FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"Pharmaceutical Compositions"
2. APPLICANT
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956
(c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008,
Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner
in which it is to be performed.



Technical field
The present invention relates to pharmaceutical compositions comprising a
therapeutically effective isomer of a betamimetic agent for the treatment of
bronchoconstriction, asthma and related disorders thereof.
Background and prior art
Asthma is described as a chronic disease that involves inflammation of the pulmonary
airways and bronchial hyperresponsiveness that results in the clinical expression of a
lower airway obstruction that usually is reversible. Treatment of asthma and other related
disorders have been known to employ p-2 (beta2) agonists, also known as p-2
adrenoreceptor agonists. Such p-2 adrenoreceptor agonists are known to provide a
bronchodilatory effect to patients, resulting in relief from the symptoms of
breathlessness. Short-acting beta2 adrenoreceptors like salbutamol and terbutaline are
recommended for the relief of acute symptoms, while long-acting agents like salmeterol,
formoterol and bambuterol are used preferably in combination with other drugs for long-
term asthma control.
Salbutamol pressurized inhalations are official in the British pharmacopoeia and are used
for the treatment of asthma.
Dey pharmaceutical's patent US 6,702,997 relates to an albuterol inhalation solution,
system, kit and method for relieving bronchospasm in children suffering from asthma
which comprises about 0.63 mg or about 1.25 mg albuterol.
Hydrophilic matrix type tablets based on salbutamol and a process for their preparation is
described in US 5,132,116.
U.K. Pat. GB2120942 describes Salbutamol composition. The composition comprises of
an aqueous dispersion of one or more cellulose derivatives containing salbutamol and/or
one or more of its physiologically acceptable salts which is formulated as a liquid
preparation suitable for oral administration.
It has been proved that racemic albuterol, a commonly used broncho dilator, is an exact
50:50 mixture of two enantiomers, R- and S- isomers of salbutamol. In-vitro studies
2

suggest that the two enantiomers have different binding affinities for the beta-
adrenoreceptor, may exert opposing effects on inflammation, demonstrate different
effects on the mucociliary transport, and display differing pharmacokinetics. The R-
isomer has greater bronchodilatory effects than the racemate and may have anti-
inflammatory properties. S-isomer has markedly less affinity for the beta-adrenoreceptor.
Several methods for preparation of levoalbuterol have been described in the prior arts
such as US patent application number 20040115136 by King Code which describes a
method of preparation of levalbuterol tartarate. It further relates to levalbuterol L-tartrate
possessing properties desirable for use in a metered dose inhaler.
US 5,547,994 by Sepracor describes a method for treating asthma, using the optically
pure R (-) isomer of albuterol, which is substantially free of the S (+) isomer, a potent
bronchodilator for relieving the symptoms associated with asthma in individuals.
CN1413976 by Suzhou Junning New Drug Dev CT (CN) describes the synthesis of
levosalbutamol.
US patent application number US2004054215 by CIPLA Limited, discloses a method for
obtaining an optically pure R-isomer of albuterol.
The present invention hereby provides a pharmaceutical composition comprising a
therapeutically effective isomer of a betamimetic agent or a salt, solvate, ester,
derivatives & polymorph thereof, thereby providing a novel formulation.
Objective of the invention
The object of the present invention is to provide pharmaceutical compositions, which
provides the advantages of potent and selective therapeutic activity by employing the
therapeutically more effective isomer of betamimetic agent.
3

It is another object of the present invention to provide a formulation, which comprises of
a combination of the therapeutically more effective isomer of betamimetic agent, its salts,
solvates, esters, derivatives, isomers & polymorphs thereof, an anti-cholinergic agent
salts, solvates, esters, derivatives, isomers & polymorphs thereof, thereby providing
novel formulation for patients with chronic disorders of respiratory tract such as asthma
and COPD,
It is still another object of the present invention to provide for formulations which
employs the therapeutically effective isomer of betamimetic agent or salts, solvates,
esters, derivatives, isomers & polymorphs thereof, thereby providing a more potent
formulation and therefore avoiding side effects associated with higher dosages.
Another object of this invention is to provide for a pharmaceutical composition for
treatment in respiratory disorders such as asthma, Chronic Obstructive Pulmonary
Disorder (COPD) disorders resulting in bronchoconstriction.
It is yet another object of this present invention to provide for a method of preparation of
the pharmaceutical composition of the present invention.
A further object of the present invention is to provide different dosage forms comprising
levosalbutamol with other pharmaceutically acceptable carriers.
Summary of the invention
The present invention provides a novel pharmaceutical composition comprising a
therapeutically effective isomer of betamimetic agent, salts, solvates, esters, derivatives,
isomers & polymorphs thereof, in a dosage form suitable for oral administration or as an
inhalation.
It is also provided by the present invention a suitable method for preparing the said novel
pharmaceutical compositions.
4

The present invention also aims to provide a novel pharmaceutical composition for the
treatment of respiratory and related disorders such as asthma, COPD, and such other
disorders, which result in bronchoconstriction.
Description of the invention:
Betamimetic agents are known to provide a bronchodilator effect to patients by acting on
the p-2 adrenergic receptors in the airway smooth muscles and the bronchial smooth
muscles, resulting in relief from the symptoms of breathlessness. More particularly,
betamimetic agents have been shown to increase the conductance of potassium channels
in airway muscle cells, leading to membrane hyperpolarization and relaxation. Therefore
being very selective in their activity, they are preferred class of bronchodilators. This
class comprises of compounds such as salbutamol, salmeterol, formoterol, rimeterol,
acebutolol.
The present invention describes the advantages associated by employing the
therapeutically effective isomers of these compounds. Compounds such as salbutamol,
salmeterol and formoterol are known to exist as their R- and S-isomers and in all the
three cases the R-isomers are more active than the S-isomers. Difference in activity is
such that the S-isomer has markedly less affinity for the beta-adrenoreceptors than the R-
isomer. The R-isomer has greater bronchodilatory effects and has anti-inflammatory
properties. Therefore, the R-isomers are much more therapeutically active, and are
therefore the preferred drug of choice. Although, use of only these compounds helps to
bring about sufficient dilation of the bronchial vessels so as to provide relief but in order
to avoid development of tolerance to such drugs there are often given in combination
with other bronchodilators.
Salbutamol is available as a racemic mixture comprising R and S form. The
bronchodilatory property of racemic salbutamol is attributable entirely to (R)-
salbutamol, which has an approximately 100 fold greater binding affinity for beta-2
receptors as compared to (S)- salbutamol. This divergent pharmacology accentuates the
need of levo salbutamol over racemic salbutamol in the treatment of asthma and other
5

airway diseases. Levosalbutamol is a more potent bronchodilator when administered as
the single enantiomer compared with the same amount in a racemic mixture.
Levosalbutamol produces comparable efficacy at nearly one-fourth the dose of racemic
salbutamol, simultaneously reducing the beta-mediated side effects.
The present invention now discloses pharmaceutical compositions containing a
therapeutically effective isomer of betamimetic agent salts, solvates, esters, derivatives,
isomers & polymorphs thereof, and more preferably levosalbutamol. The active
ingredient of all these compositions is levosalbutamol sulfate. The drug levosalbutamol
sulfate can be micronised, has good flow properties and desired bulk density and hence
may be formulated with pharmaceutical diluents and/or carriers to provide
pharmaceutical compositions suitable for use in respiratory and related disorders such as
asthma and COPD therapy.
By the use of therapeutically effective isomer i.e. levosalbutamol, the dosage of the
betamimetic agent to be administered is reduced to half or even less. Due to lesser-
administered dosage, there are lesser cardiovascular complications, which are associated
with higher doses of bronchodilators. Therefore, the use of such a composition
comprising of a therapeutically effective isomer results in increased patient compliance.
The present invention therefore provides different dosage forms comprising
levosalbutamol salts, solvates, esters, derivatives, isomers & polymorphs thereof, along
with suitable pharmaceutically acceptable carriers.
The term levosalbutamol is used in the entire specification in a broad sense to include its
salts, solvates, esters, derivatives, isomers & polymorphs thereof, polymorphs or
derivatives of levosalbutamol or mixtures thereof
According to one aspect of the present invention levosalbutamol may be formulated as a
solid oral dosage form e.g. tablet, capsule, extended release granules/tablet etc. These are
formulated by techniques known to any person skilled in the art.
6

Levosalbutamol can be blended with diluents, binders, disintegrants, glidants, lubricant
and the resulting mixture is compressed. The tablets may be coated or uncoated.
According to another aspect of the present invention levosalbutamol may be formulated
as liquids. The liquid formulation may comprise one or more of suitable ingredients for
liquid formulation like thickeners, sweeteners, buffering agents, preservatives, artificial
colors, chelating agents/sequestering agents and flavours and other ingredients in addition
to levosalbutamol.
The formulation of the present invention has a pH in the range of 3.0 to 5.0.
In a further aspect of the present invention, there is provided a process for manufacture of
a pharmaceutical composition comprising levosalbutamol in a suitable liquid carrier
which can be made according to the techniques known in the art.
The manufacturing process comprises, dissolving preservative, sequestering agent and
buffers in specified amount of purified water followed by addition of the drug. This is
followed by the addition of other ingredients to the above solution. The pH is checked
and finally the volume is made up.
The levosalbutamol according to the present invention can be administered in a dose of
30mcg to 8mg.
According to yet another aspect of the present invention the levosalbutamol may be
formulated as metered dose inhaler, dry powder inhalation or inhalation solution.
The drug when used in formulation as an inhalable dosage form yields a good fine
particle dose.
For the dry powder inhalation, the drug may be separately finely divided or optionally
together with a finely divided pharmaceutically acceptable carrier, which is preferably
present and may be chosen from materials known as carriers in dry powder inhalation
compositions, for example saccharides, including monosaccharides, disaccharides,
polysaccharides and sugar alcohols. The dry powder is in capsules of gelatin packed in
blisters or alternatively, the dry powder may be contained as a reservoir in a multi-dose
7

dry powder inhalation device. The particle size of the active ingredient and that of the
carrier where present in dry powder compositions, can be reduced to the desired level by
conventional methods, for example by grinding in an air-jet mill, ball mill or vibrator
mill, microprecipitation, spray-drying, lyophilisation or recry stall isation from
supercritical media.
For inhalation solutions, the combination may be combined with suitable excipients such
as tonicity agents, pH regulators, chelating agents hi a suitable vehicle. The liquid
vehicles include, but are not limited to, polar solvents, compounds that contain hydroxyl
groups or other polar groups. Such solvents include, but are not limited to, water or
alcohols, such as ethanol, isopropanol, and glycols including propylene glycol,
polyethylene glycol, polypropylene glycol, glycol ether, glycerol and polyoxyethylene
alcohols.
Further polar solvents also include protic solvents, including, but not limited to, water,
aqueous saline solutions with one or more pharmaceutically acceptable salt(s), alcohols,
glycols or a mixture thereof. For a saline solution as the solvent or as a component
thereof, particularly suitable salts are those which display no or only negligible
pharmacological activity after administration.
Further according to the present invention there is also provided a process for
manufacture of the inhalation solution comprising levosalbutamol which can be made
according to the techniques known in the art.
The process comprises dissolving the drug, chelating agents, isotonicity adjusting agents
and any other suitable ingredient in the vehicle and adjusting the pH using suitable pH
adjusting agent.
The levosalbutamol may be combined with suitable excipients such as tonicity agents, pH
regulators, chelating agents, complexing agents in a suitable vehicle to form an inhalation
solution.
8

Most of the inhalation solutions are formulated with sodium chloride as an isotonicity-
adjusting agent.
Preferably a nasal inhalation formulation as provided by the present invention has a pH in
the range of 3 to 5.
The aerosol formulation according to the present invention may optionally comprise in
addition to levosalbutamol and atleast one propellant, other pharmaceutically acceptable
agents like cosolvents, antioxidants or surfactants. The pressurized inhalable dosage form
also has good suspension quality, Levosalbutamol may be administered in the doses of
0.63 meg to 1.5 mg upto 3-4 times daily.
The propellant according to the present invention includes atleast one propellant selected
from propellant 11 (dichlorodifluoromethane), propellant 12
(monofluorotrichloromethane), Propellant 114, 1,1,1,2-tetrafluoroethane (HFA134a) and
1,1,1,2,3,3,3-heptafluoropropane (HFA227), or mixtures of two or more such halogen-
substituted hydrocarbons.
In a preferred embodiment the aerosol composition may comprise of levosalbutamol and
either propellant 11 or propellant 114 or a combination thereof and propellant 12
In another preferred embodiment of the present invention the aerosol may comprise of
levosalbutamol and either propellant 11 or propellant 114 or a combination thereof and
propellant!2 with surface-active agents known in the art.
Surfactants may be added to improve the homogeneity of dispersion. Various surfactants
known in the art like oils and such like are used.
In the compositions for inhalation particle size of the active drug is particularly
important. The preferred particle size is between 2 u to 5u, It has also been found that the
9

particle size has a considerable influence on the proportion of active substance in the
aerosol which is delivered for inhalation.
In yet another embodiment levosalbutamol and/or surfactant can be micro-milled with
propellant 11 or propellant 114 or a combination thereof to improve the FPD. The slurry
so formed is then filled in canisters, and charged with propellant 12.
In a further embodiment of the present invention there is provided a process for the
manufacture of CFC aerosol which process comprises of (a) Addition of levosalbutamol
with or without surfactant with either propellant 11 or propellant 114 or a combination
thereof, (b) Filling the slurry in the canisters, (c) Crimping with the suitable valve and (d)
charging with propellant 12 through the valve.
In yet another preferred aspect of the present invention the aerosol composition may
comprise levosalbutamol and either 1,1,1,2-tetrafluoroethane (HFA134a) or 1,1,1,2,3,3,3-
heptafluoropropane (HFA227) or a combination thereof.
In a further aspect of the present invention there is provided a process for the
manufacture of the above aerosol composition which method comprises of (a) Addition
of levosalbutamol. (b) Crimping the canister with the metered valve (c) charging with
either 1,1,1,2-tetrafluoroethane (HFA134a) or 1,1,1,2,3,3,3-heptafluoropropane
(HFA227) or a combination thereof.
In another embodiment levosalbutamol can be micro-milled using beads for about 24-48
hours, more preferably for 24 hours. The beads are added in a proportion of 1:1 with the
HFA propellant. The levosalbutamol particles so obtained help to improve the respirable
fraction of the formulation.
In another preferred aspect of the present invention the aerosol composition may
comprise levosalbutamol, either 1,1,1,2-tetrafluoroethane (HFA134a) or 1,1,1,2,3,3,3-
10

heptafluoropropane (HFA227) or a combination thereof and a cosolvent. In such a case
the cosolvent has a greater polarity than the propellant.
Typically the cosolvent is present in a proportion of 0.01 to 5 % of the formulation. The
cosolvent used may be selected from the group of glycols, particularly propylene glycol,
polyethylene glycol and glycerol or alcohols like ethanol. Typically the cosolvent is
ethanol.
In a preferred aspect of the present invention there is provided a process for the
manufacture of the above composition which method comprises (a) Addition of
levosalbutamol to the canister, (b) Addition of the cosolvent to (a) and sonication of the
same, (c) Crimping the canister with the metered valve (d) charging with either 1,1,1,2-
tetrafluoroethane (HFA134a) or 1,1,1,2,3,3,3-heptafluoropropane (HFA227) or a
combination thereof.
In yet another preferred embodiment the aerosol composition may comprise of
levosalbutamol, and either 1,1,1,2-tetrafluoroethane (HFA134a) or 1,1,1,2,3,3,3-
heptafluoropropane (HFA227) or a combination thereof, surfactant and the said
cosolvent.
The surface-active agent stabilizes the formulation and helps in the lubrication of a valve
system in the inhaler. Some of the most commonly used surface active agents are those
known in the art.
In another aspect of the present invention there is provided a process for the manufacture
of the above composition which method comprises (a) Addition of levosalbutamol to the
canister, (b) Addition of the cosolvent and the surfactant solution to (a) and sonication of
the same, (c) Crimping the canister with the metered valve (d) charging with either
1,1,1,2-tetrafluoroethane (HFA134a) or 1,1,1,2,3,3,3-heptafluoropropane (HFA227) or a
combination thereof.
11

In yet another aspect of the present invention the aerosol composition may comprise of
levosalbutamol, a bulking agent and the said propellant. The bulking agent acts as a
carrier for the drug to reach the lungs and may be selected from the class of saccharides,
including monosaccharides, disaccharides, polysaccharides and sugar alcohols.
In a preferred aspect of the present invention there is provided a process for the
manufacture of the above aerosol composition which method comprises (a) Addition of
levosalbutamol to the canister, (b) Addition of the bulking agent to (a) (c) Crimping the
canister with the metered valve (d) charging with the propellant.
In a preferred aspect of the present invention the aerosol composition may comprise of
levosalbutamol, a surfactant and either 1,1,1,2-tetrafluoroethane (HFA134a) or
1,1,1,2,3,3,3-heptafluoropropane (HFA227) or a combination thereof. The surfactant may
be selected from the class of salts of stearic acids or esters-
In a preferred aspect of the present invention there is provided a process for the
manufacture of the above aerosol composition which method comprises (a) Addition of
levosalbutamol to the canister, (b) Addition of the surfactant to (a) (c) Crimping the
canister with the metered valve (d) charging with either 1,1,1,2-tetrafluoroethane
(HFA134a) or U,l,2,3,3,3-heptafluoropropane (HFA227) or a combination thereof.
The present invention may optionally contain antioxidants like citric acid, benzalkonium
chloride.
The present invention may also be formulated to be administered orally, buccally or
sublingually in the form of multi-particulates, gels, films, suppositories, elixirs, solutions
or suspensions, which may contain flavouring or colouring agents. The present invention
may also be formulated as dry powder inhalation. The present invention may also be
formulated to be administered as fast-dispersing or fast-dissolving dosage forms or as
coated particles. Suitable formulations of the present invention may be in coated or
uncoated form, as desired.
12

The present invention further provides for a method for the treatment in a mammal, such
as a human, of respiratory disorders such as asthma, disorders resulting in
bronchoconstriction, which method comprises administration of a therapeutically
effective amount of a pharmaceutical composition according to present invention.
It will be readily apparent to one skilled in the art that varying substitutions and
modifications may be made to the invention disclosed herein without departing from the
spirit of the invention. Thus, it should be understood that although the present invention
has been specifically disclosed by the preferred embodiments and optional features,
modification and variation of the concepts herein disclosed may be resorted to by those
skilled in the art, and such modifications and variations are considered to be falling
within the scope of the invention.
The following examples are for the purpose of illustration of the invention only and are
not intended in any way to limit the scope of the present invention.
Example 1: CFC inhaler

Sr.
No. Ingredients Qty /can
1. Levosalbutamol sulphate 12.00mg
2. Lecithin 0.60mg

3. Propellant 1 1 5.70g
4. Propellant 12 14.70g
Levosalbutamol sulphate and lecithin were added with propellant 11
(b) The slurry formed was filled in the canisters.
(c) This was crimped with the suitable valve and
(d) Charged with propellant 12 through the valve.
13

Example 2: HFA inhaler

Sr.
No. Ingredients Qty/can
1. Levosalbutamol sulphate 12.00mg
2. HFA 134a 18.2gm
Levosalbutamol sulphate was added to the canister.
The canister was crimped with the metered valve and
Charged with 1,1,1,2-tetrafluoroethane (HFA134a) and sonicated.
Example 3: HFA inhaler

Sr.
No. Ingredients Qty/can
1. Levosalbutamol sulphate I2.00mg
2. HFA227 20.4gm
Levosalbutamol sulfate was added to the canister.
The canister was crimped with the metered valve and
Charged with either 1,1,1,2,3,3,3-heptafluoropropane (HFA227) and sonicated
Example 4: HFA inhaler

Sr.
No. Ingredients Qty/can
1. Levosalbutamol sulphate 12.00mg
2. Alcohol 0.364gm
3. Oleic acid 0.0024 mg
4. HFA134a n.S4g
Levosalbutamol was added to the canister.
Alcohol and surfactant were added to (a) and sonicated.
The canister were crimped with the metered valve and
14

Charged with 1,1,1,2-tetrafluoroethane (HFA134a).
Example 5

Ingredients Qty/can
Levosalbutamol sulfate 12.00mg
Lactose 12.00mg
HFA134a 18.2gm
Levosalbutamol sulphate was added to the canister.
lactose was added to (a)
The canister were crimped with the metered valve and
Charged with 1,1,1,2-tetrafluoroethane (HFA134a) and sonicated.
Example 6

Ingredients Qty/can
Levosalbutamol sulfate 12.00mg
Ethanol 0.364gms
HFA227 20.136gms
Levosalbutamol was added to the canister.
Alcohol was added to (a) and Sonicated
The canister were crimped with the metered valve and
Charged with HFA227.
Example 7

Ingredients Qty/can
Levosalbutamol sulfate 12.00mg
Magnesium stearate 0.0012mg
HFA227 20.5gms
Levosalbutamol was added to the canister.
15

Magnesium stearate was added to (a)
The canister were crimped with the metered valve and
Charged with HFA227 and sonicated.
Example 8

Ingredients Qty/can
Levosalbutamol sulfate 12.00mg
Isopropyl myristate 0.0012mg
HFA227 20.5.6gms
Levosalbutamol was added to the canister.
Isopropyl myristate added to (a)
The canister were crimped with the metered valve and
Charged with HFA 227 and sonicated.
Example 9: HFA inhaler

Sr.
No. Ingredients Qty /can
1. Levosalbutamol sulphate 12.00mg
2. Alcohol 0.364gm
3. Oleic acid 0.0024 mg
4. HFA227 17.84g
Levosalbutamol was added to the canister.
Alcohol and oleic acid were added to (a) and sonicated
The canister were crimped with the metered valve and
Charged with HFA227.
16

Example 10:
Tablet formulations

Sr.
No Ingredients Qty (mg/tab)
1. Levosalbutamol sulphate 2.40
2. Starch 66.00
3. Microcrystalline cellulose 10.00
4. Lactose 130.00
5. Sodium starch glycollate 10.00
6. Starch 3.40
7. Gelatin 1.40
8. Purified water Qs
9. Colloidal silicon dioxide 1.20
10. Talc 2.60
11. Magnesium stearate 3.00
Process.
1 and a part of 2 were cosifted to form premix A. 2,3,4,5 were loaded along with premix
A into a product bowl. A starch gelatin paste was formed using 6, 7, 8. The starch gelatin
paste was sprayed into the blend in the product bowl to from granules. The granules so
obtained were lubricated with 9,10,11 and compressed.
17

Example 11

SR.
No. Ingredients Qty (mg/tab)
1. Levosalbutamol sulphate 1.20
2. Starch 33.00
3. Microcrystalline cellulose 5.00
4. Lactose 65.00
5. Sodium starch glycollate 5.00
6. Starch 1.70
7. Gelatin 0.70
8. Purified water Qs
9. Colloidal silicon dioxide 0.60
10. Talc 1.30
11. Magnesium stearate 1.50
Process.
1 and a part of 2 was cosifted to form premix A. 2,3,4,5 were loaded along with premix A
into a product bowl. A starch gelatin paste was sprayed using 6, 7, 8. The starch gelatin
paste was sprayed into the blend in the product bowl to form granules. The granules so
obtained are lubricated with 9,10,11 and compressed.
Example 12

Sr.No Ingredients Qty (mg/tab)
1. Levosalbutamol Sulfate 2.00
2. Sodium Chloride 70.00
3. Polyethylene oxide 20.00
4. Lactose monohydrate 75.50
5. Hydroxypropyl cellulose 30.00
6. Colloidal silicon dioxide 1.50
18

7. Magnesium stearate 1.00
Film coating
9. Cellulose acetate 6.6
10 Hydroxypropylmethyl cellulose 1.0
11 Polyethylene glycol 0.4
12. Ethanol qs
13. Methylene chloride qs
All the tabletting ingredients except magnesium stearate were sifted. The sifted
ingredients were then lubricated using magnesium stearate. The blend so formed was
compressed to form tablets. Cellulose acetate, hydroxypropylmethylcellulose and
polyethylene glycol were in ethanol and methylene chloride mixture to form a film
coating solution. The tablets were then coated with the film coating solution and were
drilled on laser drilling machine.
Example 13

Sr.No Ingredients Qty (mg/tab)
1. Levosalbutamol sulfate 2.4
2. Hydroxypropylmethyl cellulose 30.0
3. Lactose monohydrate 63.35
4. Talc 1.5
5. Colloidal silicon dioxide 1.5
6. Magnesium stearate 0.75
7. Magnesium stearate 0.5
Levosalbutamol sulfate and lactose were cosifted to form premix I. A blend of HPMC,
colloidal silicon dioxide, talc, magnesium stearate and premix I was made. This blend
was then subjected to slugging. The tablets so formed were then milled and further
passed through appropriate mesh. The granules so obtained were then lubricated with
magnesium stearate.
19

Example 14

Sr. No Ingredients Qty (mg/tab)
Tablets
1. Levosalbutamol Sulfate 2.00
2. Calcium sulfate 20.00
3. Croscarmellose sodium 10.00
4. Lactose monohydrate 76.50
5. Colloidal silicon dioxide 1.50
6. Ethanol qs
7. Magnesium stearate 1.00
Film coating
9. Ethyl cellulose 4.2
10 Hydroxypropylmethyl cellulose 3.4
11 Polyethylene glycol 0.4
12. Ethanol qs
13. Methylene chloride qs
Levosalbutamol sulfate, calcium sulfate, lactose monohydrate, croscarmellose sodium,
and colloidal silicon dioxide were sifted to form premix A. The premix A was granulated
using ethanol. The granules so formed were lubricated using magnesium stearate and
compressed to form tablets. Ethyl cellulose, hydroxypropylmethylcellulose and
polyethylene glycol were in ethanol and methylene chloride mixture to form a film
coating solution. The tablets were then coated with the film coating solution and were
drilled on laser drilling machine.
Example 15: liquid

Sr.No Ingredients Qty (%w/v)
1. Levosalbutamol sulphate 0.0241
2. Sodium benzoate 0.200
3. Hydroxy propyl methylcellulose 0.300
20

4. Disodium edetate 0.050
5. Sodium citrate 0.100
6. Citric acid monohydrate 0.200
7. Sodium chloride 0.100
8. Sweet orange 0.200
9. Sodium saccharin 0.100
10. Sunset yellow 0.004
11. Purified water q.s. 100.00
Procedure: In specified amount of purified water was added the ingredients 2, 4, 5 and 6
and were dissolved. 1 was added to the above solution followed by ingredient 9, 7 and 3.
The pH was adjusted between 3.0 to 5.0. Ingredient 8 and 10 were added and the volume
was made up using 11 and mix for specified time.
Example 16: liquid

Sr.No Ingredients Qty (%w/v)
1. Levosalbutamol sulphate 0.0241
2. Sodium benzoate 0.200
3. Hydroxy propyl methylcellulose 0.300
4. Disodium edetate 0.050
5. Sodium citrate 0.100
6. Citric acid monohydrate 0.200
8. Sweet orange 0.200
9. Sodium saccharin 0.100
10. Sunset yellow 0.004
11. Purified water q.s. 100.00
Procedure: In specified amount of purified water was added the ingredients 2, 4, 5 and 6
and were dissolved. 11 was added to the above solution followed by ingredient 9 and 3.
The pH was adjusted between 3.0 to 5.0. Ingredient 8 and 10 were added and the volume
was made up using 11 and mix for specified time.
21

Example 17: liquid

Sr. No Ingredients Qty (%w/v)
1. Levosalbutamol sulphate 0.0241
2. Sodium benzoate 0.200
3. Sorbitol solution 70% 40.00
4. Disodium edetate 0.050
5. Sodium citrate 0.100
6. Citric acid monohydrate 0.200
7. Sodium chloride 0.100
8. Sweet orange 0.200
9. Sodium saccharin 0.100
10. Sunset yellow 0.004
11. Purified water q.s. 100.00
Procedure: In specified amount of purified water was added the ingredients 2, 4, 5 and 6
and were dissolved. 1 was added to the above solution followed by ingredient 9, 7 and 3.
The pH was adjusted between 3.0 to 5.0. Ingredient 8 and 10 were added and the volume
was made up using 11 and mix for specified time.
Example 18: liquid

Sr.No Ingredients Qty (%w/v)
1. Levosalbutamol sulphate 0.0241
2. Sodium benzoate 0.200
3. Hydroxy propyl methylcellulose 0.300
4. Disodium edetate 0.050
5. Sodium citrate 0.100
6. Citric acid monohydrate 0.200
7. Sodium chloride 0.100
8. Sweet orange 0.200
22

9. Sucrose 50.00
10. Sunset yellow 0.004
11. Purified water q.s. 100.00
Procedure: In specified amount of purified water was added the ingredients 2, 4, 5 and 6
and were dissolved. 1 was added to the above solution followed by ingredient 9, 7 and 3.
The pH was adjusted between 3.0 to 5.0. Ingredient 8 and 10 were added and the volume
was made up using 11 and mix for specified time.
Example 19

Sr.No Ingredients Qty (%w/v)
1. Levosalbutamol sulfate 0.0602
2. Sodium chloride 0.900
3. Disodium Edetate 0.050
4. Sulfuric acid QstopHS.Oto 5.0
5. Purified water Qs 100ml
The disodium edetate, sodium chloride, levosalbutamol sulfate were dissolved in water
and the pH was adjusted.
Example 20

Sr.No Ingredients Qty (%w/v)
1. Levosalbutamol sulfate 0.015
2. Sodium chloride 0.900
3. Disodium Edetate 0.050
4. Sulfuric acid QstopH3.0to5 0
5. Purified water Qs 100ml
The disodium edetate, sodium chloride, levosalbutamol sulfate were dissolved in water
and the pH was adjusted.
23

Example 21

Sr.No Ingredients Qty (%w/v)
1. Levosalbutamol sulfate 0.0304
2. Sodium chloride 0.900
3. Disodium Edetate 0.050
4. Sulfuric acid QstopH3.0to5 0
5. Purified water Qs 100ml
The disodium edetate, sodium chloride, levosalbutamol sulfate were dissolved in water
and the pH was adjusted.
Example 22

Sr.No Ingredients Qty mg/cap)
1. Levosalbutamol sulfate 1.2
2. Lactose 45.0
3. Starch 20.0
4. Microcrystalline cellulose 33.3
5. Magnesium stearate 0.5
All the ingredients were blended and filled in appropriate size capsules.
24

We claim,
1. A pharmaceutical composition comprising a therapeutically effective isomer of a
betamimetic agent or a salt, solvate, ester, derivative, isomer or polymorph
thereof substantially free of the less therapeutically effective isomer(s) of said
agent.
2. A pharmaceutical composition according to claim 1, wherein the therapeutically
effective isomer is the R-isomer of the betamimetic agent.
3. A pharmaceutical composition according to claim 1 or 2, wherein the betamimetic
agent is R-salbutamol, or R-salmeterol, or R,R-Formoterol, or a salt, solvate,
prodrug, polymorph or derivative thereof.
4. A pharmaceutical composition according to any preceding claim, wherein the
betamimetic agent is R-salbutamol sulphate.
5. A pharmaceutical composition as claimed in any of the preceding claims,
comprising suitable pharmaceutical ly acceptable excipients to form an oral or
inhalation formulation.
6. A pharmaceutical composition according to claim 4 and 5 in the form of metered
dose inhaler.
7. A metered dose inhaler according to claim 6, comprising pharmaceutical ly
acceptable excipients such as one or more hydrofluorocarbon propellants, and
optionally one or more surfactants, or one or more cosolvents and/or one or more
antioxidants.
8. A pharmaceutical composition according to claim 4 in the form of a dry powder
inhaler.
25

9. A dry powder inhaler according to claim 8, comprising pharmaceutically
acceptable carrier suitable to form a composition for a dry powder inhaler.
10. A pharmaceutical composition according to claim 4, or a dry powder inhaler
according to claim 8 or 9, wherein the pharmaceutically acceptable carrier is
saccharides, selected from monosaccharides, disaccharides, polysaccharides and
sugar alcohols.
11. A pharmaceutical composition according to claim 4 in the form of an inhalation
solution.

12. An inhalation solution according to claim 11, comprising pharmaceutically
acceptable excipients such as a polar solvent, a tonicity-adjusting agent, an acid,
and optionally a chelating agent.
13. A process for preparing a metered dose inhaler according to claim 5, 6 or 7, said
process comprises adding the active ingredients to a suitable canister, crimping
the canister with a metered dose valve, and charging the canister with propellant.

14. A process for preparing a dry powder inhaler according to claim 8, 9 or 10, said
process comprises mixing the active ingredients optionally with a suitable carrier,
and providing the composition in a dry powder inhaler.
15. A process for preparing a pharmaceutical composition according to claim 11 or
12, said process comprises dissolving or suspending the active ingredients
optionally together with chelating agents, tonicity adjusting agents and any other
suitable excipients, in a liquid vehicle, and adjusting the pH.
16. A pharmaceutical composition according to claim 4, in the form of a liquid oral
solution.
26

17. A pharmaceutical composition according to claim 16, comprising
pharmaceutically acceptable excipients such as one or more preservatives,
viscosity enhancers, sequestering agent, buffers and sweeteners.
18. A process for preparing an oral solution according to claim 16 or 17, said
process comprises: dissolving preservative, sequestering agent and buffers in
specified amount of purified water; adding the drug to this solution; adding the
sweetener and thickener with stirring at slow speed with a maintained pH; and
making up the volume using purified water.
19. A pharmaceutical composition according to claim 4, in the form of a oral solid
dosage forms such as tablets and capsules
20. A process for preparation of pharmaceutical composition according to claim 4
and 19, comprises, granulating levosalbutamol or a pharmaceutically acceptable
salt with one or more diluents and/or binders to form granules; mixing the
granules with one or more pharmaceutically acceptable excipients to form a
mixture; and compressing the mixture to form a tablet.
21. A process as claimed in claim 20, which process comprises spraying a solution
or suspension of levosalbutamol or a pharmaceutically acceptable salt in a
solvent onto inert cores to form a first layer; blending the core having the first
layer with one or more pharmaceutically acceptable excipients to form a blend.
22. A process as claimed in any of the claims 20 and 21 wherein the granules
obtained can be compressed to form tablets or wherein the granules obtained can
be encapsulated to form capsules.
Dated this the 16th day of September 2005

27