WO2013109215A1

WO2013109215A1 - Preparation of dry powder formulations comprising formoterol

Info

Publication number: WO2013109215A1
Application number: PCT/TR2013/000027
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Mahmut Bilgic
Priority date: 2012-01-16
Filing date: 2013-01-16
Publication date: 2013-07-25
Also published as: WO2013109208A1

Abstract

The present invention relates to the process for the preparation of pharmaceutical formulations in dry powder form comprising formoterol or pharmaceutically acceptable derivatives thereof in order to be used in symptomatic and/or prophylactic treatment of respiratory tract diseases, particularly asthma and COPD.

Description

PREPARATION OF DRY POWDER FORMULATIONS COMPRISING

FORMOTEROL

In case of respiratory tract diseases such as asthma or chronic obstructive pulmonary disease (COPD); stimulants such as allergen, infection, good and bad smell, smoke cause constricted muscles covering the airways, in other words bronchoconstriction, excessive secretion in glands and consequently contraction in the airways. In this case, the patient cannot exhale the inhaled air or he/she cannot inhale.

Formoterol is used in the treatment of respiratory tract diseases such as asthma and COPD. Formoterol which has the chemical name of i?ac-(R,R)-N-[2-hydroxy-5-[l-hydroxy-2-[l-(4- methoxyphenyl) propan-2-ylamino]ethyl] phenyl] formamide belongs to the group of β2- adrenergic agonists. Formoterol was first disclosed in the patent numbered US3994974.

Providing good flow characteristics of the dry powder formulations comprising formoterol is of great importance for the inhalation of said formulation effectively and thus in terms of providing an effective treatment. When the dry powder formulation comprising formoterol does not have good flow characteristics, it is observed that the formulation has low homogeneity and consequently dosing accuracy cannot be ensured during filling into capsules comprising one dose. Furthermore, the fact that the dry powder formulation does not have good flow characteristics affects emptying capacity and emptying attribute negatively during inhalation of the formulation from capsule.

The inventors have developed dry powder formulations which comprise formoterol and/or pharmaceutically acceptable derivatives thereof having good flow characteristics and high homogeneity wherein dosing accuracy is ensured and sufficient amount of active agent can be delivered to the lungs. Description of the Invention

The present invention relates to the process for the preparation of pharmaceutical formulations in dry powder form comprising formoterol and/or pharmaceutically acceptable derivatives thereof. Said process comprises the following steps: I. The entire amount of excipient is divided into five groups having equivalent weight,

II. A hole is digged in one of the equivalent group of the excipient and formoterol active agent is poured into this hole, then it is covered by the excipient which was set aside while digging the hole (Sandwich Method) and formoterol- excipient mixture is obtained,

III. Two equivalent groups of the excipient, formoterol- excipient mixture obtained in Step II and finally the remaining two equivalent groups of the excipient are added into a mixing vessel respectively and the final dry powder mixture is obtained,

IV. The final dry powder mixture is filled into the capsules.

The inventors have surprisingly seen that the dry powder formulations comprising formoterol prepared in accordance with the process of the present invention have good flow characteristics and have high homogeneity resulting in dosing accuracy and delivery of the sufficient amount of active agent to the lungs.

In step I of the process of the present invention, the excipient is micronized such that the average particle size of the excipient is in the range of in the range of 20μιη to 120 μιη, preferably 30- 100 μηι and more preferably 45- 95 μπι. Total weight of the excipient is 60- 99.99%, preferably 80%-99.95% of the total weight of the formulation. The excipient is divided into five groups having equivalent weight.

In another aspect, the present invention relates to the process for the preparation of the pharmaceutical formulation comprising formoterol in the dry powder form wherein the excipient having the average particle size in the range of 20μηι to 120 μιη, preferably 30- 100 μπι and more preferably 45- 95 μπι is used.

In another aspect, the present invention relates to the process for the preparation of the pharmaceutical formulation comprising formoterol in the dry powder form wherein the excipient is used in an amount in the range of 60-99.99%, preferably 80%-99.95% of the total weight of the formulation. In Step II of the process of the present invention, a hole is digged in one of the equivalent group of the excipient and formoterol active agent is poured into the hole, then it is covered by the excipient which was set aside while digging the hole. This method is referred as to be "Sandwich Method". The inventors have surprisingly seen that in the case that formoterol active agent is mixed with the excipient by using this method, a more homogenous formulation is obtained resulting in the delivery of the sufficient amount of active agent to the lungs and an effective treatment for inhalation.

In another aspect, the present invention relates to the process for the preparation of the pharmaceutical formulation comprising formoterol in the dry powder form wherein formoterol active agent is mixed with the excipient by using Sandwich Method comprising the steps of digging a hole in one of the equivalent group of the excipient, pouring formoterol active agent into this hole and covering active agent by the excipient.

In Step III of the process of the present invention, two equivalent groups of the excipient, formoterol- excipient mixture obtained in Step II and finally the remaining two equivalent groups of the excipient are added into a mixing vessel respectively. They are mixed in 150- 500 rpm, preferably 200-450 rpm for 5-20 minutes. The final dry powder mixture is obtained.

In another aspect, the present invention relates to the process for the preparation of the pharmaceutical formulation comprising formoterol in the dry powder form wherein the final dry powder mixture is obtained by adding two equivalent groups of the excipient, formoterol- excipient mixture obtained in Step II and finally the remaining two equivalent groups of the excipient are added into a mixing vessel respectively and then mixing them 150- 500 rpm, preferably 200-450 rpm.

In another aspect, the present invention relates to the process for the preparation of the pharmaceutical formulation comprising formoterol in the dry powder form wherein the final dry powder mixture is obtained by adding two equivalent groups of the excipient, formoterol- excipient mixture obtained in Step II and finally the remaining two equivalent groups of the excipient are added into a mixing vessel respectively and then mixing them 150- 500 rpm, preferably 200-450 rpm for 5-20 minutes.

In Step IV of the process of the present invention, the final dry powder mixture is filled into the capsules. The capsule can be made of any suitable substance though it is preferably made of a substance selected from the group comprising gelatin, chitosan, starch and/or starch derivatives, cellulose and/or cellulose derivatives or synthetic polymers and it is composed of intertwining top and bottom compartments. The top and the bottom compartments of the capsule can be made of identical or different materials.

According to this, in the case that the capsule used in the process of the present invention is made of cellulose or its derivatives, the capsule material can be selected from, but not limited to, a group comprising hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose. In the case that the capsule used in the process of the present invention is synthetic polymer, the capsule material can be selected from, but not limited to, a group comprising polyethylene, polyetheleneteraphtalate, polycarbonate or polypropylene.

In the case that the capsule material used in the process of the present invention is gelatine, additional agents such as polyethylene glycol, sorbitol, glycerol, propylene glycol, polyethylene oxide - polypropylene oxide block copolymers and/or other polyalcohols and polyethers at different molecular weights can be added into it.

In the process of the present invention, formoterol and/or its pharmaceutically acceptable derivatives used as active agent comprises its pharmaceutically acceptable solvates, hydrates, organic salts, inorganic salts, all of its esters, free base, polymorphs, crystal forms and amorphous forms and/or combinations thereof. Preferably, it is in the form of formoterol fumarate dihydrate form.

The inventors have seen that use of an active agent having an average particle size in the range of 1 μηι to 10 μηι, preferably in the range of 1.5 μηι to 7.5 μιη, more preferably in the range of 1.5 μηι to 5 μιη has a significant contribution to the formulation obtained for having proper flow characteristics and for having dose uniformity and to delivery of the active agent to the lungs in sufficient amount.

In another aspect, the present invention relates to the process for the preparation of the pharmaceutical formulation comprising formoterol in the dry powder form wherein formoterol having average particle size in the range of 1 μιη to 10 μιτι, preferably in the range of 1.5 μι^η to 7.5 μηι, more preferably in the range of 1.5 μπι to 5 μηι is used as active agent. In the dry powder formulation comprising formoterol prepared in accordance with the process of the present invention, formoterol active agent is used in an amount in the range of 1 to 60 μg, preferably in the range of 2 to 50 μg, more preferably in the range of 5 to 25 μg.

In the dry powder formulation comprising formoterol prepared in accordance with the process of the present invention, the excipient can be selected from monosaccharides (glucose etc.), disaccharides (lactose, saccharose, maltose or pharmaceutically acceptable hydrates, anhydrates or a combination thereof etc.), oligosaccharides and polysaccharides (dextrant etc.), polyalcohols (sorbitol, mannitol, xylitol etc.), salts (sodium chloride, calcium carbonate etc.) or a combination thereof. The excipient is preferably lactose, more preferably lactose monohydrate. According to the formulation prepared by the process of the present invention, the amount of the pharmaceutically acceptable excipient is in the range of 1-50 mg, preferably in the range of 2-40 mg, more preferably in the range of 5-35 mg.

The dry powder medicament prepared according to the process of the present invention is used in the treatment of many respiratory diseases, particularly in allergic or non-allergic asthma, allergic rhinitis and chronic obstructive pulmonary disease (COPD). Accordingly, the dry powder formulation prepared according to the process of the present invention is used in the treatment of, but not limited to, asthma at any stages, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), exacerbation of airway hyperactivity, bronchiectasis, chronic obstructive pulmonary including emphysema and chronic bronchitis, respiratory diseases or lung diseases (COPD, COAD or COLD), pneumoconiosis, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis, byssinosis.

The examples below are given in order to provide better understanding of the present invention, yet they do not limit the scope of the invention.

EXAMPLE 1 : Inhalation of dry powder formulations comprising formoterol from capsule

The dry powder formulation comprising formoterol can be obtained by the process of the present invention comprising the following steps;

I. The excipient lactose monohydrate is divided into five groups having equivalent weight,

II. A hole is digged in one of the equivalent group of lactose monohydrate and formoterol active agent is poured into one of the equivalent group of the excipient, then it is covered by lactose monohydrate (Sandwich Method) and formoterol- lactose monohydrate mixture is obtained,

III. Two equivalent groups of lactose monohydrate, formoterol-lactose monohydrate mixture obtained in Step II and finally the remaining two equivalent groups of lactose monohydrate are added into a mixing vessel respectively and the final dry powder mixture is obtained,

IV. The final dry powder mixture is filled into the capsules.

Claims

1. A process for the preparation of the pharmaceutical formulation comprising formoterol in the dry powder form wherein;

I. The enite amount of excipient is divided into five groups having equivalent weight, II.A hole is digged in one of the equivalent groups of the excipient and formoterol active agent is poured into this hole, then it is covered by the excipient which was set aside while digging the hole (Sandwich Method) and formoterol- excipient mixture is obtained,

IV. The final dry powder mixture is filled into the capsules.

2. The process according to claim 1 wherein total weight of the excipient is divided into five groups having equivalent weight.

3. The process according to claims 1-2 wherein formoterol active agent is mixed with the excipient by using Sandwich Method which comprises the steps of digging a hole in one of the equivalent group of the excipient, pouring formoterol active agent into this hole and covering active agent by the excipient which was set aside while digging the hole.

4. The process according to claims 1-3 wherein the final dry powder mixture is obtained by adding two equivalent groups of the excipient, formoterol-excipient mixture obtained in Step II and finally the remaining two equivalent groups of the excipient into a mixing vessel respectively and then mixing them 150- 500 rpm.

5. The process according to claims 1-4 wherein the final dry powder mixture is obtained by adding two equivalent groups of the excipient, formoterol-excipient mixture obtained in Step II and finally the remaining two equivalent groups of the excipient into a mixing vessel respectively and then mixing them 200-450 rpm.

6. The process according to claims 1-5 wherein the final dry powder mixture is obtained by adding two equivalent groups of the excipient, formoterol- excipient mixture obtained in Step II and finally the remaining two equivalent groups of the excipient into a mixing vessel respectively and then mixing them 150- 500 rpm for 5-20 minutes.

7. The dry powder formulation comprising formoterol prepared in accordance with the process according to claims 1-6 wherein the excipient has the average particle size in the range of 20μηι to 120 μπι.

8. The formulation according to claim 7 wherein the excipient has the average particle size in the range of 30 μπι - 100 μ^ηι.

9. The formulation according to claims 7- 8 wherein the excipient has the average particle size in the range of 45 μηι - 95 μιη.

10. The formulation according to claims 7- 9 wherein said formulation comprises the excipient in an amount in the range of 60-99.99%, preferably 80%-99.95% with respect to the total weight of the formulation.

1 1. The formulation according to claim 10 wherein said formulation comprises the excipient in an amount in the range of 80%-99.95% with respect to the total weight of the formulation.

12. The formulation according to claims 7-11 wherein said formulation comprises formoterol having average particle size in the range of 1 μηι to 10 μιη.

13. The formulation according to claim 12 wherein said formulation comprises formoterol having average particle size in the range of 1.5 μηι to 7.5 μ^ηι.

14. The formulation according to claims 12-13 wherein said formulation comprises formoterol having average particle size in the range of 1.5 μ^ηι to 5 μ^ηι.

15. The formulation according to claims 7-14 wherein said formulation comprises formoterol in an amount in the range of 1 to 60 μg.

16. The formulation according to claim 15 wherein said formulation comprises formoterol in an amount in the range of 2 to 50 μg.

17. The formulation according to claims 15-16 wherein said formulation comprises formoterol in an amount in the range of 5 to 25 μg.

18. The formulation according to claims 7-17 wherein said formulation comprises formoterol in the form of formoterol fumarate dihydrate.