"The present invention relates to a process for the preparation of a nasally administrable bioavailable pharmaceutical composition of loratadine for the treatment of allergic rhinitis.
Loratadine is a long acting, non-sedating histamine-1 -receptor (H-1 receptor) antagonist, used in the treatment of the symptoms of allergic reactions, for example, for the relief of nasal and non-nasal symptoms associated with seasonal or perennial allergic rhinitis.
Nasal administration is being suggested as an alternative route for compounds that have poor intestinal absorption or high hepatic first pass metabolism. Nasal administration often provides more rapid or complete absorption than the oral route. The reasons attributed are, the nose has a large surface area available for drug absorption due to the coverage of the epithelial surface by numerous microvilli; the sub-epithelial layer is highly vascularised; and venous blood from the nose passes directly into the systemic circulation and, therefore, avoids the loss of drug by first pass metabolism in the liver.
It has been observed that the local application of anti-histamines on a mucosal surface such as nasal mucosa is associated with adverse effects particularly on cilia present on these surfaces. These adverse effects include inhibition of ciliary movement and hypersensitivity reactions. The anti-histamines of phenothiazines class are strongly associated with hypersensitivity reactions. The local application of anti-histamines for the treatment of disease like allergic rhinitis has not been fully explored for the obvious reasons.
Loratadine is currently available in oral dosage forms such as conventional tablets, orally disintegrating tablets and syrups. Loratadine is extensively metabolized in the liver prior to availability in systemic circulation. An alternative route is desirable, which can provide therapeutic plasma levels of loratadine, rapid onset of action, ease of administration and reduced side effects in comparison to oral administration. These advantages are offered by administration of loratadine by nasal route.
"No commercial dosage form of loratadine is believed to be available which can be administered by nasal route.
We have surprisingly found a pharmaceutical composition of loratadine, which can alleviate symptoms of allergic rhinitis when administered by nasal route.
The nasal administration of these aqueous pharmaceutical compositions requires only a fraction of the oral dose of loratadine to elicit a therapeutic response. The reduced amount of drug also considerably reduces the adverse effects.
The onset of action is fast due to rapid absorption from mucosal surface. It may also contribute to alleviating symptoms of allergic rhinitis by local effect. The present pharmaceutical compositions are stable and free from particulate matter thereby non-irritating to the nasal mucosa.
The process for the preparation of these aqueous pharmaceutical compositions of loratadine is simple, less time consuming and hence economical.
Therefore, in one general aspect it provides an aqueous pharmaceutical composition of loratadine for nasal administration.
In another general aspect, it provides a bioavailable dosage form of loratadine for nasal administration comprising an aqueous pharmaceutical composition of loratadine.
In another general aspect, it provides an aqueous pharmaceutical composition of loratadine for nasal administration for treatment of symptoms of allergic rhinitis.
In another general aspect, it provides a stable aqueous pharmaceutical composition of loratadine free from nasal irritation.
In another general aspect, it provides an aqueous pharmaceutical composition comprising a solid dispersion of loratadine with a pharmaceutically acceptable carrier.
Tn another general aspect, it provides an aqueous pharmaceutical composition comprising water-soluble complex of loratadine and cyclodextrin for nasal administration.
In another general aspect, it provides a bioavailable dosage form of loratadine for nasal administration comprising an aqueous pharmaceutical composition comprising water-soluble complex of loratadine and cyclodextrin for nasal administration.
In another general aspect, it provides an aqueous pharmaceutical composition comprising water-soluble complex of loratadine and cyclodextrin for the treatment of symptoms of allergic rhinitis.
In another general aspect, it provides a stable aqueous pharmaceutical composition comprising water-soluble complex of loratadine and cyclodextrin free from nasal irritation.
In another general aspect, it provides a process for the preparation of aqueous pharmaceutical composition of loratadine for nasal administration.
In another general aspect, it provides a process for the preparation of a bioavailable dosage form of loratadine for nasal administration comprising an aqueous pharmaceutical composition of loratadine.
In another general aspect, it provides a process for the preparation of aqueous pharmaceutical compositions comprising loratadine for the treatment of symptoms of allergic rhinitis.
In another general aspect, it provides a process for the preparation of stable aqueous pharmaceutical compositions of loratadine free from nasal irritation.
In another general aspect, it provides a process for the preparation of aqueous pharmaceutical composition comprising a solid dispersion of loratadine with a pharmaceutically acceptable carrier.
In another general aspect, it provides a process for the preparation of aqueous pharmaceutical compositions comprising water-soluble complex of loratadine and cyclodextrin for nasal administration.
In another general aspect, it provides a process for the preparation of a bioavailable dosage form of loratadine for nasal administration comprising an aqueous pharmaceutical composition comprising water-soluble complex of loratadine and cyclodextrin for nasal administration.
In another general aspect, it provides a process for the preparation of aqueous pharmaceutical compositions comprising water-soluble complex of loratadine and cyclodextrin for the treatment of symptoms of allergic rhinitis.
In another general aspect, it provides a process for the preparation of stable aqueous pharmaceutical compositions comprising water-soluble complex of loratadine and cyclodextrin, which are free from nasal irritation.
In another general aspect it provides a process for the preparation of aqueous pharmaceutical compositions of loratadine comprising dissolving loratadine in presence of cyclodextrin(s) to form water-soluble loratadine cyclodextrin complex.
In another general aspect it provides a process for the preparation of aqueous pharmaceutical compositions of loratadine comprising dissolving loratadine in water in presence of hydroxypropyl-p-cyclodextrin to form water soluble loratadine hydroxypropyl-p-cyclodextrin complex.
In another general aspect it provides a method of treating allergic rhinitis by nasally administering a bioavailable pharmaceutical composition of loratadine.
Loratadine is practically insoluble in water and shows highest solubility between pH 2 to 3. However, such a formulation of pH 2 to 3 would cause irritation to nasal mucosa. An aqueous formulation of loratadine having a pH of about 7 would be desirable.
We have developed an aqueous pharmaceutical composition comprising loratadine
having a pH suitable for nasal administration. Particularly, these formulations have
pH of from about 4 to about 8, more particularly from about 5 to about 8. These
formulations comprise a solid dispersion of loratadine with a carrier in a
pharmaceutically acceptable aqueous vehicle. Generally, the solid dispersion may
be prepared by dissolving loratadine and the carrier in a common solvent followed by
removal of the solvent by evaporation. The dried solid dispersion can then be
incorporated in a pharmaceutically acceptable vehicle. The carrier may be selected
from cyclodextrin, polyethylene glycol, polyvinylpyrrolidone, cellulose derivatives
such as hydroxypropyl methylcellulose, hydroxypropylcellulose,
carboxymethylcellulose and like.
In one embodiment, there is provided an aqueous formulation of loratadine comprising a solid dispersion of loratadine with cyclodextrin which forms a water-soluble complex of loratadine with cyclodextrin.
The concentration of loratadine in aqueous compositions can be from about 0.1 mg/mL to about 15mg/ml_ and particularly from about 1mg/mL to about 10mg/ml_ weight by volume of the composition.
Cyclodextrins (CD) are cyclic oligosaccharides typically containing 6(a-CD), 7-(p-CD), or 8(y-CD) glucopyranose units. The present compositions include derivatives of cyclodextrins such as alkyl and alkoxy substituted cyclodextrins. Particularly suitable derivatives include p-cyclodextrins such as dimethyl-p-cyclodextrins, trimethyl-|3-cyclodextrins, sulphobutylether-p-cyclodextrins and hydroxypropyl-p-cyclodextrin. A particularly suitable cyclodextrin is hydroxypropyl-p-cyclodextrin.
The concentration of cyclodextrin can be from about 1% to about 50%, particularly from about 1 % to about 40%, more particularly from about 1 % to about 30% weight by volume of the composition.
Generally, 15% weight by volume solution of a cyclodextrin such as hydroxypropyl-p-cyclodextrin is able to solubilize 0.5% weight by volume of loratadine. The solubility
of loratadine has been found to be directly proportional to the concentration of cyclodextrin; for example, a 30% weight by volume solution of hydroxypropyl-p-cyclodextrin solubilizes about 1.0% weight by volume of loratadine. The amount of loratadine that can be solubilized depends upon the type and amount of cyclodextrin being used. Generally, the ratio of loratadine to cyclodextrin is from about 1:20 to about 1:40 weight by weight, particularly from about 1:25 to about 1:35 weight by weight.
The pharmaceutically acceptable aqueous vehicle can be purified water, water for injection. The vehicle further comprise isotonicity adjusting agents such sodium chloride, glucose, mannitol, sorbitol, xylitol and glycerol; pH modifiers include acids such as citric acid, hydrochloric acid, and bases such as sodium hydroxide, sodium citrate; buffers such as phosphate, acetate and citrate buffer. Additionally, viscosity enhancers can also be used such as xanthan gum, cellulosic ethers such as methyl cellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose and the like. Also the present compositions can include preservatives like benzalkonium chloride, benzyl alcohol, chlorhexidine gluconate and disodium EDTA. Generally the concentration of the preservative can be from about 0.001% to about 2% depending upon the selected preservative.
A typical composition for nasal delivery will comprise from about 0.1 mg to about 15mg/mL of loratadine, in a 1% to about 50% weight by volume solution of a cyclodextrin prepared in a pharmaceutically acceptable aqueous vehicle such as water.
The aqueous pharmaceutical compositions of the invention can be prepared by any conventional technique known in the art. For example, cyclodextrin is dissolved in a pharmaceutically acceptable aqueous vehicle and loratadine is added to the above solution with stirring to give a clear solution. The process can be accelerated by heating.
The present formulation can be administered in the nasal cavity using a spray device such as those supplied by Valois and Pfeiffer. These devices may be single dose or
Vnultidose systems. Depending upon the choice whether a preservative free pump is used such as VP7/100 D CS 20 Ag supplied by Valois, the aqueous vehicle may or may not comprise preservatives. Generally, these aqueous compositions are to be administered in the form of spray but they can also be instilled into the nose with a dropper. A typical dosage range for a 5mg/mL loratadine nasal spray composition comprises from about 45µL to about 300µL per nostril, particularly from about 50µlL
to about 200µL per nostril, more particularly from about 60µL to about 150µL per nostril.
The following examples are given for the purpose of illustrating the invention and not intended to limit the scope in any way.
EXAMPLE 1
An aqueous pharmaceutical composition was prepared comprising loratadine (5mg/ml), hydroxypropyl-p-cyclodextrin 15% w/v and water for injection in which:
Each ml contains
Loratadine 5mg
Hydroxypropyl-p-cyclodextrin 15 % w/v
Water for injection q.s to 1 ml
Procedure:
1. Hydroxypropyl-p-cyclodextrin was dissolved in water for injection
2. The solution was heated to 60-70°C and loratadine added to it with continuous stirring till a clear solution was obtained.
3. The volume was made up with water for injection.
4. The solution was filtered through 0.2µ nylon filter and filled in USP Type I clear glass vials (15-30ml).
5. The vials were sealed with metered dose nasal spray pumps.
6. The actuators were placed on the nasal spray pumps.
The stability of the aqueous composition prepared as per Example 1 was determined at 40°C/75% RH for a period of 3 months. The results of the same are summarized in Table 1.
Table 1: Stability data of loratadine nasal spray composition prepared as per Example 1 stored at 40°C/75% relative humidity for 3 months

(Table Removed)
The data clearly indicates that loratadine nasal spray composition prepared as per Example 1 is stable.
EXAMPLE 2
The sub nasal toxicity study was conducted in Sprague Dawley rats to determine the toxicity profile of the above aqueous loratadine nasal spray composition (5mg/ml) when applied daily for 90 days in the nasal cavity of rats.
Loratadine nasal spray composition was administered to rats via nasal route at the dose levels ranging from Oml/animal to 0.4ml/animal. Male and female animals from control and different dose groups survived through the dosing period of 90 days and recovery period of 28 days. No significant dose related signs of intoxication were observed in animals during the dosing and recovery periods. The animals showed normal food intake and body weight gain throughout the study. Ophthalmologic
examination conducted prior to and at the end of dosing did not reveal any abnormality attributable to the treatment. Haematological investigations in control and test groups at the end dosing period and recovery showed no abnormalities. Clinical chemistry and urine analysis did not reveal any abnormality and organ weight data was found to be comparable to respective controls. Histopathological examination of nasal cavity and other organs was found normal and showed no abnormalities.
EXAMPLE 3
An open label non-comparative two dose level study was conducted to assess the efficacy and tolerability of loratadine nasal spray (5mg/ml). Loratadine nasal spray was administered as two sprays per nostril either once a day or twice a day in a total of 44 patients. Twenty one patients received loratadine 4mg (2mg bid) and 23 patients received loratadine 2mg (once a day) for 2 weeks. Nasal symptoms like rhinorhoea, nasal stiffness, nasal itching and sneezing were assessed. The results are presented in Table 2
Table 2: Efficacy and tolerability studies of Loratadine nasal spray

(Table Removed)
EXAMPLE 4
A single dose, randomized, two treatment, two way cross over study was conducted to evaluate the pharmacokinetic parameters and to compare the bioavailability of loratadine nasal spray (test, 5mg/ml) and loratadine 10mg oral tablets (reference) in 12 healthy human male volunteers.
The reference dose was one tablet containing loratadine 10mg and with the test preparation the dose was two nasal sprays, in each nostril i.e. each spray delivered 100(µL/spray or a total of 2mg of loratadine. The various pharmacokinetic parameters were evaluated and are given in Table 3.
Table 3: Pharmacokinetic Parameters of Loratadine Nasal Spray Vs
Loratadine tablet

(Table Removed)
Graph-1 shows the bioavailability of nasal spray in comparison to oral tablet.
GRAPH 1: MEAN PLASMA CONCENTRATION-TIME PROFILE OF 12 VOLUNTEERS
SHOWING LORATADINE PLASMA LEVELS GIVEN BY ORAL TABLET AND NASAL SPRAY.
(Figure Removed)
On the basis of comparison of the AUC (0-36) after single administration, the relative bioavailability of the nasal spray was found to be 52.31 % of that of the reference.
Although the invention has been described in connection with specific embodiments, various modifications and variations of the described compositions and their methods of use as well as the concept of the invention will be apparent to those skilled in the art. Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. For example, the present formulation may comprise preservatives such as benzalkonium chloride, viscosity enhancers such as water-soluble cellulosic ethers as disclosed in examples 5, 6, 7 and 8 given below.

(Table Removed)

EXAMPLE 8
Loratadine 5mg
Hydroxypropyl-p-cyclodextrin 15 % w/v
Hydroxypropylmethylcellulose 2-3%
Water for injection q.s to 1 ml

WE CLAIM:
1. A nasally administrate bioavailable pharmaceutical composition of loratadine for the treatment of allergic rhinitis.
2. The pharmaceutical composition according to claim 1 wherein it gives the similar bioavailability as given by an orally administered composition.
3. The pharmaceutical composition according to claim 1 wherein it gives similar bioavailability as given by orally administered composition at reduced dose.
4. The pharmaceutical composition according to claim 1 wherein it gives similar bioavailability as given by orally administered composition at 1/5th of the oral dose.
5. The pharmaceutical composition according to claim 1 wherein it has reduced side effects.
6. The pharmaceutical composition according to claim 1 wherein it is free from nasal irritation.
7. The pharmaceutical composition according to claim 1 wherein loratadine concentration is from about 0.1mg/mL to about 15mg/mL weight by volume.
8. The pharmaceutical composition according to claim 7 wherein loratadine concentration is from about 1mg/mL to about 10mg/ml_ weight by volume.
9. The pharmaceutical composition according to claim 1 wherein it comprises a solid dispersion of loratadine with a carrier in a pharmaceutically acceptable aqueous vehicle.
10. The pharmaceutical composition according to claim 9 wherein the carrier is selected from cyclodextrin, polyethylene glycol, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcellulose, and carboxymethylcellulose.
11. The pharmaceutical composition according to claim 10 wherein the carrier is cyclodextrin.
12. The pharmaceutical composition according to claim 11 wherein the ratio of loratadine to cyclodextrin is from about 1:20 to about 1: 40 weight by weight.
13. The pharmaceutical composition according to claim 12 wherein the ratio of loratadine to cyclodextrin is from about 1:25 to about 1: 35 weight by weight.
14. The pharmaceutical composition according to claim 11 wherein cyclodextrin concentration is from about 1% to about 50% weight by volume.
15. The pharmaceutical composition according to claim 14 wherein cyclodextrin concentration is from about 1 % to about 40% weight by volume.
16. The pharmaceutical composition according to claim 15 wherein cyclodextrin concentration is from about 1% to about 30% weight by volume.
17. The pharmaceutical composition according to claim 11 wherein the cyclodextrin is selected from a-cyclodextrin, p-cyclodextrin and y-cyclodextrin.
18. The pharmaceutical composition according to claim 17 wherein the cyclodextrin is p-cyclodextrin.
19. The pharmaceutical composition according to claim 18 wherein p-cyclodextrin is hydroxypropyl-p-cyclodextrin.
20. The pharmaceutical composition according to claim 18 wherein p-cyclodextrin is sulphobutylether-p-cyclodextrin.
21. The pharmaceutical composition according to claim 9 wherein the pharmaceutically acceptable aqueous vehicle is water/water for injection.
22. The pharmaceutical composition according to claim 21 wherein it further comprises one or more of tonicity adjusting agents, pH modifiers, buffers viscosity enhancers and preservatives.
23. The pharmaceutical composition according to claim 22 wherein the tonicity adjusting agent is selected from sodium chloride, glucose, mannitol sorbitol, xylitol and glycerol.
24. The pharmaceutical composition according to claim 23 wherein the tonicity adjusting agent is sodium chloride.
25. The pharmaceutical composition according to claim 22 wherein the pH modifier is selected from an acid or a base.
26. The pharmaceutical composition according to claim 25 wherein the pH modifier is an acid.
27. The pharmaceutical composition according to claim 26 wherein the acid is citric acid.
28. The pharmaceutical composition according to claim 26 wherein the acid is hydrochloric acid.
29. The pharmaceutical composition according to claim 25 wherein the pH modifier is a base.
30. The pharmaceutical composition according to claim 29 wherein the base is sodium hydroxide.
31. The pharmaceutical composition according to claim 29 wherein the base is sodium citrate.
32. The pharmaceutical composition according to claim 22 wherein the buffer is selected from phosphate, acetate and citrate buffer.
33. The pharmaceutical composition according to claim 22 wherein the viscosity enhancer is selected from xanthan gum, carboxymethyl cellulose, chitosan, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxymethyl cellulose, hydroxyethylcellulose, carboxyvinyl polymer and combinations thereof.
34. The pharmaceutical composition according to claim 1 wherein the pH of the aqueous pharmaceutical composition is from about 4 to about 8.
35. The pharmaceutical composition according to claim 34 wherein the pH of the aqueous pharmaceutical composition is from about 5 to about 8.
36. A process for the preparation of a nasally administrable bioavailable pharmaceutical composition of loratadine for the treatment of allergic rhinitis.
37. The process according to claim 36 wherein the pharmaceutical composition comprises a solid dispersion of loratadine with a carrier in a pharmaceutically acceptable aqueous vehicle.
38. The process according to claim 37 wherein the carrier is selected from cyclodextrin, polyethylene glycol, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcellulose, and carboxymethylcellulose.
39. The process according to claim 38 wherein the carrier is cyclodextrin.
40. The process according to claim 36 wherein the pharmaceutical composition comprises a water-soluble complex of loratadine with cyclodextrin(s) in a pharmaceutically acceptable aqueous vehicle.
41. The process according to claim 40 wherein the process comprises dissolving loratadine in a pharmaceutically acceptable aqueous vehicle in presence of cyclodextrin(s) to form water-soluble loratadine-cyclodextrin complex.
42. The process according to claim 40 wherein the ratio of loratadine to cyclodextrin is from about 1:20 to about 1: 40 weight by weight.
43. The process according to claim 42 wherein the ratio of loratadine to cyclodextrin is from about 1:25 to about 1: 35 weight by weight.
44. The process according to claim 40 wherein cyclodextrin concentration is from about 1% to about 50% weight by volume.
45. The process according to claim 44 wherein cyclodextrin concentration is from about 1% to about 40% weight by volume.
46. The process according to claim 45 wherein cyclodextrin concentration is from about 1% to about 30% weight by volume.
47. The process according to claim 39 wherein the cyclodextrin is selected from a-cyclodextrin, p-cyclodextrin and y-cyclodextrin.
48. The process according to claim 47 wherein the cyclodextrin is p-cyclodextrin.
49. The process according to claim 48 wherein p-cyclodextrin is hydroxypropyl-p-cyclodextrin.
50. The process according to claim 47 wherein p-cyclodextrin is sulphobutylether-P-cyclodextrin.
51. The process according to claim 37 wherein the pharmaceutically acceptable aqueous vehicle is water/water for injection.
52. The process according to claim 51 wherein it further comprises one or more of tonicity adjusting agents, pH modifiers, buffers viscosity enhancers and preservatives.
53. The process according to claim 52 wherein the tonicity adjusting agent is selected from sodium chloride, glucose, mannitol, sorbitol, xylitol and glycerol.
54. The process according to claim 53 wherein the tonicity adjusting agent is sodium chloride.
55. The process according to claim 52 wherein the pH modifier is selected from an acid or a base.
56. The process according to claim 55 wherein the pH modifier is an acid.
57. The process according to claim 56 wherein the acid is citric acid.
58. The process according to claim 56 wherein the acid is hydrochloric acid.
59. The process according to claim 55 wherein the pH modifier is a base.
60. The process according to claim 59 wherein the base is sodium hydroxide.
61. The process according to claim 59 wherein the base is sodium citrate.
62. The process according to claim 52 wherein the buffer is selected from phosphate, acetate and citrate buffer.
63. The process according to claim 52 wherein the viscosity enhancer is selected from xanthan gum, carboxymethyl cellulose, chitosan, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxymethyl cellulose, hydroxyethylcellulose, carboxyvinyl polymer and combinations thereof.
64. The process according to claim 36 wherein the pH of the pharmaceutical composition is from about 4 to about 8.
65. The process according to claim 64 wherein the pH of the pharmaceutical composition is from about 5 to about 8.
66. A method of treating allergic rhinitis by nasally administering a bioavailable pharmaceutical composition of loratadine.
67. The method according to claim 66 wherein the pharmaceutical composition comprises a water-soluble loratadine-cyclodextrin complex.