WO2000037079A1 - Compositions ophtalmiques comprenant de la pheniramine et un emolliant tel qu'une pvp - Google Patents

Compositions ophtalmiques comprenant de la pheniramine et un emolliant tel qu'une pvp Download PDF

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Publication number
WO2000037079A1
WO2000037079A1 PCT/US1999/030950 US9930950W WO0037079A1 WO 2000037079 A1 WO2000037079 A1 WO 2000037079A1 US 9930950 W US9930950 W US 9930950W WO 0037079 A1 WO0037079 A1 WO 0037079A1
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Prior art keywords
percent
pheniramine
compositions
demulcent
weight
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PCT/US1999/030950
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English (en)
Inventor
Mark B. Abelson
Matthew S. Jonasse
Richard V. Smerbeck
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Bausch & Lomb Incorporated
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Publication date
Application filed by Bausch & Lomb Incorporated filed Critical Bausch & Lomb Incorporated
Priority to AU22165/00A priority Critical patent/AU2216500A/en
Publication of WO2000037079A1 publication Critical patent/WO2000037079A1/fr

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    • 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
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • compositions comprising pheniramine.
  • pheniramine and derivatives thereof when employed in combination with an effective amount of a demulcent to maintain comfort, provide an improved response to allergic conditions, including the alleviation of redness comparable to compositions with conventional vasoconstrictors.
  • Compositions according to the present invention have also been found to alleviate the symptoms of dryness, in addition to allergic symptoms.
  • Allergic responses include what is referred to as allergic conjunctiva, which is basically a hypersensitivity reaction, which may occur as a component of hayfever or an independent ocular allergy.
  • allergic conjunctiva is basically a hypersensitivity reaction, which may occur as a component of hayfever or an independent ocular allergy.
  • allergic responses to ragweed, pollen and animal hair may result in minor eye symptoms of itching and redness.
  • the eye particularly the conjunctiva, has a relatively large number of mast cells. When allergens are present, they can bind to the immunoglobulin on the surface of these mast cells and trigger the breakdown, or what is known as the degranulation, of the cell. On degranulation, mast cell components, including histamines, are released into the environment outside the mast cell.
  • these components can be responsible for symptoms associated with allergic responses such as itching, redness, lid swelling, vasodilatation and chemosis (edema of the conjunctiva).
  • allergic responses such as itching, redness, lid swelling, vasodilatation and chemosis (edema of the conjunctiva).
  • the patient commonly complains of a burning of the eyes.
  • Antihistamines are compounds which are administered to prevent histamines, released from mast cells in response to the presence of allergens, from binding to, for example, nerves and smooth muscle cells of the conjunctival blood vessels causing redness, itching and swelling.
  • topical antihistamines do not block the release of histamine, but rather inhibit the allergic reaction by competing with histamine for the histamine receptors on effector cells.
  • antihistamine has been used to describe drugs that act as H,-receptor antagonists. Although antihistamines reliably relieve the symptoms of itching found in allergic conjunctivitis, they are believed to have little effect on chemosis and redness.
  • topical antihistamines are commonly formulated in combination with a vasoconstrictor to create a product that also helps to relieve ocular injection.
  • Clinically available antihistamines that competitively antagonize histamine to some extent include ethanolamines, ethylenediamines, alkylamines, phenothiazines or piperidines.
  • Antihistamine preparations commercially available for topical ophthalmic use include 0.3 percent pheniramine maleate (an alkylamine), 0.5 percent antazoline phosphate (an ethylenediamine), and 0.1 percent pyrilamine maleate (also an ethylenediamine).
  • Conventional vasoconstrictors include, for example, ephedrine, naphazoline, phenylephrine, and tetrahydrozoline.
  • One commercially available product for treating allergic conjunctivitis is a sterile aqueous ophthalmic solution containing 0.025 percent naphazoline hydrochloride and 0.3 percent pheniramine maleate, further in combination with the inactives hydroxypropyl methylcellulose, sodium chloride, sodium borate, and edetate disodium, preserved with 0.01 percent benzalkonium chloride.
  • Such products combine the effects of the antihistamine, pheniramine maleate, with the decongestant or vasoconstrictor naphazoline.
  • vasoconstrictors can mask other medical conditions such as infection, abrasion, or eye trauma.
  • vasoconstrictors will remove non-specific redness, whereas it is desired to remove redness only due to an allergic response, not due to, for example eyestrain or infection, where such redness may be a good signal that some medial treatment may be necessary or advisable.
  • demulcents are known for topical administration to the eye to protect and lubricate mucous membrane surfaces and relieve dryness and irritation.
  • Conventional demulcents include carboxymethyl cellulose, hydroxyethyl cellulose and other cellulose derivatives, dextran, gelatin and polyols such as glycerin, polyethylene glycol, polysorbate, propylene glycol, polyvinyl alcohol, and povidone.
  • polyvinylpryrrolidone also referred to as povidone or PVP
  • PVP polyvinylpyrrolidone
  • compositions for effectively treating the symptoms of allergic reaction including redness, without the use of vasoconstrictors. It would further be desirable to provide a single composition that would effectively respond to a fuller range of symptoms, including dryness, itching, and burning. It has been found that, contrary to intuition (because allergic responses may include watering of the eyes), dryness is often associated with allergic conditions, and that compositions that alleviate the symptoms of dryness more fully respond to the range of symptoms associated with the allergic responses. It would, therefore, be desirable to be able to effectively and simultaneously treat both dryness and allergic reactions by the administration of a single composition. Finally, it would be desirable if such compositions could be administered to patients irrespective of whether they were wearing contact lenses.
  • an object of the present invention to provide improved ophthalmic compositions comprising an antihistamine for treating allergic responses, including redness and itching, without the use of a vasoconstrictor. It is a further object to provide an ophthalmic composition designed to alleviate dryness. Finally, it is an object to provide methods for treating ophthalmic allergic conditions through administration of the disclosed compositions.
  • compositions for preventing and treating ophthalmic allergic responses comprising relatively higher amounts of the antihistamine pheniramine or derivatives thereof, in combination with a demulcent, in the absence of a vasoconstrictor.
  • demulcents such as povidone or polyvinylalcohol are employed not only to maintain comfort at higher concentrations of pheniramine, but also to alleviate dryness.
  • the present compositions have been found to provide effective relief of itchy, red and swollen eyes without producing significant side effects.
  • the compositions can be formulated as solutions, suspensions, gels or ointments for topical administration to the eye.
  • this invention is directed to methods for preventing and treating ophthalmic allergic responses using the compositions of the present invention.
  • Pheniramine is a well-established anti-histaminic compound. Pheniramine, the free base and its ophthalmically acceptable salts, is a compound of the alkylamine type that is commonly used as an antihistamine for local and generalized allergic reactions.
  • maleate salt it is soluble in water and may be represented by the following formula:
  • Pheniramine may be prepared in the manner described by Sperber, et al. in U.S. Patent No. 2,567,245 and 2,676,964. Alternately, pheniramine is also commercially available from Loftus Bryan Chemicals Ltd., Rathdrum Co. (Wicklow, Ireland) or Kongo Chemical Co. (Toyama, Japan). Derivatives of pheniramine include, for example, the halogenated derivatives chloropheniramine and bromopheniramine.
  • compositions can be employed to relieve redness without the stinging otherwise resulting from the increased dosage of pheniramine.
  • a vasoconstrictor is not necessary to alleviate redness.
  • the present compositions have been found to effectively alleviate redness due to allergic response, albeit not as rapidly as a vasoconstrictor.
  • the present invention may remove redness, for example, over a period of five (5) to ten (10) minutes.
  • Such compositions have also been found to alleviate dryness and the so-called stinging and burning associated with the allergic response.
  • pheniramine maleate in addition to pheniramine maleate, other substantially non-toxic or non-irritating pheniramine salts that may be topically administered according to this invention include those derived from organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, acetic, citric, succinic, citric, lactic, tartaric, benzoic acids and the like.
  • the present composition produces the desired effect without irritation or stinging from the increased amount of pheniramine. It has been found that the incorporation of an effective amount of a demulcent allows higher effective lower dosages to be comfortably administered in ophthalmic compositions. For example, povidone or polyvinylalcohol- containing ophthalmic compositions of pheniramine maleate relieve redness and reduce itching and burning with reduced or no stinging, compared to ophthalmic compositions not containing the indicated polymeric demulcents.
  • a preferred demulcent employed in the ophthalmic solution of the present invention is povidone, which is a Category I demulcent in the OTC Ophthalmic Drug Products Monograph of the USFDA.
  • Polyvinylpyrrolidone (PVP) is a linear homopolymer or copolymer comprising at least about 80 percent, preferably at least about 90 percent of repeat units derived from l-vinyl-2-pyrrolidone monomers, the polymer more preferably comprising at least about 95 percent or essentially all of such repeat units, the remainder selected from polymerization-compatible monomers, preferably neutral monomers, such as alkenes or acrylates.
  • PVP povidone
  • polyvidone polyvidone
  • l-vinyl-2-pyrolidinone l-ethenyl-2-pyrolionone
  • PVP has an average molecular weight of about 10,000 to 250,000, preferably 30,000 to 100,000.
  • Such materials are sold by various companies, including ISP Technologies, Inc. under the trademark PLASDONETM K- 29/32, BASF under the trademark KOLLIDONTM for USP grade PVP, for example KOLLIDONTM K-30 or K-90 ( BASF Corporation, NV Division, 3000 Continental, Mount Olive, New Jersey 07628-1234, USA).
  • PVP also acts as a water-soluble viscosity builder.
  • Other or combinations of viscosity-builders or demulcents may optionally be employed in the present composition, for example, cellulose derivatives, glycerin and the like. Such viscosity-builders or demulcents may be employed in a total amount ranging from about 0.01 to about 5.0 weight percent or less.
  • the viscosity of the final formulation is 10 cps to 50 cps.
  • the demulcents are suitably present in a total amount of 0.1 to 5.0 percent by weight, preferably greater than 0.5 percent by weight, more preferably 0.75 to 2.0 weight percent.
  • solutions of this invention will also contain water and one or more other components that are commonly present in ophthalmic solutions.
  • solutions according to the present invention may contain buffers, various surfactants, stabilizers, isotonic agents and the like which aid in making ophthalmic compositions more comfortable to the user.
  • the aqueous solutions of the present invention are typically adjusted with tonicity agents to approximate the osmotic pressure of normal lachrymal fluids which is equivalent to a 0.9 percent solution of sodium chloride or a 2.5 percent solution of glycerol.
  • the solutions are made substantially isotonic with physiological saline used alone or in combination, otherwise if simply blended with sterile water and made hypotonic or made hypertonic the lenses will lose their desirable optical parameters.
  • excess salt or other tonicity agent may result in the formation of a hypertonic solution that will cause stinging and eye irritation.
  • An osmolality of about 225 to 400 mOsm/kg is preferred, more preferably 280 to 320 mOsm/kg.
  • the pH of the present solutions should be maintained within the range of 5.0 to 8.0, more preferably about 6.0 to 8.0, most preferably about 6.5 to 7.8.
  • Suitable buffers may be added, such as boric acid, sodium borate, potassium citrate, citric acid, sodium bicarbonate, TRIS and various mixed phosphate buffers (including combinations of Na 2 HPO 4 , NaH 2 PO 4 and KH 2 PO 4 ) and mixtures thereof. Borate buffers are preferred.
  • buffers will be used in amounts ranging from about 0.05 to 2.5 percent by weight, and preferably, from 0.1 to 1.5 percent.
  • Ethylene- diaminetetraacetic acid (EDTA) and its salts (disodium) are preferred examples. They are usually added in amounts ranging from about 0.01 to about 0.2 weight percent.
  • compositions of the present invention can function as artificial tears and can be used, as needed, for the temporary relief of eye irritation of discomfort.
  • many people suffer from eye conditions in which the eye's tear system fails to provide adequate tear volume or tear film stability necessary to remove irritating environmental contaminants such as dust, pollen, or the like.
  • the film on the eye tends to become discontinuous. Because of their emollient and lubricating effect, artificial tears can be used to soothe the eye.
  • compositions for treating the symptoms of allergy that have been on the market are not recommended for use with lenses in place.
  • An advantage of one embodiment of the present invention is that the compositions can be used with or without the lenses in place, so that contact lenses do not have to be removed.
  • aqueous ophthalmic solutions used in accordance with this invention may be formulated, for example, in accord with the procedures set forth in Chapter 83 of Remington's Pharmaceutical Sciences. 14th Edition, Mack Publishing Company.
  • Such ophthalmic solutions are sterile and may contain a bacteriological preservative to maintain sterility during use.
  • the quaternary ammonium bacteriostats such as benzalkonium chloride are satisfactory for this purpose.
  • An antioxidant may also be employed if desired.
  • suitable antioxidants include sodium bisulfite, N-acetylcysteine salts, sodium ascorbate and other water-soluble ophthalmologically acceptable antioxidants known to the pharmaceutical art.
  • the quantity of a solution to be administered daily may vary from 1 to 3 drops and will depend mainly on the severity of the allergy reaction.
  • Compositions according to the present invention can be applied by instilling about 1 or 2 drops in the affected eye(s) as needed, for the temporary relief of symptoms due to allergic reaction.
  • EXAMPLE 1 An example of an aqueous solution of the invention, useful as an ophthalmic solution for the treatment of allergic symptoms, is prepared with the following ingredients:
  • boric acid may be used to adjust pH
  • the chemical ingredients in Table 1 are weighed, charged into a 100 Kg vessel with 94.0 kg of purified water, and heated to a temperature > 80°C. While initiating agitation, the water temperature is maintained at > 80°C. With continued agitation, the following raw materials are added to the batch in the order listed, allowing each to dissolve before adding the next: sodium borate, sorbic acid, EDTA, boric acid, sodium chloride, potassium chloride, pheniramine maleate, and polyvinylpyrrolidone K30. While cooling the batch to 20°-30°, the ingredients are mixed thoroughly for not less than 20 minutes. The solution temperature is maintained between 20° and 30°C.
  • the pH is adjusted as necessary to 7.0 to 7.4, using suitable increments of the appropriate raw material.
  • the batch is brought to its final weight with purified water.
  • the final osmolality is 280 to 330 mOsm/Kg.
  • the bottles and caps to be employed are ethylene-oxide-sterilized and the dropper tips gamma-sterilized.
  • the solution is then aseptically dispensed into sterilized bottles by filter-sterilization, after which the bottles and caps are aseptically fit into bottles.
  • EXAMPLE 2 This example illustrates the comfort assessment of four (4) vehicles for use with pheniramine maleate, the latter at a concentration of 0.45 percent. The comfort of each vehicle in mild to moderate dry-eye subjects was evaluated during exposure in a dry-eye chamber. The four (4) formulations tested were as follows;
  • each subject completed a Baseline Dry-Eye Comfort Scale.
  • An ophthalmic exam was again performed including visual acuity, slit lamp biomicroscopy, fluorescein staining, tear break-up time and Rose Bengal staining.
  • Subjects then entered the dry-eye chamber.
  • One (1) drop of a test formulation labeled for the appropriate visit was instilled into the left eye at visit 2, alternating eyes at each subsequent visit.
  • the subjects completed the Dry-Eye Comfort Scale Evaluation. After 60 minutes exposure subjects exited the dry-eye chamber and the ophthalmic examination completed.
  • Comfort scores were analyzed for each sensory attribute and for total score of all attributes. Analysis was done as 30 minute score minus baseline score and 60 minutes minus baseline score. None of the formulations showed statistical significance in symptom scores at 30 minutes for burning, blurry, gritty, and tight symptoms.
  • Formulation B showed statistically significant score difference in the dry parameter with an average symptom score change toward improvement of 1.27 units on a nine (9) unit scale.
  • Formulation C showed statistically significant score difference in the stinging and foreign body sensation parameters with an average symptom score change toward improvement of 1.13 units for stinging and 0.80 units for foreign body sensation on a nine (9) unit scale.
  • Formulation D showed statistically significant score difference in the stinging and scratchy parameters with an average symptom score change toward improvement of 0.93 units for stinging and 0.47 units for scratchy on a nine- (9) unit scale.
  • Formulation C showed a statistically significant score difference in total symptom score with an average score to improvement of 4.47 units on a 56 unit scale.
  • Formulation B showed a statistically significant score difference in the burning parameter with an average symptom score change toward improvement of 0.80 units on a nine- (9) unit scale.
  • Formulation C showed statistically significant score difference in the burning and dry parameters with an average symptom score change toward improvement of 1.60 units for burning and 1.07 units for dry on a nine- (9) unit scale.
  • Formulation D showed statistically significant score difference in the stinging and tight parameters with an average symptom score change toward improvement of 1.47 units for stinging and 1.07 units for tight on a nine- (9) unit scale.
  • Formulation C showed a statistically significant score difference in total symptom score with an average score to improvement of 5.20 units on a nine- (9) unit scale. Formulation C demonstrated a statistically significant improvement in total ocular comfort scores at both 30 and 60 minutes post-chamber exposure with an average improvement of 4.83 units.
  • a negative number indicates an improvement with respect to a negative (undesired) attribute, for example, burning.
  • Formulations B, C, and D all show statistically significant improvements in some parameter of comfort after exposure to the dry-eye chamber.
  • Formulation C performed especially well, exhibiting a one-unit change or improvement in dryness, as well as an overall improvement in total comfort scores of greater than five (5) units.
  • the above results indicate that the most preferred combination is polyvinylpyrrolidone and pheniramine.

Abstract

La présente invention concerne des compositions comprenant de la phéniramine. On a découvert, en particulier, que des concentrations relativement élevées de phéniramine, lorsqu'elles sont associées à une quantité efficace d'un émollient comme la povidone permettant de maintenir un certain confort, offrent une meilleure réponse aux états allergiques, notamment une réduction des rougeurs comparable à celle que l'on obtient avec des compositions à base de vasoconstricteurs classiques. La présente composition est également destinée à davantage réduire les symptômes de brûlures et de dessèchements par rapport aux compositions uniquement à base de phéniramine.
PCT/US1999/030950 1998-12-22 1999-12-22 Compositions ophtalmiques comprenant de la pheniramine et un emolliant tel qu'une pvp WO2000037079A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU22165/00A AU2216500A (en) 1998-12-22 1999-12-22 Ophtalmic compositions comprising pheniramine and a demulcent such as pvp

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US21932698A 1998-12-22 1998-12-22
US09/219,326 1998-12-22

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WO2000037079A1 true WO2000037079A1 (fr) 2000-06-29

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005004842A3 (fr) * 2003-06-30 2005-04-21 Alza Corp Formulations pour microprojections revetues contenant des contre-ions non volatils

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0317405A1 (fr) * 1987-11-10 1989-05-24 Marc Plamondon Solution ophtalmique comprenant un complexe de iodure-polyvinylpyrrolidone
US5188826A (en) * 1988-02-08 1993-02-23 Insite Vision Incorporated Topical ophthalmic suspensions
US5591426A (en) * 1993-07-02 1997-01-07 Bausch & Lomb Incorporated Ophthalmic solution for artificial tears
WO1998032421A1 (fr) * 1997-01-29 1998-07-30 Bausch & Lomb Incorporated Compositions ophtalmiques comportant de la glycerine et du propylene glycol

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0317405A1 (fr) * 1987-11-10 1989-05-24 Marc Plamondon Solution ophtalmique comprenant un complexe de iodure-polyvinylpyrrolidone
US5188826A (en) * 1988-02-08 1993-02-23 Insite Vision Incorporated Topical ophthalmic suspensions
US5591426A (en) * 1993-07-02 1997-01-07 Bausch & Lomb Incorporated Ophthalmic solution for artificial tears
WO1998032421A1 (fr) * 1997-01-29 1998-07-30 Bausch & Lomb Incorporated Compositions ophtalmiques comportant de la glycerine et du propylene glycol

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005004842A3 (fr) * 2003-06-30 2005-04-21 Alza Corp Formulations pour microprojections revetues contenant des contre-ions non volatils

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Publication number Publication date
AU2216500A (en) 2000-07-12
AR022119A1 (es) 2002-09-04

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