TASTE-MASKED POWDER FOR SUSPENSION COMPOSITIONS OF
METHYLPREDNISOLONE
FIELD OF THE INVENTION
The present invention relates to taste-masked powder for suspension compositions of
methylprednisolone and its process of preparation.
BACKGROUND OF THE INVENTION
Methylprednisolone, (6a, 11) - 11, 17, 21-trihydroxy-6-methyl-pregna-l, 4-diene-3, 20 -
dione, is a corticosteroid. It is a synthetic glucocorticoid drug similar to a natural hormone
produced by adrenal glands. Methylprednisolone per se is sold in USA and Canada under the
brand name Medrol® as 4, 8, 16 and 32 mg oral tablets. Methylprednisolone acetate and
sodium succinate salts are available as injectable preparations. It relieves inflammation
(swelling, heat, redness, and pain) and is used to treat certain forms of arthritis; skin, blood,
kidney, eye, thyroid, and intestinal disorders (e.g., colitis); severe allergies; and asthma.
Methylprednisolone is also used to treat certain types of cancer.
Methylprednisolone and some of its pharmaceutically acceptable salts were originally
disclosed and claimed in US 2,897,218 and GB 853,981 patents. These patents exemplify
oral dosage forms including tablets, capsules, liquid suspensions or solutions of the drug. US
4,874,613 patent discloses a pharmaceutical dosage unit (comprising a plurality of subdosage
units disposed within a container) suitable for masking the unpleasant taste of orally
administered methylprednisolone and which facilitates swallowing-.
US 5,874,418 patent describes sulfoalkyl ether cyclodextrin (SAE-CD) based formulations of
methylprednisolone wherein a major portion of the therapeutic agent is not complexed with
the SAE-CD and which is useful in modifying the bioavailability and/ or rate of
bioabsorption of therapeutic agents. SAE-CD based controlled release pharmaceutical
formulations including multi-layered, osmotic pump, coated, and uncoated tablet, minitablet,
pellet, micropellet, particle, powder, and granule dosage forms are disclosed in US 6,046,177
patent. Aqueous, anti-inflammatory methylprednisolone compositions containing
cyclodextrin in solution form suitable as nasal/ oral/ throat spray are disclosed in US
20060045850 Al and US 20060120967 Al patent applications.
Sublingual methylprednisolone formulations are disclosed in WO/1999/040898 patent
application. US 20040265380 Al application describes orodispersible effervescent tablets.
US 20070059346 Al application discloses orally-dissolvable, edible films of the drug.
Mouth dissolving tablets as buccal dosage formulations of methylprednisolone are disclosed
in US 20080317850 Al application. US 20090263476 Al application discloses a rapidly
disintegrating buccal dosage form containing methylprednisolone, at least one noneffervescent
base such as an alkali metal or alkaline earth metal oxide or hydroxide, and a
disintegrant.
A wide variety of oral formulations have been suggested for methylprednisolone, but i
practice the formulation most commonly used is a tablet, which may or may not be scored to
assist in breaking it in half. Tablets, however, suffer from the disadvantage that they provide
a fixed and inflexible dose of the steroid. While this may be quite acceptable or even
desirable when treating adults, it represents a considerable problem to the physician when
treating pediatrics and geriatrics patient group. Swallowing a tablet is difficult for children
and elderly patients. In addition, in children, there is a considerable variation in body weight
and thus very considerable variations in the amount of the steroid which is desired to be
administered. Administering the right dose is particularly critical in case of steroids as an
excessive dose can have growth retarding effects in growing children. Further in elderly
patients, dose titration of steroids is necessary as the administered dose depends upon the
severity of clinical manifestation of a disease or co-morbidity and accompanying
concomitant medication being administered.
Liquid formulations are ideal candidates for pediatric and geriatric use as they are convenient
to swallow and the dosage can be accurately controlled. US 4,448,774 patent discloses
aqueous pharmaceutical solution comprising methylprednisolone, preservative, chelating
agent, and being substantially free of ethanol (particularly suitable for children). However, as
methylprednisolone is very unpalatable, these types of solubilized preparations have the
drawback of a lingering bitter after-taste and thus, poor patient compliance.
Another viable alternative to this limitation is to deliver the drug in the form of suspension.
Ready-made suspensions, however, suffer from the disadvantage that on long storage they
lack stability and with the passage of time they tend to settle down and even cake leading to
inadequate or improper dosing.
There still exists a need for improved, stable and efficiently taste-masked oral compositions
of methylprednisolone with good patient compliance and acceptance, especially for children
and elderly patients.
There is also a need for a simple efficient process for making such a taste-masked powder for
suspension compositions having easy reconstitution, better in-use stability and prolonged
shelf life.
SUMMARY OF THE INVENTION
One embodiment provides dry taste-masked powder for suspension compositions suitable for
use as a liquid suspension for children or elderly patients. The compositions include
methylprednisolone or its salt/ derivative and pharmaceutically acceptable excipients selected
from the group consisting of suspending agents, viscosity enhancers, coating agents,
preservatives, flavouring agents, sweeteners, opacifiers, lubricants, glidants, wetting agents,
surfactants, buffering agents, and diluents.
Another embodiment provides the enhanced taste-masking capability of compositions by
granulating, coating, complexing with ion-exchange resin, forming inclusion complex of the
drug with cyclodextrin or forming solid-dispersion before admixing the drug with other
additives or excipients.
Further, embodiment provides a taste-masked composition of methylprednisolone, wherein
the amount of methylprednisolone varies from about 0.01-50 % by weight of the dry tastemasked
powder for suspension composition. Upon reconstitution, the amount of drug in the
oral suspensions ranges from 2 to 40 mg/ 5mL and preferably from 4 to 24 mg/ 5mL.
Still further embodiment provides a method of preparing a dry methylprednisolone powder
for suspension composition, which is suitable for suspension in water and/ or water miscible
suitable solvents to form an orally administerable product which comprises admixing, at
ambient temperature and humidity conditions, dried taste-masked methylpredniosolone
granules with substantially dry pharmaceutically acceptable excipients selected from the
group consisting of suspending agents, viscosity enhancers, coating agents, preservatives,
flavouring agents, sweeteners, opacifiers, lubricants, glidants, wetting agents, surfactants,
buffering agents, and diluents to form a dry admixture, and transferring the dry admixture to
a sealable storage container.
Still further embodiment provides process for masking the bitter, lingering taste of
methylpredniosolone. The process includes, but is not limited to (i) simple admixture of drug
and taste-masking agent (e.g., sweetener, flavour, etc) followed by granulation & drying, and
optionally coating; (ii) loading non-pareil beads with drug followed by coating with a
polymer, which dissolves/disintegrates in acidic pH of stomach, but is resistant to salivary
pH; (iii) mixing drug with thermodiffusible taste-masking substance; (iv) complexing the
drug with ion-exchange resin; (v) forming inclusion complex of drug with cyclodextrin; and
(vi) forming solid-dispersion of the drug.
DETAILED DESCRIPTION OF THE INVENTION
In view of the description presented in the background, it would be advantageous to develop
an oral taste-masked powder for suspension compositions suitable for use as a liquid
suspension for children and elderly patients.
Further, it would be advantageous to provide a process for the preparation of such a
suspension that is convenient, economical, and requires simple machinery.
It has now been unexpectably found that the unpleasant taste and stability problem may be
addressed by employing methylprednisolone in taste-masked powder for suspension
compositions. The external vehicle is pleasantly flavoured and the insoluble drug remains
suspended, does not come in direct contact with the tongue and thus, does not impart bitter
taste to the preparation. To further enhance the organoleptic properties, other simple and cost
effective techniques may be employed to taste-mask the bitter drug before suspending. Since
the preparation is reconstituted just prior to usage, its physical & chemical stability is
enhanced and caking problem & uneven dosing is avoided. The suspension formed is
particularly convenient for pediatric and geriatric patients.
"Methylprednisolone", as used includes methylprednisolone and its salts, esters o.¾
derivatives. The compositions include a mixture of methylprednisolone and pharmaceutically
acceptable excipients selected from the group consisting of suspending agents, viscosity
enhancers, coating agents, preservatives, flavouring agents, sweeteners, opacifiers,
lubricants, glidants, wetting agents, surfactants, buffering agents, and diluents.
Methylprednisolone may be present at up to about 50 % by weight of the dry powder for
suspension composition. Upon reconstitution, each 5 mL of oral suspension may contain up
to 40 mg and preferably 4 to 24 mg of methylprednisolone.
"Dry powder", as used herein, includes any composition which is dry and flowable such as,
for example, granules, flakes, spheroids and other forms which can be readily prepared and
when added to an ingestible liquid and mixed, give the desired liquid suspension.
The term "suspending agent" or "viscosity enhancer", as used herein, refers to an agent or a
mixture of agents that increases the thickness of a liquid thereby making it slow to flow. For
example, in a suspension a viscosity enhancer will help to keep the active ingredient
suspended to allow accurate dosing. They may be selected from one or more cellulosic
derivatives, gums, polysaccharides, alginates, acrylic acid copoymers, polyvinyl pyrrolidone,
or combinations thereof. Representative suspending agents or viscosity enhancers include,
but are not limited to, acacia, alginic acid, bentonite, carbomer, carboxymethylcellulose
calcium, carrageenan, colloidal silicon dioxide, dextrin, gelatin, guar gum, hydroxyl ethyl
cellulose, hydroxyethyl propylcellulose, hydroxyl propyl cellulose (HPC), hydroxypropyl
methylcellulose, methylcellulose, maltodextrin, microcrystalline cellulose (MCC),
polydextrose, polyvinyl alcohol, povidone, propylene glycol alginate, sodium alginate,
sodium carboxymethylcellulose, starch, tragacanth, xantham gum, and mixtures thereof.
Preferred suspending agents or viscosity enhancers are Avicel® CL 6 11 and mixture of
xanthan gum & HPC (Klucel® LF).
The term "preservative", as used herein, refers to an agent or mixture of agents that is used to
protect a composition against microbes (e.g., yeast, mold; bacteria, etc). Representative
preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride,
benzoic acid, benzyl alcohol, bronopol, butyl paraben, chlorobutanol, chlorocresol,
chlorhexidine, cresol, ethylenediaminetetraacetic acid, ethyl paraben, imidurea, methyl
paraben, phenol, phenylmercuric salts, potassium sorbate, propylene glycol, propyl paraben,
sodium benzoate, sodium citrate, sodium propionate, sorbic acid, thiomerosol, and mixtures
thereof. A preferred preservative is sodium benzoate or mixture of parabens, which impart
synergistic preservative action.
The term "flavouring agent", as used herein, refers to an agent or a mixture of agents that is
natural or artificial in origin and adds flavour to a mixture. Representative flavouring agents
include, but are not limited to, banana, black currant, caramel, cherry, chocolate, cream,
grenadine, mint, raspberry, strawberry, tutti frutti flavours, and mixtures thereof. To enhance
organoleptic properties, combination of flavours may be used. For example, strawberry and
banana flavours may be used together.
The term "sweetener", as used herein, refers to both bulk (caloric) and intense (non-caloric)
sweeteners, which impart sweet taste to the preparation. Examples of bulk sweeteners are
dextrose, fructose, glucose, hydrogenated glucose syrup, isomalt, maltitol, maltose, mannitol,
sorbitol, sucrose, xylitol, and mixtures thereof. Examples of intense sweeteners are
acesulfame, alitame, aspartame, cyclamate, dihydrochalcone sweetener, monellin,
neohesperidin, neotame, saccharin, stevioside, sucralose, the pharmaceutically acceptable
salts thereof such as sodium or calcium saccharin, acesulfame potassium or sodium
cyclamate, and mixtures thereof. Sweetener type, combination and proportion may be varied
in various compositions. For example, acesulfame potassium at a proportion of 0-0.9% by
weight and sucrose at a proportion of 0-90% by weight may be used alone or in combination.
The term "opacifier", as used herein refers to an agent or a mixture of agents which when
added to a preparation make the ensuing system opaque. Representative opacifier agents
include, but are not limited to, pharmaceutically acceptable metal oxides, especially titanium
dioxide.
The term "lubricant", as used herein refers to an agent or a mixture of agents that lessens or
prevents friction. Representative lubricants include, but are not limited to, calcium stearate,
colloidal silicon dioxide, corn starch, hydrogenated vegetable oil, magnesium oxide,
magnesium stearate, sodium lauryl stearate, sodium stearyl fumarate, stearic acid, talc, zinc
stearate, and mixtures thereof. A preferred lubricant is sodium stearyl fumarate.
The term "glidant", as used herein, refers to an agent or a mixture of agents that facilitates
the flow of powders in the manufacturing process. Representative glidants include, but are
not limited to, calcium stearate, colloidal silicon dioxide, fumed silica, magnesium stearate,
magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate, and
mixtures thereof. A preferred glidant is fumed silica (Aerosil® 200).
The term "wetting agent" or "surfactant", as used herein, refers to a surface active agent or a
mixture of agents that lower the interfacial tension between a solid & a liquid or two liquids.
It may be natural or synthetic in origin. Further, it may be non-ionic, anionic, cationic or
amphoteric in nature. Representative examples include, but are not limited to, acacia,
poloxamers, polysorbates such as Tween® 40, 60 & 80, sodium lauryl sulphate, sodium
monolaurate (Span® 20), tragacanth, and mixtures thereof.
The term "buffering agent", as used herein, refers to an agent or a.mixture of agents that can
maintain the original acidity or basicity of a composition. Representative buffering agents
include, but are not limited to, citric acid, disodium hydrogen phosphate, lactic acid,
monosodium citrate, phosphoric acid, potassium citrate, sodium citrate, sodium hydrogen
carbonate, sodium hydroxide, sodium phosphate, succinic acid, tartaric acid, and mixtures
thereof. The amount of buffering agent used is dependent on (a) the desired pH; and (b) the
amount of methylprednisolone per L of the suspension.
The term "diluent", as used herein, refers to an agent or mixture of agents that when added to
a formulation makes that formulation thinner or less concentrated or acts as filler and may
also improve manufacturability. Diluents can also serve other functions. For example, a
diluent can also act as a sweetener and/ or a suspending agent. Representative diluents
include, but are not limited to, dextrose, fructose, lactose, maltitol, microcrystalline cellulose,
sorbitol, starch, sucrose, xylitol, and mixtures thereof. Preferred diluents are sucrose and
microcrystalline cellulose.
The term "non-pareil sphere" or "pellet", as used herein, refers to an agent or a mixture of
agents that otherwise is inert, but acts as an excellent active pharmaceutical ingredient
carrier. Representative examples include, but are not limited to, sucrose, microcrystalline
cellulose and starch.
The term "taste-masking pH-sensitive polymer", as used herein, refers to a polymer or a
mixture of polymers, which disintegrate or dissolve at acidic pH in the stomach but are
resistant to near neutral pH in the mouth. Representative examples include, but are not
limited to, cationic polymers synthesized from dimethylaminoethyl methacrylate and neutral
methacrylic acid esters alone or in combination with small quantities of retardant polymers
like, ethyl cellulose, Eudragit®, hydroxyl propyl cellulose and hydroxypropyl methyl
cellulose. These polymers may also be used as coating agents. Preferred taste-masking pHsensitive
polymers are Eudragit® E 100 and Eudragit® E PO.
The term "plasticizer", as used herein, refers to an agent or a mixture of agents that increases
the plasticity or fluidity of the material to which it is added and imparts softness and
flexibility to the final product, which may be a coat. Representative examples include, but are
not limited to, dibutyl sebacate, glycerol, propylene glycol, triethyl citrate, and mixtures
thereof.
The term "polyethylene glycol", as used herein, refers to an agent or a mixture of agents,
belonging to a family of water-soluble linear polymers, which melt at not more tha 60 °C
and solidify at room temperature. Representative examples include, but are not limited to
various viscosity grades of polyethylene glycol (PEG) like, PEG 1500, PEG 3350, PEG
6000, and mixtures thereof.
The term "antioxidant", as used herein, refers to an agent or a mixture of agents, which are
capable of slowing or preventing the oxidation of other molecules or substances.
Representative examples include, but are not limited to, ascorbic acid, butylated hydroxy
anisole, butylated hydroxy toluene, gallic acid, maleic acid, propyl gallate, sodium
bisulphate, sodium metabisu lphite, tocopherols, and mixtures thereof.
The term "solvent", as used herein, refers to an agent or a mixture of agents in the form of a
liquid, which is used for dissolving another solid or liquid, or as a dispersing or granulating
media. Solvent employed may be aqueous, hydroalcoholic or organic in nature with varying
polarity. Preferred alcohols employed in hydroalcoholic solvent system include, but are not
limited to, ethyl alcohol and isopropyl alcohol alone or in combination. Representative
examples of solvent employed include, but are not limited to, acetone, dichloromethane,
ethyl alcohol, isopropyl alcohol, water, and mixtures thereof.
The term "ion-exchange resin", as used herein, refers to an agent or a mixture of agents,
which can exchange their mobile ions of equal charge with the surrounding medium. Being
high molecular weight water insoluble polyelectrolytes, the resins are not absorbed by the
body and are therefore inert. For optimal taste-masking, drug to ion-exchange resin ratio may
be varied from 1:0.1 to 0.1:1. Representative examples of ion-exchange resins include, but
are not limited to, Amberlite ® CG 50, Amberlite ® IRP-64, Amberlite ® IRP-69, Indion® 204,
Indion® 214, Indion® 234, Indion® CRP 244, Indion® CRP 254, and mixtures thereof.
The term "cyclodextrin", as used herein, refers to an agent or a mixture of agents, capable of
forming stable inclusion complex and masking the bitter taste of the drug by either
decreasing its oral solubility on ingestion or decreasing the amount of drug particles exposed
to taste buds thereby reducing the perception of bitter taste. For optimal taste-masking, drug
to cyclodextrin ratio may be varied from 1:0.1 to 0.1:1. Representative examples of
cyclodextrin include, but are not limited to, alpha cyclodextrin, gamma cyclodextrin, beta
cyclodextrin, cyclodextrin derivative, and mixtures thereof. A preferred cyclodextrin is beta
cyclodextrin.
The term "thermodiffusible substance", as used herein, refers to an agent or a mixture of
agents, which are liquid at elevated temperatures and solid at room temperature. For optimal
taste-masking, drug to thermodiffusible substance ratio may be varied from 1:0.1 to 0.1 :1.
Representative examples of thermodiffusible substances include, but are not limited to,
beeswax, candelilla wax, camauba wax, glyceryl behenate, microcrystalline wax, oricury,
ozokerite, paraffin wax, polyethylene glycol (PEG) wax, PEG 1500, PEG 3350, PEG 6000,
hydrogenated vegetable oil, shellac, and mixtures thereof.
The term "triglyceride", as used herein, refers to small chained, medium chained or long
chained triglyceride, which is an ester of fatty acids and glycerol. Suitable triglycerides for
use may be natural, semi-synthetic or synthetic in origin. Representative examples of
triglycerides include, but are not limited to, Acomed®, Captex®, Mazol®, Miglyol®, Myritol®,
Neobee®, Sefsol®; and naturally occurring or partially/ fully hydrogenated plant, vegetable &
fish oils such as castor oil, coconut oil, olive oil, palm oil, peanut oil, sesame oil, shark oil,
soybean oil, sunflower oil, etc, and mixtures thereof. Preferred triglycerides are Captex® 350
and Miglyol® 812.
The term "solid-dispersion", as used herein, refers to a product formed when the drug is
made to interact physically or chemically with one or more hydrophilic or hydrophobic
substances. The product formed has improved organoleptic properties and optionally, altered
solubility and/ or altered physicochemical properties. Representative examples of
hydrophilic/ hydrophobic substances capable of forming a solid-dispersion include, but are
not limited to, ethyl cellulose, Eudragit®, mannitol, poloxamer, polyethylene glycol, sorbitol,
sucrose, urea, and polymers, like carbopol, copovidone, polyvinyl alcohol, polyvinyl
pyrrolidone, hydroxypropyl methyl cellulose, and mixtures thereof.
Pharmaceutical compositions as described herein are presented as dry powder suspension
composition for constitution with an ingestible liquid such as water before use. The dry
powder for suspension composition can be packed in suitable containers to provide multidose
liquid suspension.
The dry powder after reconstitution with water is set to provide a liquid suspension
containing 4 to 24 mg of methylprednisolone per 5mL of liquid suspension. The dry powder
for suspension composition is stable on storage and when constituted with an ingestible
liquid for administration, the corresponding liquid suspension is stable physically and
chemically for the duration in which the therapy is required.
The dry powder for suspension composition may be prepared by the procedure that includes,
but is not limited to, dry blending of methylprednisolone as such or taste-masked drug and
pharmaceutically acceptable excipients selected from the group consisting of suspending
agents, viscosity enhancers, coating agents, preservatives, flavouring agents, sweeteners,
opacifiers, lubricants, glidants, wetting agents, surfactants, buffering agents, and diluents.
These are then filled into a bottle or a suitable container in an amount suited to a dosage
regimen. A suitable ingestible liquid, particularly water, is added in an amount sufficient to
provide methylprednisolne in desired dosage strength.
Embodiments include one or more of the following features. For example, the composition
may exhibit enhanced taste-masking capability by granulating methylprednisolone with
sweeteners & flavours, and optionally coating with coating agents; coating drug loaded non
pareil beads with taste-masking polymers; complexing methylprednisolne with ion-exchange
resin; forming inclusion complex of the drug with cyclodextrin; or forming solid-dispersion
of the drug before admixing with other additives or excipients at ambient temperature and
humidity conditions and transferring into sealable storage container.
The following examples illustrate various aspects of the invention; but are not intended to be
limiting the scope of the invention.
Example 1
* On dry weight basis of final product
Brief Manufacturing Procedure:
1) Granulate methylprednisolone, sucrose & sucralose with isopropyi alcohol & water
mixture and dry.
2) Sift the dried granules using SS sieve # 30 mesh.
3) Blend the sifted granules with Avicel® CL 6 1, hydroxy, propyl cellulose, xanthan gum,
titanium dioxide, flavour mixture, Aerosil® 200, sodium benzoate, butylated hydroxy
anisole, sodium citrate, citric acid and sodium stearyl fumarate.
4) Fill in dry powder for suspension composition into final container.
Example 2
Step 1 - Methylprednisolone loading on non-pareil spheres and coating
*On dry weight basis of drug loaded non-pareil sphere coated with Eudragit
¾ Particle size distribution of unloaded spheres range from about 250 to 600 or (sieve #
45/60 to sieve # 35/40).
Step 2 - Preparation of suspension blend
*On dry weight basis of final product
Brief Manufacturing Procedure:
1) Dissolve methylprednisolone, ethyl cellulose, and hydroxy propyl cellulose in acetone &
dichloromethane mixture.
2) Load the non-pareil beads with the solution of step 1 in fluidized bed dryer. Dry the
loaded beads.
3) Prepare solution of Eudragit® E 00 in acetone & isopropyl alcohol mixture and coat the
drug loaded beads in fluidized bed dryer.
4) Blend the resultant granules with suspension blend of step 2 in rapid mixer.
5) Fill i dry powder for suspension composition into final container.
Example 3
* On dry weight basis of final product
Brief Manufacturing Procedure:
1) Melt polyethylene glycol (below 60°C) and add sodium metabisulphite to the molten
mass under continuous stirring. Allow the molten mass to solidify. Mill the solidified
mass using SS sieve # 30 mesh.
2) Pass drug, sucralose, maltodextrin, Avicel® CL 6 11 and sucrose through SS sieve # 30
mesh and mix them geometrically in rapid mixer granulator.
3) Add the milled and sieved mass obtained in step 1 to the blend obtained in step 2 in rapid
mixer granulator and mix to obtain homogeneous blend.
4) Dissolve sodium benzoate in acetone and use it for granulating the blend obtained in step
5) Dry the wet granules of step 4 and sift the dried granules through SS sieve # 20 mesh.
6) Lubricate the granules of Step 5 with flavour mixture.
7) Fill i dry powder for suspension composition into final container.
Example 4
Step 1 - Formation of drug-resin complex
* On dry weight basis of drug-resin complex
Step 2 - Preparation of suspension blend
* On dry weight basis of final product
Brief Manufacturing Procedure:
1) Dissolve methylprednisolone sodium succinate in ethyl alcohol & water mixture and add
known weight of ion-exchange resin to the solution under stirring to obtain uniform
slurry.
2) Adjust the pH of the slurry using acidic or alkaline buffering agent.
3) Continue stirring until drug-resin complexation equilibrium is achieved.
4) Wash obtained resinates with minimum amount of isopropyl alcohol to remove
uncomplexed drug.
5) Dry the complexes overnight in a hot air oven at 40°C and then store in tightly closed
dessicator.
6) Mix the above obtained dried resinates with the suspension blend of step 2.
7) Fill in dry powder for suspension composition into final container.
Example 5
Step 1 - Formation of inclusion complex
*On dry weight basis of final product
Brief Manufacturing Procedure:
) Granulate methylprednisolone, cyclodextrin, and polyvinyl pyrrolidone with acetone and
dry.
2) Sift the dried granule using SS sieve # 30 mesh.
3) Mix the sifted granules with sucrose, sucralose, hydroxy propyl cellulose, xanthan gum,
titanium dioxide, flavour mixture, and Aerosil® 200.
4) Lubricate the final blend with sodium stearyl fumarate.
5) Fill in dry powder for suspension composition into final container.
Example 6
*On dry weight basis of final product
Brief Manufacturing Procedure:
1) Melt polyethylene glycol.
2) Add, to the above molten mass, drug & poloxamer and stir.
3) Congeal the above mixture using spray congealing technique.
4) Mill and sift the above material using SS sieve # 30 mesh.
5) Blend the sifted material with carrageenan, sucralose, hydroxyl propyl cellulose, xanthan
gum, titanium dioxide, flavour, and Aerosil® 200.
6) Lubricate the final blend with magnesium stearate.
7) Fill in dry powder for suspension composition into final container.
Example 7
Step 1 - Formation of drug-lipid granulate
Brief Manufacturing Procedure:
1) Dissolve or disperse methylprednisolone and Miglyol® 812 along with poloxamer in
sufficient quantity of acetone. Mix it for sufficient time.
2) Adsorb the above dispersion on sucrose pellets.
3) Dry the drug-lipid granulates and sift it through SS sieve # 30 mesh.
4) Blend the dried drug-lipid granules with xanthan gum, microcrystalline cellulose,
sucrose, sucralose and flavour mixutre.
5) Lubricate the final blend with sodium stearyl fumarate.
6) Fill in dry powder for suspension composition into final container.
Example 8
Step 1 - Formation of solid-dispe
Brief Manufacturing Procedure:
1) Dissolve and mix methylprednisolone and Kollidon® VA 64 in sufficient quantity of
isopropyl alcohol & dichloromethane mixture. Dry the solution in vacuum try drier and
sift it through SS sieve # 30 mesh.
2) Blend the dried drug-Kollidon solid-dispersion with xanthan gum, microcrystalline
cellulose sucrose, sucralose, and flavour mixutre.
3) Lubricate the final blend with sodium stearyl fumarate.
4) Fill in dry powder for suspension composition into final container.
Example 9
*On dry weight basis of final product
Brief Manufacturing Procedure:
1) Dissolve methylprednisolone & part of flavour mixture, and optionally polyethylene
glycol, in acetone, ethyl alcohol & isopropyl alcohol mixture.
2) Mix Avicel® CL 6 11 with sucrose in a rapid mixer granulator and granulate the mixture
with the solution obtained above.
) Dry and sift the granules using SS sieve # 30 mesh. Optionally, coat the obtained
granules with Eudragit® E PO dispersion or solution.
) Blend the sifted granules with hydroxyl propyl cellulose, sodium benzoate, butylated
hydroxy anisole, acesulfame, carrageenan, titanium dioxide, flavour mixture, Aerosil®
200, sodium citrate, citric acid, and sodium stearyl fumarate.
) Fill in dry powder for suspension composition into final container.
CLAIMS
1. A dry taste masked powder composition comprising a steroid or its salts or
derivatives and pharmaceutically acceptable excipients.
2. The composition of claim 1 comprising one or more pharmaceutically acceptable
excipients selected from the group consisting of suspending agent, viscosity enhancer,
coating agents, preservatives, flavouring agents, sweeteners, opacifiers, lubricants,
glidants, wetting agents, surfactants, resins, buffering agents, complexing agents and
diluents.
3. The composition of claim 1 wherein the steroid is methylprednisolone.
4. The composition of claim 1 is in the form of a liquid suspension upon reconstitution.
5. The composition of claim 1 wherem the composition is prepared by granulation
method.
6. The composition of claim 1 comprising about 0.01- 50% by weight of the dry taste
masked powder of steroid.
7. The composition according to claim 4 comprising 2 to 40 mg/ 5 ml of steroid.
8. The composition according to claim 4 wherein the reconstitution is prior to the usage.
9. The dry taste masked powder composition according to claim 1 comprising granules,
flakes or spheroids.
10. The composition according to claim 1 wherein dry powder is prepared by solid
dispersion.
11. The composition according to claim 1 wherein dry powder is prepared by
complexation with complexing agent.
12. The composition according to claim 1 wherein dry powder is prepared by using non
pareil spheres.
13. The composition according to claim 1 wherein dry powder is prepared by drug resin
complexation.
14. The composition according to claim 1 wherein dry powder is prepared by drug lipid
granulates.
15. The composition according to claim 1 wherein dry powder is prepared by solvent
evaporation technique.
16. The dry taste masked powder composition as herein disclosed and exemplified.
17. The process of preparation of dry taste masked powder composition as herein
disclosed and exemplified.