Note: Descriptions are shown in the official language in which they were submitted.
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Drug Formulation and Delivery Using Crystalline Methylated Cyclodextrins
Field of the Invention
[001] The present invention is directed to pharmaceutical compositions
containing crystalline methylated cyclodextrins, which enhance the solubility
of
the pharmaceutically active agent of the formulation.
Background of the Invention
[002] Among drug candidates under evaluation/development, the
problem of inadequate aqueous solubility is likely to be encountered with
relatively high frequency. Inadequate aqueous solubility is a significant
hurdle in
formulating such compounds into a simple, isotonic, ready-to-inject aqueous
solution. For oral administration, poor aqueous solubility of drugs can
jeopardize
the dissolution rate and bioavailability. Inadequate aqueous solubility
reflects a
less than desirable free energy of transfer from the solid phase to the
aqueous
solution. This may result from two causes: (a) polar compounds may exhibit low
water solubility as a result of strong crystalline interaction due to
intermolecular
electrostatic attraction and/or hydrogen bonding in the crystal; or (b)
lipophilic/hydrophobic compounds are likely to exhibit low water solubility
due to
unfavorable free energy of solvation by water. No matter the cause of the
solubility problem, cyclodextrin complexation, micellar solubilization,
cosolvency,
and solutropy are four strategies that are commonly employed in circumventing
the problem.
[003] However, in general, a disadvantage of micellar solubilization is the
large quantity of surfactant required to provide the several orders of
magnitude
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[004] increases in solubility often desired. In addition, surfactant toxicity
at high concentrations, particularly hemolysis, is a well-documented problem.
The rapid reversibility of solubilization is another difficulty in the use of
micellar
solution as an approach for parenteral or oral route.
[005] Oftentimes, non-aqueous solvents can effectively dissolve the
drugs with inadequate aqueous solubility. For example, carbamazepine
solubility
in propylene glycol is about 310 fold of carbamazepine aqueous solubility.
However, the toxicity of the non-aqueous solvents is a major concern. A 40%
propylene glycol/water cosolvent system is near the upper limit in terms of
its
organic solvent composition for physiological compatibility. Based on
metabolic
and toxicological data, the WHO has set an acceptable daily intake of
propylene
glycol at up to 25 mg/kg body weight. Additionally, the solubility enhancement
generally is significantly reduced in the mixture of non-aqueous solvent and
water, compared to non-aqueous solvent alone.
[006] The term "solutropy" was introduced to describe solubilization by
the addition of a large amount of a second solute in both aqueous and
nonaqueous solvents. The solubility enhancement either via solvent structure
modification or via chemical complexation has been demonstrated in
pharmaceutical applications. The following are the examples of hydrotropes
commonly used in the pharmaceutical industry: nicotinamide, sodium salts of
benzoic, naphtholic, and nicotinic acids, urea, sorbitol, fructose, sodium
salicylate, sodium glycinate, and gentisate sodium. Toxicity of these
hydrotropes, however, is a major concern. Furthermore, the solubility
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enhancement is compound-dependent and only modest enhancement can be
expected using the hydrotrope approach.
[007] Pharmaceutical applications of cyclodextrins have been considered
for over 30 years. Cyclodextrins are cyclic oligosaccharides composed of 6-8
dextrose units (a-, [i-, and y-cyclodextrins, respectively) joined through 1-4
bonds. Because the interior of these molecules are relatively lipophilic and
the
exterior relatively hydrophilic, they tend to form inclusion complexes.
[008] Safety is a major issue with any new material. Two of the parent
cyclodextrins, i.e., a- and R-cyclodextrins, are known to be parenterally
unsafe
due to severe nephrotoxicity. However, a- and [3-cyclodextrins have been used
orally in both food products and in various approved pharmaceuticals. Other
than the safety issue, low aqueous solubility is another drawback to using the
parent cyclodextrins, which is especially true for R-cyclodextrin; the ring
cavity for
a-cyclodextrin is simply too small to encapsulate the drug molecules, in most
cases.
[009] Modification of the parent cyclodextrins to improve safety while
maintaining the ability to form inclusion complexes with various substrates
has
been the goal of numerous research groups. The most significant cyclodextrin
derivatives are the following: hydroxypropyl [3-cyclodextrin,
glucuronyiglucosyl R-
cyclodextrin, sulfobutylether R-cyclodextrin, and methylated [3-cyclodextrin.
These modified cyclodextrins and parent cyclodextrins provide have assisted
formulators in overcoming solubility problems of poorly water-soluble drugs in
various applications, i.e., parenteral, oral, buccal, ophthalmic, nasal,
dermal,
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rectal, and pulmonary routes. While several cyclodextrins
have been approved for use in pharmaceutical products, such
as Sporanox (Janssen), Zeldox/Geodon (Pfizer), and Vfend
(Pfizer), there is a need to find additional cyclodextrins
to contribute to the formulators' arsenal. Although
cyclodextrins are not the solution to all the solubility
problems, they definitely have higher potential than other
solubilization techniques.
Detailed Description of the Invention
[0009a) According to one aspect of the present
invention, there is provided a pharmaceutical dosage form
comprising a pharmaceutically active agent, a solubilizing
agent which is crystalline methylated a- or is- or y-
cyclodextrin or any mixture thereof, and an inactive
carrier, with the proviso that the pharmaceutically active
agent is not naproxen or carbamazepine.
[0009b1 According to another aspect of the present
invention, there is provided a pharmaceutical dosage form
comprising a pharmaceutically active agent, a solubilizing
agent which is crystalline methylated a- or f- or y-
cyclodextrin or any mixture thereof, and an inactive
carrier, wherein the pharmaceutically active agent is a
derivative of carbamazepine.
[00101 The present invention is directed to
cyclodextrin derivatives that, it has now been found, are
useful in pharmaceutical applications, and act as
solubilizing agents. These cyclodextrin derivatives are
crystalline methylated cyclodextrins, more specifically,
crystalline methylated a-, g-, and/or y- cyclodextrins.
Preferably, the cyclodextrin is crystalline methylated
S-cyclodextrin. Generally, the compounds may be produced by
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methylating a mole of a-, fs-, and/or y- cyclodextrin
with 3-6 moles of dimethyl sulfate in water using calcium
hydroxide as a base (i.e., base of minimal effective
basicity). Crystals start to separate from concentrated
solutions of the methylated a-, t-, and/or y- cyclodextrins.
The yield of crystals in such reactions is between 30
to 70%. Additionally, any of the methods disclosed in US
Patent Nos. 5,681,828 and 5,935,941 can be used to produce
the cyclodextrin derivatives usable in the compositions of
the present invention.
[0011] In one aspect of the invention is
crystalline methylated fs-cyclodextrin, which is stable
against heat and humidity. This crystalline
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cyclodextrin derivative has good water solubility, and at room temperature
preparations with solubility around 15% can easily be made. In addition,
crystalline methylated fl-cyclodextrin has much better solubilization efficacy
than
other commercially available cyclodextrins and cyclodextrin derivatives.
Additionally, the parent compound, $-cyclodextrin, is less expensive than
gamma-cyclodextrin, which makes it more desirable. Methods of making this
compound are disclosed in the `828 and `941 patents, supra, for instance
Example 11 of both patents teaches such a method.
[0012] More specifically, the invention is directed to pharmaceutical
compositions containing the crystalline methylated a-, R-, and/or y-
cyclodextrins
and a pharmaceutically active agent. As preferred embodiments are
compositions containing crystalline methylated a-cyclodextrin. For all
practical
purposes, the active agent is one that has proven difficult to solubilize in
aqueous
solutions, although the invention is not necessarily limited thereto. In other
words, the active agent is one that is poorly soluble in aqueous solutions, it
being
understood that "poorly soluble" is generally meant to denote an agent that
has
low aqueous solubility. Poorly soluble can be defined here as one part of
solute
required more than 100 parts of solvent to dissolve the solute.
[0013] The compositions may contain any one of the cyclodextrin
derivatives or may have any combination of mixtures thereof. In a preferred
embodiment, the cyclodextrin is only crystalline methylated /(3-cyclodextrin.
[0014] The compositions are not limited to containing only one active
agent; there may be more than one agent. For instance, there may be one agent
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with low solubility and one without, or two agents with low solubility, etc.
Further,
"pharmaceutically active agent" is intended to include, other than therapeutic
drugs, diagnostic and nutritional agents.
[0015] The compositions are generally in a solid form or liquid form.
Typically, they are in dosage unit form, such as tablet, powder, sachet, bead,
pellet, osmotic dosage form, etc., but they may as well be in a liquid, cream
or
aerosol form for use in various applications, i.e., parenteral, oral, buccal,
ophthalmic, nasal, dermal, rectal, and pulmonary routes. Preferably, for
patient
convenience, the compositions are in an oral delivery form, such as a tablet,
capsule or osmotic dosage form, for example. Most preferably, however, the
compositions are in an osmotic dosage form, several of which are described
inter
alia in US Patent Nos. 6,110,498, and 6,284,276.
[0016] Additional pharmaceutically acceptable carriers or excipients may
be present in the compositions as desired, these additional substances having
essentially no substantial affect on the solubility performance that is key to
the
present invention. Such excipients/carriers are well known in the art, and are
described in Gennaro et at., Remington's Pharmaceutical Sciences (18th ed.,
Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical
Preparations and their Manufacture).
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[0017] The compositions of the present invention can be formulated and
used in various applications, i.e., parenteral, oral, buccal, ophthalmic,
nasal,
dermal, rectal, and pulmonary routes.
[0018] The present invention is demonstrated in the following examples, it
being understood that these are for illustrative purposes only, and the
invention is
not intended to be limited thereto.
Example:
Materials and Methods
Materials
[0019] A crystalline methylated,8-cyclodextrin, molecular weight 1200
amu, was supplied by Pitha & Pitha. Hydroxypropyl [i-cyclodextrin, R-
cyclodextrin, and y-cyclodextrin were received as a gift from Cerestar.
Methylated,B-cyclodextrin (amorphous) was a gift from Wacker-Chemie.
Glucuronylgiucosyl- R-cyclodextrin was purchased from Wako Pure Chemical
Industries, Ltd.
Methods
[0020] An excess of drug substance was added to 20 ml glass liquid
scintillation vials (Kimble Glass Inc., Vineland, NJ) containing 10 ml of the
media
with a specific amount of solubilizer. The sample vials were then rotated
using
an end-over-end mechanical rotator at 50 rpm at room temperature for 48 hours
to reach equilibrium solubility. The samples were filtered through a 0.45 m
filter
(AcrodiscTM CR PTFE membrane filter, Gelman Sciences, Ann Arbor, MI). After
discarding the first mL of the filtrates to eliminate any membrane adsorptive
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effect, the filtrates were collected for high-performance liquid
chromatography
(HPLC) analysis for drug concentration.
Results and Discussion
[0021] While the use of a-, [3-, or y-cyclodextrin as complexing agents
would be considered a classical approach, recently developed chemically
modified a-, [3-, and y-cyclodextrins, particularly the crystalline methylated
R-
cyclodextrins, represent a novel class of solubilizing agents with improved
water
solubility, solubilization potency, and safety profile. Table 1 shows the
solubilization potency of the crystalline methylated fl-cyclodextrin with
carbamazepine compared to three commercially available cyclodextrins. When
compared on a weight basis, the crystalline methylated /3-cyclodextrin clearly
outperforms other cyclodextrins. It may be noted that the parent R-
cyclodextrin
suffers a significant drawback of low aqueous solubility (i.e., 1.8 % w/v).
Micellar
solubilization is another commonly used approach to improve solubility of
poorly-
water soluble drugs. However, in general, a disadvantage of micellar
solubilization is the large quantity of surfactant required to provide the
several
orders of magnitude increases in solubility often desired. In addition,
surfactant
toxicity at high concentrations, particularly hemolysis, is a well-documented
problem. The rapid reversibility of solubilization is another difficulty in
the,use of
micellar solution as an approach for parenteral or oral route. Oftentimes,
nonaqueous solvents can effectively dissolve the drugs with inadequate aqueous
solubility. For example, carbamazepine solubility in propylene glycol is about
310 fold of carbamazepine aqueous solubility (Table 2). However, the toxicity
of
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the non-aqueous solvents is a major concern. A 40% propylene glycol/water
cosolvent system is near the upper limit in terms of its organic solvent
composition for physiological compatibility. Based on metabolic and
toxicological
data, the WHO has set an acceptable daily intake of propylene glycol at up to
25
mg/kg body weight.
[0022] Table 3 shows the solubilization potency of crystalline methylated
/3-cyclodextrin with fenofibrate, compared to hydroxypropyl R-cyclodextrin.
The
crystalline methylated /3-cyclodextrin outperforms hydroxypropyl R-
cyclodextrin in
the aqueous system.
[0023] In the oxcarbazepine case, crystalline methylated / -cyclodextrin
behaves much better than other cyclodextrins tested in terms of solubilization
potency (Table 4). Again, in the glipizide case, crystalline methylated $-
cyclodextrin outperforms other commercially available cyclodextrins in terms
of
solubilization potency, in contrast to no solubility enhancing for y-
cyclodextrin
(Table 5).
Conclusions
[0024] Consistently, crystalline methylated f1-cyclodextrin provides
superior solubilization efficiency for four model compounds, compared to other
parent cyclodextrins and derivatives. Additionally, cyclodextrins are capable
of
enhancing the solubility of drugs in non-aqueous polar vehicles.
[0025] Other than the direct use of methylated cyclodextrins as solubilizer
in a liquid form (i.e., injectable solution, Liquid filled capsule, oral
suspension,
oral syrup), dried inclusion complexes of the present invention can be
prepared
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by mixing the methylated cyclodextrin with the water-
insoluble or slightly water-soluble compound according to
known methods, such as the coprecipitation method (Crassons,
et al., 5th Int. Conf. Pharmaceutical Technology, Paris,
May 30 to June 1, 1989), lyophilization or spray drying
method (Kurozumi et al., Chem. Pharm. Bull., 23, 3062
(1975); Kata et al., Pharmazie, 39, 856 (1984)), and
milling/kneading/granulating method (J. Szejtli et al.,
"Cyclodextrins and their inclusion complexes", Akadecimial
Kiado, Budapest (1982), p. 109-114; Kyowa Jap. Prov. Pat.
Pubin. No. 106698 (1982)).
[0026] The inclusion compounds prepared can be
incorporated into various dosage forms. The dosage forms
include, but are not limited to, the following: capsule,
tablet, powder, beads, ointment, and lotion. In addition,
the cyclodextrin derivatives of the invention can act as
solubilizing agents in sustained-release dosage form.
Especially for osmotic pumps, the present cyclodextrin
derivatives can also function as osmotic agents providing
the influx of water and osmotic pressure to push the drug
molecule out of such systems.
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Table 1
Solubility of Carbamazepine in Aqueous Solution of Various Cyclodextrins
Concentrati Carbamazepine Solubility, mg/ml (solubility
on. enhancement ratio)'
%(w/v) Cavasol Cryst. HP-p -
Cyclodextri W7M3 Methylated cyclodextri
n2 ,6-CD 4 n
0 0.113 0.113 0.113 0.113
1 0.669 5.9 -- -- --
2 1.186 1.068 (9.5) 1.542 1.243
(10.5) 13.7 (11.0)
-- 2.581 3.590 2.875
(22.8) (31.8) (25.4)
7.5 -- 3.765 5.367 4.874
(33.3) (47.5) (43.1)
-- 5.248 6.964 6.019
(46.4) (61.6) (53.3)
-- 10.906 14.955 10.712
(96.5) (132.4) (94.8)
'Solubility enhancement ratio is the ratio between the drug solubility in the
vehicle containing various amounts of cyclodextrins and the drug solubility in
the
vehicle alone
AAqueous solubility of 3-cyciodextrin is very poor; at 2% level, it requires
heating
to dissolve it completely.
3Cavasol W7M is a trade name for methyl-(3-cyciodextrin from Wacker-Chemie
GmbH.
4Crystalline methylated,8-cyclodextrin from Pitha & Pitha, LLC. At 20% w/v
concentration, it requires heating to facilitate its dissolution.
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Table 2
Solubility of Carbamazepine in Selected Vehicles
Carbamezepine Solubility, mg/ml
Water Propylene PEG 400 Transcutol
Glycol
0.113 35.330 77.918 78.094
Table 3
Solubility of Fenofibrate in Selected Vehicles Containing Various Amounts of
Crystalline methylated fi-Cyclodextrin or Hydroxypropyl 13-cyclodextrin
Concentrati Fenofibrate Solubilit , mg/ml (solubility enhancement ratio
on, %w/v Cryst. HP R- HP R- HP f3- HP R-
Methylated cyclodextrin cyclodextrin cyclodextrin cyclodextrin
fl-CD 2
Water Water Water:PG3 Water:PG PG
(7:3) (4:6)
0 0.011 0.011 0.024 0.084 2.773
0.55 50 -- -- -- --
16 -- 0.188 17 0.102(4) 0.272(3) 3.350 1.2
1.37(125)
-- -- -- --
28 -- 0.400 36 0.225(9) 0.448(5) 3.628 1.3
'Solubility enhancement ratio is the ratio between the drug solubility in the
vehicle containing various cyclodextrins and the drug solubility in the
vehicle
alone.
2Crystalline methylated 13-cyclodextrin was a gift from Pitha & Pitha, LLC. At
20%
w/v concentration, it requires heating to facilitate its dissolution.
3PG=Propylene Glycol
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Table 4
Solubility of Oxcarbazepine in Aqueous Solution of Various Cyclodextrins and
Tween 80
Concentrati Oxcarbazepine Solubility, mg/ml (solubility
on. enhancement ratio)'
%(w/v) Tween 80 Cavasol Cryst. HP-f3 -
W7M2 Methylated cyclodextrin
/3-CD'
0 0.07 0.07 0.07 0.07
1 0.12(1.7) 0.15(2.1) 0.23(3.3) 0.13(1.9)
2 0.172.4 0.243.4 0.31 4.4 0.192.7
0.29 4.1 0.49 7.0 0.82 11.7 0.34 4.9
0.50 7.1 0.67 9.6 1.49 21.3 0.67 9.6
'Solubility enhancement ratio is the ratio between the drug solubility in the
vehicle containing various amounts of Tween 80 or cyclodextrins and the drug
solubility in the vehicle alone.
2Cavasol W7M is a trade name for methyl-3-cyclodextrin from Wacker-Chemie
GmbH.
!Crystalline methylated ,6-cyclodextrin was a gift from Pitha & Pitha, LLC. At
20%
w/v concentration, it requires heating to facilitate its dissolution.
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Table 5
Solubility of Glipizide in Aqueous Solution of Various Cyclodextrins
Concentration Glipizide Solubility, mg/ml (solubility enhancement ratio
y-Cyclodextrin Cavasol Cryst. HP-f3 -
%(w/v) W7M2 Methylated /3- cyclodextrin
CD3
0 0.037 0.037 0.037 0.037
1 0.0244 (0.66) 0.049 (1.32) 0.1045 (2.82) 0.0575 (1.55)
2 0.0415 (1.12) 0.0626 (1.69) 0.1760 0.0727 (1.96)
(4.76)
0.0339 (0.92) 0.1740 (4.70) 0.3988 0.1281 (3.46)
(10.78)
0.0402 (1.08) 0.4882 0.9861 0.2294 (6.20)
(13.19) (26.65)
0.0366 (0.99) 0.5607 1.5513 0.3418 (9.24)
15.15 (41.93)
Solubility enhancement ratio is the ratio between the drug solubility in the
aqueous vehicle containing various cyclodextrins and the drug solubility in
the
aqueous vehicle alone.
2Cavasol W7M is a trade name for methyl-R-cyclodextrin from Wacker-Chemie
GmbH.
3Crystalline methylated /3-cyclodextrin was a gift from Pitha & Pitha, LLC. At
20%
w/v concentration, it requires heating to facilitate its dissolution.
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