3) an amount of a buffer system to sufficient maintain the pH in the range of about 3.0 to about 5.0.
• the present invention provides a stable liquid pharmaceutical composition comprising:
• the present invention provides a stable liquid pharmaceutical composition comprising:
• Sorbitol 70% Solution 225.00 Sodium Saccharin 0.40 Peach Flavor No. 609 2.50 Citric Acid, Anhydrous 0.64 Sodium Citrate 0.02 Purified Water q-s ⁇
• the stable liquid pharmaceutical compositions of the present invention such as the above-listed liquid pharmaceutical composition are useful for relief of the symptoms associated with upper airway passage congestion associated with disorders such as seasonal and perennial allergic rhinitis and for relief of the symptoms associated with upper respiratory infections such as the common cold, including nasal congestion.
• the present invention provides a stable pharmaceutical composition comprising an effective amount of loratadine or a pharmaceutically acceptable salt thereof and an effective amount of nasal decongestant or a pharmaceutically acceptable salt thereof and an effective amount of an expectorant or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.
• the present invention provides a stable oral tablet pharmaceutical composition comprising:
• the present invention provides a stable oral liquid pharmaceutical composition comprising:
• the preferred flavor is Peach Flavor No. 609, but other pharmaceutically acceptable flavors may also be used.
• the above-listed oral solution is suitable for twice-a-day administration.
• the present invention provides a stable oral tablet pharmaceutical composition comprising: Name of Inqredients Concentration Rationale % Variation
• the present invention provides a stable oral liquid pharmaceutical composition comprising: 6
• the preferred flavor is Peach Flavor No. 609, but other pharmaceutically acceptable flavors may also be used.
• the present invention provides a novel three-way combination of a slow release non-sedating antihistamine such as loratadine, and an expectorant and mucolytic agent such as ambroxol, and a nasal decongestant such as pseudoephedrine in a new liquid and tablet pharmaceutical preparations. These novel three-way combinations are indicated primarily for the symptomatic relief of allergic respiratory conditions associated with non-productive cough, nasal congestion and in the presence of mucus in the respiratory tract.
• compositions of the present invention are also indicated in the treatment of those patients who show broncho-pulmonary conditions of allergic origin or other ethiology associated with cough, where viscosity and mucous adherence are increased, obstructing permeability of the airways.
• the principal indications include but are not limited to allergic rhinitis associated with cough and nasal congestion as well as acute, chronic, spasmodic and asthmatic bronchitis; bronchial asthma; bronchiectasis; sinusitis; otitis media; pneumonia; broncho-pneumonia; atelectasis by mucous obstruction; tracheotomy and as a pre and post prophylactic agent, especially in elderly patints where an allergic condition is suspected.
• the present invention provides the use of loratadine and a nasal decongestant for the preparation of a liquid pharmaceutical composition for treatment of the symptoms associated with allergic reactions in a human.
• the present invention provides the use of loratadine and a nasal decongestant for the preparation of a liquid pharmaceutical composition for treatment of the symptoms associated with allergic rhinitis and the common cold in a human.
• the present invention provides the use of loratadine and a decongestant for the preparation of a liquid pharmaceutical composition for treatment of the symptoms associated with allergic rhinitis and the common cold including nasal congestion, sneezing, rhinorrhea, pruritus and lacrimation in a human.
• the present invention provides the use of a non-sedating antihistamine in combination with an an expectorant and a nasal decongestant for the preparation of a medicament for the treatment of allergic and inflammatory respiratory conditions with cough, nasal congestion and the presence of mucus in the respiratory tract which comprises an effective amount of a non-sedating antihistamine in combination with an effective amount of an expectorant, and an effective amount of an nasal decongestant.
• the nasal decongestant is preferably pseudoephedrine or a pharmaceutically acceptable salt thereof.
• the two- and three-way liquid pharmaceutical composition of the present invention are stable to microbial contamination for periods of at least 4 months, preferably up to 36 months storage at room temperature (25°C).
• the two- and three-way liquid pharmaceutical composition of the present invention are stable to physical and chemical degradation of the active ingredients for periods of at least 4 months, preferably up to 36 months storage at room temperature (25°C).
• the two- and three-way liquid pharmaceutical composition of the present invention are stable to microbial contamination and to physical and chemical degradation of the active ingredients for periods of at least 4 months, preferably up to 36 months storage at room temperature (25°C).
• liquid pharmaceutical compositions of the present invention are substantially free of sugar, for example, glucose or sucrose, and of ethanol and thus are suitable for pediatric use.
• liquid pharmaceutical compositions containing loratadine and a nasal decongestant, preferably pseudoephedrine, more preferably pseudoephedrine sulfate, as the active ingredients which are stable to microbial contamination, including but not limited to bacterial contamination, and to physical and chemical degradation of the active ingredients for periods of at least 4 months, preferably up to 36 months storage at room temperature (25°C).
• the preferred liquid pharmaceutical composition of Example 1 maintained a stable pH in the range of 3.3 to 4.3 and had no more than about 3% by weight change in the original amounts of loratadine and pseudoephedrine sulfate after storage at room temperature for at least 4 months and up to 36 months.
• nasal decongestants useful in the present invention include the nasal decongestant pseudoephedrine and phenylpropanolamine and phaemaceutically acceptable salt thereof, especially the hydrogen chloride and hydrogen sulfate acid addition salts.
• suitable sweeteners include sugar, e.g. glucose, as well as artificial sweeteners such as saccharin, e.g. sodium saccharin, sorbitol, aspartame, sodium cyclamate and mixtures thereof.
• saccharin e.g. sodium saccharin, sorbitol, aspartame, sodium cyclamate and mixtures thereof.
• a combination of two artifical sweeteners is used; more preferably a combination of sodium saccharin and sorbitol is used.
• the sorbitol is normally a 70 weight % aqueous solution of sorbitol in purified water.
• the liquid pharmaceutical compositions of the present invention are substantially free of sugar, for example, glucose or sucrose, and ethanol and thus are suitable for pediatric use
• substantially free of sugar and ethanol means that the liquid pharmaceutical compositions of the present invention contain less than 1 %, more preferably less than 0.5%, and most preferably contain less than 0.1 % by weight, of sugar, for example, glucose or sucrose, and of ethanol and thus are suitable for pediatric use.
• suitable flavoring agents include those flavoring agents approved for use in sweetened pharmaceuticals, foods, candies, and beverages. These flavoring agents impart flavors such as grape, cherry, citrus, peach, strawberry, bubble gum, peppermint and many others.
• suitable pharmaceutically acceptable solvents include alcohols and glycols, especially propylene glycol, ethanol and glycerin.
• suitable pharmaceutically acceptable solvents include alcohols and glycols, especially propylene glycol, ethanol and glycerin.
• the liquid pharmaceutical compositions indicated for pediatric use should be substantially free of, and most preferably should not contain ethanol. Use of a combination of propylene glycol and glycerin is preferred.
• suitable buffer systems include those capable of maintaining a pH in the range of 2.5 to 5.0, preferably about 2.9 to 4.3, more preferably 3.3 - 4.3.
• Preferred buffer systems include citric acid / sodium citrate;and acetic acid/sodium acetate. Use of sodium citrate/citric acid as the buffer system is preferred.
• the pharmaceutically acceptable liquid carrier is purified water. While we do not wish to be bound by any therapy, we believe that the unique combination of glycerin, propylene glycol, sorbitol and a sodium citrate/citric acid buffer system provide chemical and physical stability for the liquid pharmaceutical compositions of the present invention and provides the liquid pharmaceutical compositions of the present invention with effective antimicrobial protection from microbial contamination for periods of at least 4 months and up to 36 months when they are stored at room temperature. (See Table I) This particularly surprising and unexpected result is achieved without use of standard preservative such as sodium benzoate.
• the present invention provides novel pharmaceutical formulations, which contain a combination of a non-sedating antihistamine and an expectorant or contain a combination of a non-sedating antihistamine, an expectorant, and a nasal decongestant.
• the formulations of the invention are useful in the prevention and/or treatment of allergic and inflammatory conditions of the skin or airway passages with cough.
• the formulations are useful for a wide range of patient ages; specific embodiments provided herein include a tablet form for administration to humans 12 years and older, and a pediatric solution for humans aged 6-12 years.
• Also provided by the invention are methods for treating and/or preventing allergic and inflammatory conditions with related cough in humans in need of such treating and/or preventing which comprise administering an effective amount of a non-sedating antihistamine in combination with an expectorant.
• allergic and inflammatory conditions of the skin or airway passages means those allergic and inflammatory conditions and symptoms found on the skin and in the upper and lower airway passages from the nose to the lungs.
• Typical allergic and inflammatory conditions of the skin or upper and lower airway passages include seasonal and perennial allergic rhinitis, allergic rhinitis associated with cough; non-allergic rhinitis, asthma including allergic and non- allergic asthma, sinusitis, colds, bronchopulmonary conditions of allergic origin associated with cough, where viscosity and mucous adherence are increased, obstructing permeability of the airways acute, chronic, spasmodic and asthmatic bronchitis, bronchial asthma, bronchiectasis, sinusitis, otitis media, pneumonia; bronchopneumonia, atelectasis by mucous obstruction, and dermatitis, especially allergic and atopic dermatitis, and urticaria and symptomatic dermographism as well as
• a human age 6-12 years as used herein means a male or female pediatric subject of 6 years of age to 12 years of age.
• preferred embodiments of the present invention comprise treatment with loratadine and Ambroxol (See Examples 1 and 2), other antihistamines and expectorants are equally applicable in the compositions and methods taught herein. Following are non-inclusive lists of representative antihistamines and expectorants which may be used in the present invention.
• Loratadine is a non-sedating antihistamine whose technical name is 11 -(4- piperidylidene)-5H-benzo-[5, 6]-cyclohepta-[1 , 2-b]-pyridine. The compound is described in U.S. Patent No. 4,282,233. Loratadine is a potent tricyclic and antihistaminic drug with a selective antagonist of peripheric Hi receptors activity.
• the amount of loratadine which can be employed in a unit (i.e., single) dosage form of the present compositions can range from about 1.0 mg to about 15.0 mg, also from about - 2.5 mg to about 10.0 mg, preferably from about 5.0 mg. to about 10.0 mg.
• Desloratadine is a non-sedating long acting histamine antagonist with potent selective peripheral H1 -receptor antagonist activity. Following oral administration, loratadine is rapidly metabolized to descarboethoxyloratadine or desloratadine, a pharmacologically active metabolite.
• U.S. Patent Nos. 4,659,716, 5,595,997 and 4,804,666 disclose methods of making desloratadine, pharmaceutical compositions containing it and methods for using it to treat various disease states in mammals.
• the amount of desloratadine which can be employed in a unit (i.e., single) dosage form of the present compositions can range from about 0.75 mg to about 7.5 mg, also from about 1.25 mg to about 5.0 mg, preferably from about 2.5 mg. to about 5.0 mg.
• Descarboethoxyloratadine (DCL) is non-sedating antihistamine, whose technical name is 8-chIoro-6,11-dihydro-11-(4-piperidylidene)-5H- benzo[5,6] cyclohepta[1 ,2]pyridine. This compound is described in Quercia, et al., Hosp. Formul., 28: 137-53 (1993), in U.S.
• DCL is an antagonist of the H-1 histamine receptor protein.
• the H-1 receptors are those that mediate the response antagonized by conventional antihistamines.
• H-1 receptors are present, for example, in the ileum, the skin, and the bronchial smooth muscle of man and other mammals.
• the amount of DCL which can be employed in a unit (i.e. single) dosage form of the present compositions can range from about 2.5 to about 20 mg, also from about 5 to about 10 mg, preferably about 5 or 7.5 mg.
• Fexofenadine (MDL 16.455A) is a non-sedating antihistamine, whose technical name is 4-[1-hydroxy-4-(4-hydroxy-diphenylmethyl)-1-piperidinyl)butyl]- ⁇ , -dimethyl-benzene acetic acid.
• the pharmaceutically acceptable salt is the hydrochloride, also known as fexofenadine hydrochloride.
• the amount of fexofenadine which can be employed in a unit dosage form of the present composition can range from about 40 to 200 mg, also from about 60 to about 180 milligrams, also about 120 milligrams.
• Ambroxol is a bromhexine metabolite, chemically identified as trans-4(2-amino-
• 3,5-dibromobenzil, amine) ciclohexane hydrochloride which has been widely used during more than two decades as an expectorant agent or stimulating pulmonary surfactant factor.
• the compound is described in U.S. Patent No. 3,536,712.
• the amount of ambroxol which can be employed in a unit dosage form can range from about 30.0 to about 60.0 mg, preferably about 60.0 mg.
• Guaiafenesin is an expectorant, whose technical name is 3-(2- methoxyphenoxy)- 1 , 2-propanediol.
• the compound is described in U.S. Patent No. 4,390,732.
• the amount of guaiafenesin which can be employed in a unit dosage form can range from about 300.0 to about 1200.0 mg, preferably about 1200.0 mg.
• Terpin hydrate is an expectorant, whose technical name is 4-hydroxy- ⁇ , ⁇ , 4- trimethylcyclohexane-methanol.
• the amount of terpin hydrate that employed in a unit dosage form of the present composition can range from 85.0 to 680.0 milligrams.
• inert, pharmaceutically acceptable diluents, excipients and carriers can be either solid or liquid.
• Solid form preparations include powders, tablets, dispersible granules, capsules (either solid-filled, semi-solid filled or liquid-filled), sachets and suppositories.
• the powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
• Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, sachets and capsules can be used as sold dosage forms suitable for oral administration.
• Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes.
• lubricants include starch, methylcellulose, guar gum and the like. Sweetening and flavoring agents and preservatives may also be included where appropriate.
• compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimize the therapeutic effects.
• Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
• Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and pacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
• Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
• a pharmaceutically acceptable carrier such as an inert compressed gas, e.g. nitrogen.
• solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
• liquid forms include solutions, suspensions and emulsions.
• the compounds of the invention may also be deliverable transdermally.
• the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
• the compound is administered orally.
• the pharmaceutical preparation is in a unit dosage form.
• the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
• the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.01 mg to about 1000 mg preferably from about 0.01 mg to about 750 mg more preferably from about 0.01 mg to about 750 mg and most preferably from about 0.01 mg to about 250 mg according to the particular application.
• the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated.
• the total daily dosage may be divided and administered in portions during the day as required.
• a typical recommended daily dosage regimen for oral administration can range from about 5.0 to 10.0 mg/day of loratadine and 30 to 60.0 mg/day of ambroxol, in two to four divided doses.
• Dosage form - non-sedating antihistamine and expectorant formulated into a delivery system i.e., tablet, capsule, oral gel, powder for constitution or suspension in association with inactive ingredients.
• Capsule - refers to a special container or enclosure made of methyl cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising non-sedating antihistamine and an expectorant.
• Hard shell capsules are typically made of blends of relatively high gel strength bone and pork skin gelatins. The capsule itself may contain small amounts of dyes, opaquing agents, plasticizers and preservatives.
• Tablet- refers to a compressed or molded solid dosage form containing the active ingredients with suitable diluents.
• the tablet can be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation or by compaction.
• Oral gels - refers to a non-sedating antihistamine and an expectorant dispersed or solubilized in a hydrophilic semi-solid matrix.
• Powders for constitution - refers to powder blends containing the active ingredients and suitable diluents which can be suspended in water or juices.
• Diluent - refers to substances that usually make up the major portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corn rice and potato; and celluloses such as microcrystalline cellulose.
• the amount of diluent in the composition can range from about 10 to about 90% by weight of the total composition, preferably from about 25 to about 75%, more preferably from about 30 to about 60% by weight, even more preferably from about 12 to about 60%.
• Disintegrants - refers to materials added to the composition to help it break apart (disintegrate) and release the medicaments.
• Suitable disintegrants include starches; "cold water soluble” modified starches such as sodium carboxymethyl starch; natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose; microcrystalline celluloses and cross-linked microcrystalline celluloses such as sodium croscarmellose; alginates such as alginic acid and sodium alginate; clays such as bentonites; and effervescent mixtures, cross-linked povidones.
• the amount of disintegrant in the composition can range from about 2 to about 15% by weight of the composition, more preferably from about 4 to about 10% by weight.
• Binders - refers to substances that bind or "glue” powders together and make them cohesive by forming granules, thus serving as the "adhesive" in the formulation. Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include sugars such as sucrose; starches derived from wheat, corn rice and potato; natural gums such as acacia, gelatin and tragacanth; derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate; cellulosic materials such as methylcellulose and sodium carboxymethylcellulose and hydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics such as magnesium aluminum silicate.
• the amount of binder in the composition can range from about 2 to about 20% by weight of the composition, more preferably from about 3 to about 10% by weight, even more preferably from about 3 to about 6% by weight.
• Lubricant - refers to a substance added to the dosage form to enable the tablet, granules, etc. after it has been compressed, to release from the mold or die by reducing friction or wear.
• Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high melting point waxes; and water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene-glycols and d'l-leucine. Lubricants are usually added at the very last step before compression, since they must be present on the surfaces of the granules and in between them and the parts of the tablet press.
• the amount of lubricant in the composition can range from about 0.2 to about 5% by weight of the composition, preferably from about 0.5 to about 2%, more preferably from about 0.3 to about 1.5% by weight.
• Suitable glidants include silicon dioxide and talc.
• the amount of glidant in the composition can range from about
• Coloring agents - excipients that provide coloration to the composition or the dosage form.
• excipients can include food grade dyes and food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide.
• the amount of the coloring agent can vary from about 0.1 to about 5% by weight of the composition, preferably from about 0.1 to about 1 %.
• Bioavailability - refers to the rate and extent to which the active drug ingredient or therapeutic moiety is absorbed into the systemic circulation from an administered dosage form as compared to a standard or control.
• a 1000L batch of the solution of Example 1 is prepared using the following procedure:
• Step 5 Add the active solution from Step 4 to the batch in Step 3, use Purified Water to rinse the active solution vessel several times: (2 to 3 liters: three times); add the rinses to the batch. Mix until the batch is homogeneous.
• Acid as a 10% solution in purified water. Record the volume of solution added and the resulting pH.
• suitable containers for liquid compositions of the present invention include type III amber glass bottle and a high density polyethylene (“HDPE”)bottle with 30 mL graduated spoon. Store between 2° and 30°C.
• HDPE high density polyethylene
• Example 1 The procedure of Example 1 is used to prepare the following solution. Ingredient mq/ml
• the solution formulation may also be stored in 30 mL type III amber glass bottle with dropper assembly tops. Use of 30 mL HDPE white opaque bottles is also possible.
• the solution formulation of Example 1 was stored in 30 mL type III amber glass bottles with tin plate cap with a vinyl on pulp cap liner at room temperature, 35° and 45°C. Samples were removed and tested for degradation by HPLC, using loratadine and pseudoephedrine standards. The pH, Alpha color and APE tests were also performed. The results are summarized in Table I. Similar results are expected for the solution formulation of Example 2.
• the solution formulations of Examples 1 and 2 are indicated to be useful to treat pediatric patients of 2 to 8 years of age for the relief of symptoms associated with allergic rhinitis and the common cold including nasal congestion, sneezing, rhinorrhea, pruritus and lacrimation.
• the solution formulations of the present invention are useful when both the antihistamine properties of loratadine and the decongestant properties of pseudoephedrine sulfate are desired in any patient, including pediatric patients of 2-8 years of age and older.
• the stable liquid pharmaceutical compositions of the present invention are useful for relief of the symptoms associated with upper airway passage congestion associated with disorders such as seasonal and perennial allergic rhinitis and for relief of the symptoms associated with upper respiratory infections such as the common cold including nasal congestion,
• the precise dose and dosage regimen will be determined by the attending physician in view of the age and medical condition of the patient as well as the severity of the symptoms associated with upper airway passage congestion and the severity of symptoms associated with upper respiratory infections such as the common cold including nasal congestion.
• liquid pharmaceutical compositions of the present invention containing 0.50 mg/ml of loratadine and 6.0 mg/ml of pseudoephedrine sulfate may be administered to a pediatric human patient of 2 to 8 years of age in accordance with the following regimen:
• liquid pharmaceutical compositions of the present invention containing 1.0 mg/ml of loratadine and 6.0 mg/ml of pseudoephedrine sulfate may be administered to a pediatric human patient of 2 to 8 years of age in accordance with the following regimen:
• the present invention provides a novel combination of a slow release non- sedating antihistamine such as loratadine, and an expectorant and mucolytic agent such as ambroxol, in a new pharmaceutical preparation.
• the combination is indicated primarily in the treatment of those patients who show bronchopulmonary conditions of allergic origin associated with cough, where viscosity and mucous adherence are increased, obstructing permeability of the airways.
• the principal indications include but are not limited to allergic rhinitis associated with cough; acute, chronic, spasmodic and asthmatic bronchitis; bronchial asthma; bronchiectasis; sinusitis; otitis media; pneumonia; bronchopneumonia; atelectasis by mucous obstruction; tracheotomy and as a pre and post prophylactic agent.
• step 2 Discharge the contents of the blender from step 1 and pass the blend through a mechanical sieve or Oscillator equipped with a 40 mesh screen and return the sample to the twin shell blender. 3. Pass the remaining quantity of Lactose Anhydrous through the same mechanical sieve or oscillator from step 2 and return the sample to the blender from step 2.
• step 4 Charge into the blender from step 2, the Ambroxol Hydrochloride, Pseudoephedrine sulphate, Corn Starch, Cellulose microcrystalline. Blend for 20 minutes.
• step 6 Using a suitable tablet press, compress the blend from step 6 into tablets.
• step 4 Charge into the blender from step 2, the Ambroxol Hydrochloride, Pseudoephedrine sulphate, Corn Starch, Cellulose microcrystalline. Blend for 20 minutes.
• step 6 Using a suitable tablet press, compress the blend from step 6 into tablets.
• Examples 3A and 3C adults and children 12 years of age and older may take two tablets a day of these prepared in accordance with Example 3A or three tablets a day of those prepared in accordance with Example 3C.
• the solutions of Examples 3B and 3D may be administered as follows:
• Typical suitable additional drugs include analgesics such as aspirin, acetaminophen, ibuprofen, naproxen or ketoprofen for the relief of pain and, except in the case of acetaminophen, the relief of inflammation.
• Antitussives such as codeine, hydrocodone or dextromethorphan, for relief from coughing, and expectorants such as guaifenesin, for increasing cough productivity, may also be included in the syrup formulations to form combination products. Any of these additional drugs including salts thereof, and other drugs from the same therapeutic classes may be added to the solution formulations without departing from the scope of the present invention.

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