Title of Invention

A PHARMACEUTICAL EXCIPIENT SUITABLE AS A SOLUBILITY ENHANCER FOR A PHARMACEUTICAL COMPOSITION

Abstract A pharmaceutical excipient suitable as a solubility enhancer for a pharmaceutical composition comprising a poorly water soluble therapeutically active compound, said excipient comprising a mixture of : a. polyglycolyzed glycerides, and b. polyoxypropylene-polyoxyethylene block copolymers.
Full Text Field of the Invention
This invention relates to a composition especially useful as a pharmaceutical
solutibility excipient, the method of producing same, and the pharmaceutical
compositions obtained thereby. In particular, the invention has applicability to increasing
the solubility of poorly soluble therapeutically active compounds.
The invention provides a pharmaceutical solubility enhancing excipient for a
pharmaceutical composition comprising a poorly water soluble therapeutically active
compound, said excipient comprising a mixture of:
(a) saturated or unsaturated polyglycolyzed glycerides, and
(b) polyoxypropylene-polyoxyethylene block copolymers,
The invention further provides a pharmaceutical composition comprising a solid
state solution or solid state dispersion of a poorly water soluble therapeutically active
compound and a pharmaceutically acceptable excipient, said excipient comprising a
mixture of:
(a) saturated or unsaturated polyglycolyzed glycerides, and
(b) polyoxypropylene-polyoxyethylene block copolymers,
whereby the solubility of the poorly soluble therapeutically active compound in the
pharmaceutical composition is enhanced.
The invention further provides methods for making the above compositions. In
the first instance (a) and (b) are mixed to form an excipient mixture. In the second
instance, to form a pharmaceutical composition, heating said polyglycolyzed glycerides
and polyoxypropylene-polyoxyethylene block co-polymer sufficiently to melt the
ingredients.
adding the therapeutic agent to the molten mixture of polyglycolyzed glycerides
and polyoxypropylene-polyoxyethylene block co-polymer
maintaining the mixture at a sufficient temperature for a sufficient time to dissolve
or disperse the pharmaceutical agent.
The method aspect of the invention further comprises adding one or more optional
eecipients, whereby:
(A) the solubility of the therapeutically-active compound in the polyglycolyzed
glyceride:polyoxypropylene-polyoxyethylene block co-polymer mixture is
increased, or
(B) the melting point of the non-drug components is set, whereby at least one
melting point peak belonging to the non-drug components is present
between 30-80°C in the final composition, when analyzed by thermal
analytical techniques.
The method aspect of the invention further comprises.
maintaining the resulting mixture in the molten form, with constant stirring to
ensure homogenous distribution of the drug in the system, and then
subjecting the molten mixture to one or more of the following operations:
I) allowing the mixture to congeal to a solid mass, and then
extruding the mixture through a hot melt extruder into a powder;
II) milling the mixture using equipment that would maintain the
milling conditions at room temperature or below the melting point
of the non-drug components of the system to enable milling the
composition into a powder;
III) spray-congealing the mixture in a spray drier or fluidized bed drier
to a powder;
IV) congealing the mixture onto one or more optional exctpients in a
spray drier, fluidized bed drier, rotor, high shear granulator,
planetary mixer, blender, or any conventional food and
pharmaceutical processing equipment;
V) formulating the above-mentioned powders in pharmaceutical
tablets, capsules, powders for inhalation, suppositories,
suspensions, and emulsions; or
VI) congealing said mixture onto a solid pharmaceutical tablet capsule
or granule.
It has been discovered that by utilizing a mixture of: (a) saturated or unsaturated
polyglycolyzed glycerides, as exemplified by the commercial Gelucire compositions and
(b) polyoxypropylene-polyoxyethylene block copolymers, as exemplified by the
commercial Pluronic surfactants, it is possible to prepare solid state solutions or solid state
dispersions containing poorly soluble therapeutically active compounds, which
compositions, in turn, provide a high degree of solubility to the therapeutic agent.
Gelucires are polyglycolyzed glycerides prepared by the alcoholysis reaction of
natural oils with polyoxyethylene glycols. They are mixtures of monoesters, diesters
and/or triesters of glycerides of long chain C5 to C12 fatty acids, and in polyethylene
glycol mono-and/or diesters of long chain fatty acids. These preparations have a wide
range of melting points of from about 33°C to 64°C, as well as a wide range of
hydrophilic/lipophilic balance values (HLB) from about 1 to about 14. The Gelucires of
particular interest in the present invention have an HLB of above 10.
The first number in the nomenclature of a Gelucire denotes its melting point,
whereas the second number provide the HLB value. The preferred Gelucires of the
present invention are grades 44/13 and 50/13.
The Pluronic surfactants are block copolymers of polyoxyethylene and
polyoxypropylene, generally having an average molecular weight from about 3,000 to
about 15,000. The ethoxylated portion of the blocked copolymer generally constitutes
from about 30 to about 80% by weight of the molecule. Particularly good results are
achievable with Pluronic F68, F108 and F127, but in any case, it is to be noted that the
Pluronic constituent should also have an HLB above 10, irrespective of the particular
grade which is selected. For example, Pluronic F108 has an average molecular weight of
14,600, a polyoxyethylene content of about 80 weight % and an HLB value in excess of
24, and Pluronic F127 has an average molecular weight of 12,600, a polyoxyethylene
content of about 70 weight % and an HLB value from 18 to 23.
The weight ratio of the combined saturated polyglycolyzed glycerides:
polyoxypropylene-polyoxyethylene block co-polymer generally range between 0.10-99.9
to 99.9:0.10, with preferred ratios being 1:9, 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8.2, and 9:1.
These combinations especially the 5:5 ratio, yields a mixture having a melting point in the
range of 44-70°C, preferably 50°C-70oC.
The composition of saturated polyglycolized glyceride and polyglyoxyproplyene-
block copolymer is combined with a therapeutic agent, wherein said composition is
present in the final composition, the latter including the therapeutic agent, in a range of
about 0.10-99.9% by weight, with the preferred range being 5-75% by weight of the final
composition. Poorly soluble agents, e.g., therapeutic agents which have an intrinsic water
solubility of less than 10.0 g/1 are particularly benefitted by the present invention
Examples of drugs in this category are drugs belonging to the dihydropyridine class of
compounds (e.g., nifedepine, felodipine, nicardipine), omperazole, spironolactonc,
furosemide, terbutaline, riboflavine, gemfibrozil, indomethacin, ibuprofen, phenytoin,
glyburide. In addition, any drug which has a water solubility of less than 10.0 g/l
belonging to, for example, cardiovascular, cholesterol lowering, anti-hypertensive,
antiepileptic, hormonal, hypogrycemic, antiviral, immunosuppressive, antihistaminic, nasal
decongestant, antimicrobial, antiarrthrytic, analgesic, antimycobacterial, anticancer,
diuretic, antifungal, antiparasitic, protein, peptide, CNS stimulants, CNS depressants, 5-
HT inhibitors, anti-schizophrenia, anti-Alzheimer, antipsoriatic, steroidal, oligonucleotide,
antiulcer, proton pump inhibitor, anti asthmatic, bronchodialators, thrombolytics, vitamin
class of therapeutic agents, any combinations thereof may be used in this composition in
order to form solid state solutions and dispersions.
The final composition optionally comprises the following further excipients at 5-
95%, especially 10-70% by weight of the final composition. Examples of the further
excipients include, but are not limited to ascorbyl palmitate, glycerol, glyceryl monooleate,
glyceryl monostecate, glyceryl palmitosterate, triglycerides, diglycerides, monoglycerides,
diesters of PEG, monoesters of PEG, polyethylene glycol, glycery polyoxyethlene fatty
acid esters, glyceryl polyoxyethylene polyethylene glycol fatty acid esters and ethers,
polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene
sterates, polyvinyl alcohol, sorbitan fatty acid esters, polyoxyl sterates, polyethylene glycol
hydroxysterate, polyoxyethylene alcohols, anionic, cationic, amphiphillic compounds,
carbohydrates (lactose, maltodcxtrins, sucrose, starch, etc.), polyols (sorbitol, mannitol,
xylitol, etc.), microcrystalline cellulose, vitamins (ascorbic acid, niacinamide, etc.), and
inorganic compounds (calcium carbonate, dicalcium phosphate), polyoxyethylene castor
oil derivatives, propylcnc carbonate, anionic emulsifying wax, white wax, yellow wax,
hydrogenated vegetable oil, triacetin, triethyl citrate and other plasticizers (food and
pharmaceutical grade), lecithin, phospholipids, soybean oil, sesame oil, cotton seed oil,
sunflower oil, peanut oil, mineral oil, hydrogenated castor oil, water soluble and insoluble
derivatives of cellulose (e.g. ethyl cellulose, methyl cellulose, HPMC, HPC, cellulose
acetate phthalate, etc.), methacrylates and polymethacrylates (e.g., Eudragit®), canola oil,
benzoic acid and its salts, methyl-, propyl- and butyl-para-amino benzoic acid (paraben)
(preservatives), organic acids (e.g., fumaric, adipic, maleic, etc.), ethyl alcohol, saccharine,
cyclamate sodium, and other artificial sweeteners, food and pharmaceutical flavoring
agents, bioflavanoids (e.g., quercetin, isoquercetin), citrus bioflavanoids (e.g., naringin),
citrus bioflavanoid complexes, and other agents that inhibit the enzyme cytochrome P450
4A4 (also called as CYP3A4), galactose oligosaccharides (example of a functional
carbohydrate), lubricant (e.g. magnesium sterate), anti-caking agent (e.g., silicon dioxide,
sodium aluminum silicate, magnesium trisilicate, talc, etc.,), gums (locust bean gum, gum
arabic, arabinogalactan, etc.); and any combination of said excipients.
To enhance the solubility, of the therapeutically active agent, an aspect of this
invention provides that the composition of the therapeutic reactive agent, the
polyglycolyzed glyceride and the polyoxypropylene-polyoxyethylene block co-polymer
is formed into a solid state solution or solid state dispersion.)
A solid state solution is defined as a solution of the drug in a solid form. A solid
state solution of a drug is characterized by the lack of a melting point peak at the melting
point of the drug indicating the absence of the solid state of the drug. A solid state
solution-dispersion is defined as a system in which part of the system may be in the solid
solution form and part of it may be in the form of a finely dispersed solid form in the
system. This solid, state solution - dispersion is further defined as a system in which more
than 1% of the total drug content can exist as a solid solution and more than 1% of the
drug can exist as a solid dispersion with a particle size distribution such that 90% of the
particles have a diameter less than 10 microns. The weight ratio between the solid state
solubilized drug: dispersed drug may be in the range of 1.0-100:99-0. It is desirable that
30-100% of the drug exists as a solid state solution. The ratio of the amount of drug
present in the form of a solid state solution to the amount present as a solid dispersion is
easily ascertained by the use of techniques in thermal analysis such as Differential
Scanning Calorimetry (DSC), Thermal Gravimetric Analysis (TGA), and Differential
Scanning Microcalorimetry. The crystallinity of the drug is easily determined by X-ray
diffraction. Furthermore, when determined by thermal analytical techniques it is desirable
that the final composition have at least "one" distinct melting peak in the range of 30-
80°C associated with the melting point of the non-drug components of the final
composition.
To produce the final composition polyglycolyzed glycerides and
polyoxypropylene-polyoxyethylene block co-polymer are heated sufficiently to form a
melt of the ingredients, for example to at least about 20°C above the combined melting
point. The therapeutic agent is added gradually to the molten mixture of polyglycolyzed
glycerides and polyoxypropylene-polyoxyethylene block co-polymer. It is preferable to
mill or micronize the drug to a particle size range such that the particle diameter of 90%
of the particles is less than 75 microns. The mixture is maintained at a sufficient
temperature, for example, at least about 20°C above the combined melting point of the
polyglycolyzed glycerides; polyoxypropylene-polyoxyethylene block co-polymer mixture
for a sufficient time to dissolve or disperse the pharmaceutical agent.
The optional excipients may be added to the above mentioned system to,
(A) Increase the solubility of the drug in the polyglycolyzed glycerides;
polyoxypropylene-polyoxyethylenc block co-polymer system.
(B) Set the melting point of the non-drug components, such that at least "one"
melting point peak belonging to the non-drug components is present
between 30-80°C in the final composition, when analyzed by thermal
analytical techniques.
The resulting mixture is then maintained in the molten form, for example, at least
20°C above the combined melting point of the non-drug components, with constant
stirring to ensure homogenous distribution of the drug in the system. Thereafter, the
mixture may be subjected to one or more of the following operations:
I) Allowed to congeal to a solid mass, and then extruded through a hot melt
extruder into a powder.
II) Milled using equipment that would maintain the milling conditions at room
temperature or below the melting point of the non drug components of the
system to enable milling the composition into a powder.
III) Spray congealed in a spray drier or fluidized bed drier to a powder.
IV) Congealed onto one or more of said excipients in a spray drier, fluidized bed
drier, rotor, high shear granulator, planetary mixer, blender, or any
conventional food and pharmaceutical processing equipment.
V) The above mentioned powders may then be used in the formulation of
conventional, specialised, and novel pharmaceutical dosage forms such as
tablets, capsules, powders for inhalation, suppositories, suspensions, and
emulsions.
VI) Alternatively, the molten mixture can be congealed into or onto a solid
pharmaceutical dosage form such as, for example, a tablet, capsule, and/or
granule.
The entire disclosure of all applications, patents and publications, cited above and
below, and also U.S. provisional application 60/063,338 filed October 27, 1997 are hereby
incorporated by reference.
Without further elaboration, it is believed that one skilled in the art can, using the
preceding description, utilize the present invention to its fullest extent. The following
preferred specific embodiments are. therefore, to be construed as merely illustrative, and
not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the following examples, all temperatures are set forth
uncorrected in degrees Celsius and unless otherwise indicated, all parts and percentages
are by weight.
EXAMPLES
Example 1:
Three grams of Gelucire of 50/13 and 3 grams of Pluronic F68 are melted and
two grams of nifedipine are dissolved therein. The resultant solution is added to 4 grams
of sorbitol while stirring. The resultant solution is then cooled down and passed through
a 20 mesh screen. The resultant paniculate solids were solid solutions.
Example 2:
In this example, felodipine is employed as the active pharmaceutical agent. Thus,
1.5 grams of Gelucire 50/13 and 1.5 grains of Pluronic F68 were melted together and 1
gram of felodipine was added thereto. This resultant solution was then introduced into
4 grams of Sorbitol P300® while stirring. After mixing, the solution was cooled and
ultimately passed through a 20 mesh screen. The resultant paniculate solids were in a
solid state solution-dispersion system.
Example 3:
In this example, felodipine is employed as the active pharmaceutical agent. Thus,
1.5 grams of Gelucire 50/13 and 1.5 grams of Pluronic F68 were melted together and 1.5
grams of felodipine was added thereto. This resultant solution was then introduced into
4 grams of Sorbitol P300® while stirring. After mixing, the solution was cooled and
ultimately passed through a 20 mesh screen. The resultant paniculate solids were in a
solid state solution system.
Example 4:
In this example, felodipine is employed as the active pharmaceutical agent. Thus,
1 gram of Gelucire 50/13 and 1 gram of Pluronic F68 were melted together and 1.5 grams
of felodipine was admixed. This resultant solution was then added to 2.67 grams of
Avecil, a brand of microcrystalline cellulose. After mixing, the solution was cooled and
ultimately passed through a 20 mesh screen. The resultant paniculate solids were in a
solid state solution-dispersion system.
For the purposes of increasing the melting point of the composition of Examples
2, 3 and 4, Pluronic F127 can be substituted for Pluronic F68.
To determine the improvement achieved by the present invention with respect to
the solubility of pure felodipine, the formulations of Examples 3 and 4 were evaluated by
the following technique.
The solubility characteristics of the compositions of Examples 3 and 4 as
compared to pure felodipine were evaluated, as follows:
6.8 mg of felodipine and 34.8 mg of the composition of Example 3 and 34.2
Example 4 are respectively placed into 500 ml of a 40% PEG solution
maintained at 37°C.
The solution was stirred with a paddle stirrer at 50 rpm. The absorbency was measured
with a Hitachi spectrometer at 362 nm. The percent release is based on the standard
curve: absorbents = 0.216 cone, (mg/900 ml)-0.00274, and the following results were
obtained.
From the above table, it is dear that the present invention provides a substantially
enhanced solubility as compared to the pure drug.
Example 5:
For the production of tablets 121.5 mg of HPMC (hydropropylmethyl cellulose)
are mixed with 21.1 gm of Sorbitol Instant P300®, 246.88 mg of Microcrystalline
Cellulose and 59.62 mg of the composition of Example 3. 1 mg of magnesium stearate
was then added to the above mixture with stirring The resultant mixture was tableted in
a Carver® press under a pressure of 2 tons.
Example 6:
Another tablet was produced from the composition of Example 3 by the method
of Example 5 except in this case, the amount of Example 3 was 59.52 mg,
Microcrystalline Cellulose 231.98 mg, Sorbitol Instant P300® 45 mg and HPMC 112.5
mg, with sodium stearyl fumeratc (PRUV)® being substituted for magnesium stearate.
The resultant tablet has 10% sorbitol.
Example 7:
In this example, a 15% sorbitol tablet is produced in the same manner as the last
example except that the amount of sorbitol is 67.5 mg and the amount of Microcrystalline
Cellulose is 209.48 mg.
Example 8: Intrinsic Dissolution of Hydrosolve-Ibuprofen
a. Formulation:
b. Procedures:
1 .Melt Gelucire and Pluronic, and dissolve ibuprofen into the mixture.
2. Add the above solution into Sorbitol Instant while stirring.
3 Coo] down and pass through #20 mesh screen.
c. Dissolution Test Using the Dissolution Test as follows:
1.Measure 3.3 mg and 17.2 mg of ibuprofen (20 micron) and HydroSolve -
Ibuprofen, respectively.
2.Measure the dissolution profiles using 700 ml of pH 7.2 buffer and paddle at 50
rpm.
3 Measure the absorbance at 221 n.m.
Example 9: Intrinsic Dissolution Profile of Phenytoin and HydroSolve- Phenytoin
a. Formulation #4:
b. Procedures:
1 Melt Gclucire and Pluronic together.
2. Dissolve the phenytoin into above solution.
3. Congeal this suspension and pass through #20 mesh.
4. Measure about 32 and 110 mg of phenytoin and HydroSolve - phenytoin,
respectively,
5. Measure the dissolution profiles using 900 ml of D1 water and Paddle
Method at 50 rpm
6 Using D1 water as blank, measure the absorbance at 220 nm of each
sample which is filtered through 0.45 micron filters.
7. Calculate the percent released by standard curve:
Absorbance = 0.4072 x Concentration (mg/100ml) + 0.0227
Example 10: The DSC Profiles for HydroSolve System of Phenytoin
2b. Procedures:
1. Melt Geiucire and Piuronic together.
2. Disperse the phenytoin into above solution since pheytoin cannot completely.
3. Mix the above suspension with sorbitol P300 while stirring.
4. Measure the DSC profile.
2b. Procedures:
1. Melt Geiucire and Piuronic together.
2 Dissolve/disperse the phenytoin into above system.
3. Congeal this suspension and pass through #20 mesh.
4. Measure the DSC profile.
The preceding examples can be repeated with simitar success by substituting the
genetically or specifically described reactants and/or operating conditions of this invention
for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the
essential characteristics of this invention, and without departing from the spirit and scope
thereof, can make various changes and modifications of the invention to adapt it to
various usages and conditions.
WE CLAIM.
1. A pharmaceutical composition comprising a solid state solution or solid state
dispersion of a poorly water soluble therapeuticaLly active compound with an
intrinsic water solubility of less than 10.0 g/l and a pharmaceutically acceptable
excipient, said excipient comprising a mixture of:
(a) polyglycolyzed giycerides composition wherein said composition is a
mixture of monoesters, diesters and/or triesters of glycerides of
C8-18-long-chain fatty acids and polyethylene glycol mono- and/or diesters
of said fatty acids, and
(b) polyoxypropylene-polyoxyethylene block copolymers,
whereby the solubility of the poorly soluble therapeuticaily active compound in
the pharmaceutical composition is enhanced and the mixture of the poorly
soluble therapeuticaily active compound and the excipient is granulated,
pelleted, extruded, extrusion spheronized, or spray congealed.
2. A pharmaceutical composition of claim 1, wherein the composition of C8-18-long-
chain fatty acids in the giycerides in the composition of (a) comprise fatty acid, C16-fatty acid and 3. A pharmaceutical composition of claim 1 or 2, wherein (b) is a block copolymer of
polyoxypropylene-polyoxyethylene having an average molecular weight from
3,000 to 15,000 and the ethoxylated portion of the block copolymer constitutes
from 30 to 80% by weight of the molecule.
4. A pharmaceutical composition of anyone of claims 1 to 3, wherein the
composition comprising the solid state solution or solid state dispersion of a
poorly water soluble therapeuticaily active compound and the excipient is in the
form of a granule, particle, pellet, tablet or sphere and is coated with an agent that
modifies the release profile of the therapeuticaily active compound.
5. A pharmaceutical composition of claim 4, wherein the agent that modifies the
release profile of the therapeuticaily active compound is a polymer of cellulose or
a derivative thereof, alginic acid or a derivative thereof, polyvinyl alcohol or a
derivative thereof acrylic acid polymer, polymethacrylates, acrylic acid or a
derivative thereof, lactic acid or a derivative thereof or gelatin.
A pharmaceutical excipient suitable as a solubility enhancer
for a pharmaceutical composition comprising a poorly water
soluble therapeutically active compound, said excipient comprising
a mixture of:
a. polyglycolyzed glycerides, and
b. polyoxypropylene-polyoxyethylene block copolymers.

Documents:

58-CAL-1999-FORM-27.pdf

58-cal-1999-granted-abstract.pdf

58-cal-1999-granted-claims.pdf

58-cal-1999-granted-correspondence.pdf

58-cal-1999-granted-description (complete).pdf

58-cal-1999-granted-form 1.pdf

58-cal-1999-granted-form 18.pdf

58-cal-1999-granted-form 2.pdf

58-cal-1999-granted-form 3.pdf

58-cal-1999-granted-form 5.pdf

58-cal-1999-granted-letter patent.pdf

58-cal-1999-granted-pa.pdf

58-cal-1999-granted-reply to examination report.pdf

58-cal-1999-granted-specification.pdf

58-cal-1999-granted-translated copy of priority document.pdf


Patent Number 212601
Indian Patent Application Number 58/CAL/1999
PG Journal Number 49/2007
Publication Date 07-Dec-2007
Grant Date 04-Dec-2007
Date of Filing 27-Jan-1999
Name of Patentee MERCK PATENT GESELLSCHAFT MIT BESCHRANKTER HAFTUNG
Applicant Address FRANKFURTER STRASSE 250, 64293 DARMSTADT
Inventors:
# Inventor's Name Inventor's Address
1 SIVA NARAYAN TALLAVAJHALA 8 LANGHANS COURT, DIX HILLS, NY 11746
2 XIUYING LIU 107 SIMI COURT, CHERRY HILL, NJ 08003
PCT International Classification Number C 08 B 1/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 97-063338 1997-10-27 U.S.A.