U.S. patent application number 10/004481 was filed with the patent office on 2002-05-16 for derivatized carbohydrates, compositions comprised thereof and methods of use thereof.
Invention is credited to Blair, Julian A..
Application Number | 20020058067 10/004481 |
Document ID | / |
Family ID | 22084508 |
Filed Date | 2002-05-16 |
United States Patent
Application |
20020058067 |
Kind Code |
A1 |
Blair, Julian A. |
May 16, 2002 |
Derivatized carbohydrates, compositions comprised thereof and
methods of use thereof
Abstract
Derivatized carbohydrates are provided which can be used to form
a variety of materials including solid delivery systems. The
derivatized carbohydrates are generally carbohydrates, wherein at
least a portion of the hydroxyl groups on the carbohydrate are
substituted with a branched hydrophobic chain, such as a
hydrocarbon chain, via, for example, an ether or ester linkage. The
solid delivery systems can be used for delivery and release of a
variety of substances, and are, for example, in the form of tablets
for oral administration, or in the form of powders, microspheres or
implants for intravenous, intradermal, transdermal, pulmonary or
other route of administration. The derivatized carbohydrates can be
processed to form a solid matrix having a substance, such as a
therapeutic agent, incorporated therein. In one embodiment, the
solid matrix is provided in a solid dose form which is capable of
releasing a therapeutic substance in situ at various controlled
rates.
Inventors: |
Blair, Julian A.; (St. Ives,
GB) |
Correspondence
Address: |
Madeline I. Johnston
Morrison & Foerster LLP
755 Page Mill Road
Palo Alto
CA
94304
US
|
Family ID: |
22084508 |
Appl. No.: |
10/004481 |
Filed: |
November 1, 2001 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10004481 |
Nov 1, 2001 |
|
|
|
09218845 |
Dec 22, 1998 |
|
|
|
60068754 |
Dec 23, 1997 |
|
|
|
Current U.S.
Class: |
424/484 ; 514/53;
536/123.13 |
Current CPC
Class: |
C07H 15/04 20130101;
C07H 3/04 20130101; A61K 9/145 20130101 |
Class at
Publication: |
424/484 ; 514/53;
536/123.13 |
International
Class: |
A61K 009/14; A61K
031/7016; C07H 003/04 |
Claims
1. A substituted carbohydrate having the structure defined by a
Formula selected from the group consisting of 3wherein, in each of
Formula 1-4: one or more of R.sub.1-8 are independently NHR.sub.9,
N(R.sub.9).sub.2, O(C.dbd.O)R.sub.9, or OR.sub.9, wherein R.sub.9
is a branched, saturated or unsaturated, C3-C8 hydrocarbon; and the
remainder of R.sub.1-8 are independently H, NHR.sub.10,
N(R.sub.10).sub.2, O(C.dbd.O)R.sub.10, or OR.sub.10, wherein
R.sub.10 is a C1-C4 straight chain alkyl group.
2. The substituted carbohydrate according to claim 1 wherein one or
more of R.sub.1-8 are independently O(C.dbd.O)R.sub.9, and
O(C.dbd.O)R.sub.9 is the acid acyl group of an acid selected from
the group consisting of isobutyrate, pivalate,
2,2-dimethylbutyrate, 3,3-dimethylbutyrate, and 2-ethyl butyrate;
wherein the remainder of R.sub.1-8 are independently
O(C.dbd.O)R.sub.10; and wherein R.sub.10 is selected from the group
consisting of methyl, ethyl, propyl and butyl.
3. A substituted carbohydrate selected from the group consisting of
trehalose hexa-3,3-dimethylbutyrate, trehalose
diacetate-hexa-3,3-dimethy- lbutyrate, trehalose
octa-3,3-dimethylbutyrate, lactose isobutyrate-heptaacetate,
lactose 3-acetyl-hepta-3,3-dimethylbutyrate and lactose
octa-3,3-dimethylbutyrate.
4. A composition comprising a substituted carbohydrate according to
claim 1, 2, or 3, and a substance capable of being released from
the composition.
5. The composition according to claim 4, wherein the substituted
carbohydrate is in the form of a solid matrix having the substance
incorporated therein.
6. The composition according to claim 5, further comprising at
least one physiologically acceptable glass selected from the group
consisting of carboxylate, nitrate, sulfate, bisulfate, a
hydrophobic carbohydrate derivative, and combinations thereof.
7. The composition according to claim 5, wherein the composition is
in the form of a solid delivery system selected from the group
consisting of lozenge, tablet, disc, film, suppository, needle,
microneedle, microfiber, particle, microparticle, sphere,
microsphere, powder, and an implantable device.
8. The composition according to claim 5, wherein the substance is a
pharmaceutically active chemical.
9. The composition according to claim 8, wherein the substance is
selected from the group consisting of lipids, proteins, peptides,
peptide mimetics, hormones, saccharides, nucleic acids, and protein
nucleic acid hybrids.
10. The composition according to claim 9, wherein the proteins are
selected from the group consisting of enzymes, growth hormones,
growth factors, insulin, monoclonal antibodies, interferons,
interleukins and cytokines.
11. The composition according to claim 5, wherein the substance is
immunogenic and is selected from the group consisting of live
viruses, attenuated viruses, nucleotide vectors encoding antigens,
bacteria, antigens, antigens plus adjuvants and haptens coupled to
carriers.
12. A method of making a solid delivery system, the method
comprising processing a substituted carbohydrate according to claim
1, 2, or 3, and a substance to be released therefrom, thereby to
form a solid matrix having the substance incorporated therein.
13. A method of making a solid delivery system, the method
comprising: a) forming or obtaining a substituted carbohydrate
according to claim 1, 2, or 3, which is capable of forming a
vitreous glass; and b) processing the substituted carbohydrate and
a substance to be released therefrom, thereby to form a solid
matrix having the substance incorporated therein.
14. The method according to claim 12 wherein the processing step
comprises: i) melting the substituted carbohydrate; ii)
incorporating the substance in the melt, wherein the melt
temperature is sufficient to fluidize the substituted carbohydrate,
and insufficient to substantially inactivate the substance; and
iii) quenching the melt.
15. The method according to claim 12 wherein the processing step
comprises: i) dissolving or suspending the substituted carbohydrate
and the substance in a solvent effective in dissolving at least one
of the substituted carbohydrate and the substance; and ii)
evaporating the solvent.
16. The method according to claim 13 wherein the forming comprises
reacting free hydroxyl groups on a carbohydrate with at least one
acid acyl group including a branched hydrocarbon chain thereon,
thereby to form the substituted carbohydrate.
17. The method according to claim 12 wherein the method further
comprises incorporating into the matrix at least one
physiologically acceptable glass-forming material selected from the
group consisting of carboxylate, nitrate, sulfate, bisulfate, a
hydrophobic carbohydrate derivative and combinations thereof.
18. The method according to claim 12 wherein the method further
comprises processing the matrix into a form selected from the group
consisting of lozenge, tablet, disc, film, suppository, needle,
microneedle, microfiber, particle, microparticle, sphere,
microsphere, powder, and an implantable device.
19. The method according to claim 18 wherein the substance is a
pharmaceutically active chemical.
20. The method according to claim 19 wherein the substance is
selected from the group consisting of lipids, proteins, peptides,
peptide mimetics, hormones, saccharides, nucleic acids, and protein
nucleic acid hybrids.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. patent application
Ser. No. 60/068,754, filed Dec. 23, 1997.
STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED
RESEARCH
[0002] Not applicable.
TECHNICAL FIELD
[0003] This invention relates to derivatized carbohydrates,
compositions comprised thereof and methods for their use. The
derivatized carbohydrates can be used to form solid delivery
systems useful for the dissolution, encapsulation, storage and
delivery of a variety of therapeutic and diagnostic molecules.
BACKGROUND ART
[0004] Solid delivery systems are useful in a wide variety of
applications such as controlled release of labile molecules,
particularly bioactive materials such as organic pharmaceutical
compounds, enzymes, vaccines and biological control agents such as
pesticides and pheromones.
[0005] Drugs and other biologically active agents are frequently
administered orally by means of solid dosage forms, such as tablets
and capsules. Other oral solid dosage forms include lozenges and
other hard candies. Solid dosage forms can also be implanted, such
as subcutaneously for drug delivery. Additionally, solid dosage
forms can be delivered intravenously, or by inhalation to the
pulmonary system.
[0006] Solid dose delivery of bioactive materials to biological
tissues such as mucosal, dermal, ocular, subcutaneous,
intramuscular, intradermal and pulmonary offers several advantages
over methods such as hypodermic injection and transdermal
administration via so-called "patches". Using injection, there is a
risk of infection using conventional needles and syringes. Dosing
using multidose vials is sometimes variable, and physical
discomfort often attends hypodermic injection. Devices used for
administering drugs transdermally usually comprise a reservoir
layer of drug and a laminated composite which adheres to the skin,
i.e., transdermal patches, such as described in U.S. Pat. No.
4,906,463. Many drugs can not be effectively delivered
transdermally, nor have transdermal drug release rates for those
capable of such delivery been perfected. Additionally, transdermal
patches often cause topical reactions, in many instances precluding
their long-term use.
[0007] Subdermal implantable therapeutic systems have been
formulated for slow release of certain pharmaceutical agents for
extended periods of time such as months or years. A well-known
example is the Norplant.RTM. implant for delivery of steroid
hormones. In membrane permeation-type controlled drug delivery, the
drug is encapsulated within a compartment enclosed by a
rate-limiting polymeric membrane. The drug reservoir can contain
either drug particles or a dispersion (or solution) of solid drug
in a liquid or a solid type dispersing medium. The polymeric
membrane can be fabricated from a homogeneous or a heterogeneous
nonporous polymeric material or a microporous or semipermeable
membrane. The encapsulation of the drug reservoir inside the
polymeric membrane can be accomplished by molding, encapsulation,
microencapsulation, or other techniques.
[0008] The implants release drugs by dissolution of the drug in the
inner core and slow release across the outer matrix. The drug
release from this type of implantable therapeutic system is
dependent on drug dissolution rate in the polymeric membrane, often
causing a biphasic release rate. The inner core substantially
dissolves; however, generally, the outer matrix does not
dissolve.
[0009] Implants are placed subcutaneously by making an incision in
the skin and forcing the implants between the skin and the muscle.
At the end of their use, if not dissolved, these implants must be
surgically removed. U.S. Pat. No. 4,244,949 describes an implant
which has an outer matrix of an inert plastic such as
polytetrafluoroethylene resin.
[0010] Other implantable therapeutic systems involve matrix
diffusion-type controlled drug delivery. The drug reservoir is
formed by the homogeneous dispersion of drug particles throughout a
lipophilic or hydrophilic polymer matrix. The dispersion of drug
particles in the polymer matrix is accomplished by blending the
drug with a viscous liquid polymer or a semisolid polymer at room
temperature, followed by cross-linking of the polymer, or by mixing
the drug particles with a melted polymer at an elevated
temperature. The drug reservoir can also be fabricated by
dissolving the drug particles and/or the polymer in an organic
solvent followed by mixing and evaporation of the solvent in a mold
at an elevated temperature or under vacuum. The rate of drug
release from this type of delivery device is generally not
constant. An example of this type of implantable therapeutic system
is the Compudose implant.
[0011] A variety of formulations have been provided for
administration in aerosolized form to mucosal surfaces,
particularly "by-inhalation" (naso-pharyngeal and pulmonary).
Compositions for by-inhalation pharmaceutical administration
generally comprise a liquid formulation of the pharmaceutical agent
and a device for delivering the liquid in aerosolized form. U.S.
Pat. No. 5,011,678 describes suitable compositions containing a
pharmaceutically active substance, a biocompatible amphiphilic
steroid and a biocompatible (hydro/fluoro) carbon propellant. U.S.
Pat. No. 5,006,343 describes suitable compositions containing
liposomes, pharmaceutically active substances and an amount of
alveolar surfactant protein effective to enhance transport of the
liposomes across a pulmonary surface. U.S. Pat. No. 5,608,647
describes methods for administering controlled amounts of aerosol
medication from a valved canister.
[0012] One drawback to the use of aerosolized formulations is that
maintenance of pharmaceutical agents in aqueous suspensions or
solutions can lead to aggregation and loss of activity and
bioavailability. The loss of activity can be partially prevented by
refrigeration; however, this limits the utility of these
formulations. The use of powdered formulations overcomes many of
these drawbacks. The requisite particle size of such powders is
0.5-5 microns in order to attain deep alveolar deposition in
pulmonary delivery. Unfortunately, powders of such particle size
tend to absorb water and clump, thus diminishing deposition of the
powder in the deep alveolar spaces. PCT GB95/01861 described
powders suitable for use in by-inhalation delivery. The powders are
of uniform particle size and can be produced with varying degrees
of hydrophobicity to reduce clumping and increase drug release in
the surfactant environment of the lung.
[0013] Solid dose delivery vehicles for ballistic, transdermal
administration have also been developed. For example, in U.S.
Patent No. 3,948,263, a ballistic animal implant comprised of an
exterior polymeric shell encasing a bioactive material is described
for veterinary uses. Similarly, in U.S. Patent No. 4,326,524, a
solid dose ballistic projectile comprising bioactive material and
inert binder without an exterior casing is disclosed. Delivery is
by compressed gas or explosion. Ballistic delivery at the cellular
level has also been successful. Klein (1987) Nature, 327:70-73.
There are few existing formulations suitable for ballistic
delivery. Powder formulations of pharmaceuticals generally used are
unsuitable for ballistic administration, because they vary in size,
shape and density. The particles described in PCT GB95/01861 are
useful for ballistic delivery due to their discrete size.
[0014] For drug delivery, it is advantageous to provide solid drug
delivery systems of defined size, shape, density and dissolution
rate. It is also advantageous to provide solid drug delivery
systems that are capable of sustained, controlled release of the
drug. It is further advantageous to provide solid dose delivery
systems that can be formulated using simple and economical
methods.
[0015] PCT/GB 90/00497 describes slow release glassy systems for
formation of implantable devices. The described implants are
bioabsorbable and need not be surgically removed. However, these
devices are severely limited in the type of bioactive material that
can be incorporated as these must be stable to heat and/or solvent
to enable incorporation into the delivery device. PCT WO 93/10758
describes a carbohydrate glass matrix for the sustained release of
a therapeutic agent, which includes a carbohydrate, a therapeutic
agent, an agent that inhibits recrystallization of the matrix, and
a water insoluble wax which modifies release of the therapeutic
agent from the matrix.
[0016] PCT WO 96/03978 describes solid dose delivery systems, which
include a vitreous vehicle loaded with a bioactive substance, and
which are capable of releasing the substance at a controlled rate.
The controlled release is achieved by the use of glass-forming,
hydrophobically derivatized carbohydrates as solid vehicles, with
the choice of derivative group selected to reduce solubility of the
matrix material in aqueous media.
[0017] All references cited herein are hereby incorporated herein
by reference.
DISCLOSURE OF THE INVENTION
[0018] Derivatized carbohydrates are provided, as well as
compositions comprised thereof and methods of use thereof. The
derivatized carbohydrates are generally polyol carbohydrates,
wherein at least a portion of the hydroxyl groups on the
carbohydrate are substituted with a branched hydrophobic chain,
such as a hydrocarbon chain, via, for example, an ether or ester
linkage. The derivatized carbohydrates are in one embodiment
oligosaccharide ester derivatives, such as ester derivatives of
disaccharides.
[0019] The derivatized carbohydrates can be formed by modification
of carbohydrates. Suitable carbohydrates include, but are not
limited to, glucose, lactose, cellobiose, sucrose, trehalose,
raffinose, melezitose and stachyose. The hydroxyl groups of the
carbohydrate can be substituted, for example via ester or ether
linkages, with a branched hydrocarbon chain, such as a C3 to C30
branched hydrocarbon chain. The branched hydrocarbon chain can be a
C3 to C30 hydrocarbon chain, for example, a C3 to about a C20
hydrocarbon chain. In a preferred embodiment, the hydrocarbon chain
includes about a C3 to C8 hydrocarbon chain. The carbohydrate can
be substituted, for example, by esterification of one or more of
the hydroxyl groups on the carbohydrate with an acid such as a
fatty acid including a branched hydrocarbon chain. Mixed esters and
ethers of acids including a branched hydrocarbon chain can be
formed, e.g., isobutyrate, pivalate, 2,2-dimethylbutyrate,
3,3-dimethylbutyrate, and 2-ethyl butyrate. Optionally, one or more
of the remaining hydroxyl groups can be substituted via an ester
bond with an acid such as acetate, propionate, or butyrate.
[0020] In one embodiment, the substituted carbohydrate can be
substituted trehalose (Formula 1) substituted sucrose (Formula 2),
substituted lactose (Formula 3), or substituted cellobiose (Formula
4), as shown below. Both .alpha. and .beta. anomers and mixtures
thereof are encompassed by the invention. 1
[0021] In each of Formulas 1-4, one or more of R.sub.1-8 are
independently NHR.sub.9, N(R.sub.9).sub.2, O(C.dbd.O)R.sub.9, or
OR.sub.9, wherein R.sub.9 is a branched, saturated or unsaturated,
C3-C20 hydrocarbon, e.g., a C3-C8 hydrocarbon, and preferably a
C5-C6 hydrocarbon. O(C.dbd.O)R.sub.9 can be, for example, an acid
acyl group of an acid such as isobutyrate, pivalate,
2,2-dimethylbutyrate, 3,3-dimethylbutyrate, 2-ethyl butyrate. In
each of Formula 1-4, the remainder of R.sub.1-8 are independently
OH, NHR.sub.10, N(R.sub.10).sub.2, O(C.dbd.O)R.sub.10, or
OR.sub.10, wherein R.sub.10 is alkyl, for example a C1-C4 alkyl
group, such as methyl, butyl, or propyl.
[0022] Preferred derivatized carbohydrates include trehalose
hexa-3,3-dimethylbutyrate, trehalose
diacetate-hexa-3,3-dimethylbutyrate, trehalose
octa-3,3-dimethylbutyrate, lactose isobutyrate-heptaacetate,
lactose 3-acetyl-hepta-3,3-dimethylbutyrate and lactose
octa-3,3-dimethylbutyrate.
[0023] Derivatized carbohydrates within the scope of the invention
further include carbohydrates, such as disaccharides, wherein one
or more of the free hydroxyl groups are derivatized, for example
into an amine or sulfur group, to which hydrophobic branched
hydrocarbon chains can be attached, for example, via an amide or
thiol linkage.
[0024] Compositions, such as delivery systems, comprising the
derivatized carbohydrates, and other components such as bioactive
agents, carbohydrates, lipids, surfactants, binders, and any other
constituents suitable for use in drug delivery are also encompassed
by the invention. A wide variety of compositions can be
incorporated into the compositions including diagnostic,
therapeutic, prophylactic and other biologically active agents. The
compositions can be in a vitreous or crystalline form, or mixtures
thereof.
[0025] Solid dose delivery systems including a substituted
carbohydrate can have incorporated therein a substance capable of
being released from the solid delivery system. In a preferred
embodiment, the solid dose delivery system comprises the
substituted carbohydrate in the form of a vitreous glass matrix
having the substance incorporated therein. Advantageously, drugs
and bioactive agents are thereby provided in a solid,
non-hygroscopic, glassy matrix, which undergoes a controlled,
surface-led devitrification when immersed in aqueous environments
and subsequently effects a sustained release of drugs therein.
[0026] Properties of the glassy matrix, such as the release rate of
the substance, can be modulated by choice of modified carbohydrate,
and other incorporated materials. The glass matrix can be modified,
for example, by the addition of different glass formers with known
release rates. Other materials can be incorporated into the glass
matrix during processing to modify the properties of the final
composition, including physiologically acceptable glass formers
such as carboxylate, nitrate, sulfate, bisulfate, and combinations
thereof. The delivery systems can further incorporate any other
suitable carbohydrate and/or hydrophobic carbohydrate derivative,
such as glucose pentaacetate or trehalose octaacetate.
[0027] The delivery systems can be in any of a variety of forms
including a lozenge, tablet, disc, film, suppository, needle,
microneedle, microfiber, particle, microparticle, sphere,
microsphere, powder, or an implantable device.
[0028] The invention further encompasses methods of making the
delivery systems. In one embodiment, the method comprises forming
or obtaining a substituted carbohydrate capable of forming a
vitreous glass; processing the substituted carbohydrate and a
substance to be released therefrom; and forming a solid matrix
having the substance incorporated therein.
[0029] The processing step can be implemented by melting the
substituted carbohydrate and incorporating the substance in the
melt, at a temperature sufficient to fluidize the substituted
carbohydrate, and insufficient to substantially inactivate the
substance, and then quenching the melt. The melt can be processed
into a variety of forms. The processing step can be also
implemented by dissolving or suspending the substituted
carbohydrate and the substance in a solvent effective in dissolving
at least one of the derivatized carbohydrates and the substance,
and evaporating the solvent.
[0030] The invention also encompasses methods of delivering
bioactive materials by providing the delivery systems described
above and administering the system to a biological tissue.
Administration can be by any suitable means including mucosal,
oral, topical, subcutaneous, intraperitoneal, intradermal,
intramuscular, intravenous and by-inhalation.
[0031] The delivery systems are uniquely suited to delivery of
hydrophobic substances such as pesticides, pheromones, steroid
hormones, peptides, peptide mimetics, antibiotics and other organic
pharmaceuticals such as synthetic corticosteroids, bronchodilators,
immunomodulators and immunosuppressants. The invention encompasses
these delivery systems. The delivery systems are also suitable for
delivery of a wide variety of non-medical substances, such as
compounds used in agricultural applications, including pesticides,
enzymes or other substances added to laundry detergents; and dyes
or colorants.
BRIEF DESCRIPTION OF THE DRAWINGS
[0032] FIG. 1 is a graph depicting the release of a model
hydrophilic bioactive agent, diltiazem hydrochloride (DZM)
formulated (10% loading) in a single straight chain hydrophobically
derivatized carbohydrate (HDC), trehalose octaacetate (closed
diamonds), or branched chain HDC, trehalose
octa-3,3,dimethylbutyrate (closed squares) showing the much slower
release of DZM from the branched chain HDC formulation in a
standard US Pharmacopeia (USP) in vitro dissolution test.
[0033] FIG. 2 is a graph depicting the release of DZM formulated
(10% loading) in a mixture (1:1 ratio) of a straight (trehalose
octaacetate) and branched (trehalose octapivalate) chain HDCs
(closed diamonds), or two branched chain HDCs, trehalose
octa-3,3,dimethylbutyrate and trehalose octapivalate (closed
squares) showing the delayed release of DZM from the composite
branched chain HDCs formulation in a standard USP in vitro
dissolution test.
[0034] FIG. 3 is a graph depicting the release of a model
hydrophobic bioactive agent, fluticasone propionate formulated in a
single straight chain HDC, trehalose octaacetate (Q1, closed
diamonds), or branched chain HDC, trehalose
octa-3,3,dimethylbutyrate (Q2, closed squares) showing the much
slower release of active from the branched chain HDC formulation in
a standard USP in vitro dissolution test.
BEST MODE FOR CARRYING OUT THE INVENTION
[0035] To improve the glass-forming characteristics of such
hydrophobically derivatized carbohydrates, increasing the carbon
chain length of the derivative group was examined, but it was found
that this parameter is limited, as longer carbon straight chains
than, for example C4, yield oils and not solids. It was found that,
surprisingly, the use of longer carbon chains in a branched chain
instead gave hydrophobically derivatized carbohydrates that formed
suitable glasses, both vitreous and crystalline, for use to
formulate actives, and facilitate their controlled delivery,
enabling their use in solid dose delivery systems.
[0036] Derivatized carbohydrates are provided, as well as
compositions comprised thereof and methods of use thereof. The
derivatized carbohydrates are generally carbohydrates wherein at
least a portion of the hydroxyl groups on the carbohydrate are
substituted with a branched hydrophobic chain, such as a
hydrocarbon chain, via, for example, an ether or ester linkage. The
derivatized carbohydrates can be formed by modification of
carbohydrates, including, but not limited to, glucose, lactose,
cellobiose, sucrose, trehalose, raffinose, melezitose and
stachyose. The hydroxyl groups of the carbohydrate can be
substituted, for example via ester or ether linkages, with a
branched hydrocarbon chain, for example a C3 to about a C20
hydrocarbon chain. In a preferred embodiment, the hydrocarbon chain
is about a C3 to C8 hydrocarbon chain. Preferred derivatized
carbohydrates include trehalose hexa-3,3-dimethylbutyrate;
trehalose diacetate-hexa-3,3-dimethylbutyrate; trehalose
octa-3,3-dimethylbutyrate; lactose octa-3,3-dimethylbutyrate;
lactose 3-acetyl-hepta-3,3-dimethylbutyrate; and lactose
isobutyrate-heptaacetate.
[0037] The derivatized carbohydrates are particularly useful in
forming solid vehicles, such as vitreous glass matrices. The solid
vehicles, such as vitreous glasses, can be processed into different
solid forms, including tablets, powders, lozenges, implants and
microspheres. A wide variety of substances can be incorporated into
the solid matrices, including diagnostic, therapeutic,
prophylactic, antimicrobial, insecticidal, environmental, and other
bioactive agents. In the medical field, the solid matrices are
useful as biodegradable solid materials for controlled delivery and
release of the incorporated substance.
[0038] Formation of Derivatized Carbohydrates
[0039] The derivatized carbohydrates are formed in one embodiment
by the esterification of the free hydroxyl groups on a
carbohydrate. Additional other methods known in the art can be used
such as etherification of the free hydroxyls. In one embodiment, at
least a portion of the free hydroxyl groups are esterified with a
branched hydrocarbon chain acid, or mixtures thereof. Additionally,
optionally, all or a portion of the remainder of the free hydroxyls
are esterified with another acid, such as alkyl acids, e.g., acetic
acid, propionic acid, butyric acid, or mixtures thereof. A wide
variety of partial and mixed esters can be formed. Suitable acids
for ester formation with free hydroxyls on the carbohydrate that
include a branched hydrocarbon chain include isobutyrate, pivalate,
2,2-dimethylbutyrate, 3,3-dimethylbutyrate, and 2-ethyl
butyrate.
[0040] Carbohydrates which can be substituted at the hydroxyl group
include disaccharides such as trehalose, sucrose, lactose and
cellobiose, the structures of which are shown below. Either pure
anomers or anomer mixtures can be used. 2
[0041] Methods for esterifying the carbohydrates are available in
the art. For example, the carbohydrates can be treated with
dimethylbutyroyl chloride in anhydrous pyridine to form the
dimethylbutyroylated carbohydrate. Additionally, partial or mixed
esters can be formed by manipulation of the reaction conditions and
reagent amounts. Such partial and/or mixed esters are also
encompassed by the invention.
[0042] The invention encompasses a variety of derivatized
carbohydrates. Preferred derivatized carbohydrates include
trehalose hexa-3,3-dimethylbutyrate, trehalose
diisobutyrate-hexaacetate, trehalose
diacetate-hexa-3,3-dimethylbutyrate, trehalose
octa-3,3-dimethylbutyrate and lactose isobutyrate-heptaacetate.
[0043] The reaction product can be characterized structurally by
methods known in the art, including, but not limited to, nuclear
magnetic resonance spectroscopy (NMR) and its material science
properties characterized by differential scanning calorimetry
(DSC). The characteristic melting points and Tgs (glass transition
temperatures) for the derivatized carbohydrates can also be
determined by DSC and other methods known in the art.
[0044] Properties of Derivatized Carbohydrates
[0045] Many carbohydrates fail to readily crystallize when dried
from solvent. In the absence of crystal growth, an alternative
solid state, that of an amorphous, optically transparent vitreous
glass is formed. A thermodynamic transition (Tg), measured by
calorimetry, is characteristic of the viscous state and defines the
temperature range over which the highly viscous state collapses
into a more fluid rubbery state. Eventually, as the temperature
continues to rise, the viscosity will fall further, resulting in a
liquid melt.
[0046] In the usual process to form a vitreous glass, a high
temperature melt is quenched (cooled quickly) to solidify without
crystallization to a vitreous glass. Most glassy materials can
theoretically quench to a vitreous glass, however, factors such as
low melt viscosity, thermodynamically favorable crystalline states
and thermal degradation, limit their potential to form vitreous
rather than crystalline solids.
[0047] The glass matrices formed from derivatized carbohydrates as
described herein can be used to stabilize labile bioactive
molecules immobilized within the glassy matrix, both crystalline
and vitreous. Preferably, the glassy state is vitreous. Preferred
derivatized carbohydrates have high Tgs in the vitreous form, e.g.,
about 40.degree. C. to 85.degree. C., and are physically stable.
The vitreous glass matrices formed therefrom have increased
hydrophobicity, and thus have many applications as drug delivery
vehicles, particularly for administration as sustained or delayed
release forms. The derivatized carbohydrates permit solid matrices
to be formed therefrom with selected controlled release properties.
Without being limited to any one theory, it is believed that when
the solid amorphous matrix is immersed in aqueous environments,
drug release is effected by a controlled devitrification or
crystallization, which begins over the surface of the glass
particle. As water interacts with the glass, the devitrification
front proceeds further into the glass. The crystalline matrix thus
formed allows the previously entrapped drug to diffuse into the
surrounding environment at a rate dependent on both HDC and
drug.
[0048] The invention enables the preparation and use of derivatized
carbohydrates having glass transition temperatures (Tgs) high
enough to form stable glasses to allow the formulation of actives
such as drugs. In parallel, the glasses undergo a slow, controlled
devitrification when immersed in water. The methods of the
invention permit the formulation of drugs in very hydrophobic
glassy matrices, which can sustain drug release over long time
periods.
[0049] Derivatized carbohydrates can also be used to form solid
matrices that have a partially or substantially crystalline
structure. Additionally, glasses can also be formed which form a
partially or substantially crystalline structure over time after
incorporation of active.
[0050] Using the methods disclosed herein, in one embodiment,
C.sub.5 and C.sub.6 branched chain fatty acid derivatives of
trehalose, and other carbohydrate molecules such as lactose,
cellobiose, sucrose, raffinose and stachyose can be made, which can
be melted and quenched to glasses with higher Tgs, e.g., greater
than about 30.degree. C., preferably greater than about 40.degree.
C.
[0051] The Tgs of the vitreous forms of the compositions
encompassed herein are typically less than about 200.degree. C.,
typically about 10.degree. C. to 100.degree. C., preferably about
20.degree. C. and 85.degree. C. The derivatized carbohydrates can
be used to form vitreous glass matrices, wherein the tendency to
crystallize from the melt or with reducing solvent, is low.
Mixtures of derivatized carbohydrates also can be used to form the
glass matrices. Glasses formed using the derivatized carbohydrates
preferably have melt temperatures suitable for the incorporation of
substances such as biologically active compounds, without thermal
degradation, and have Tgs above ambient temperatures.
[0052] Both devitrification of the vitreous matrix and the fluidity
of the melt at temperatures close to Tg can be controlled by choice
of the degree and type of substitution of the carbohydrate, and by
the addition of modifiers such as other derivative sugars and
certain organic compounds. Suitable derivative sugars and organic
compounds are described for instance, in PCT GB95/01861.
[0053] As used herein, ambient temperatures are those of the
surrounding environment of any given environment. Typically,
ambient temperatures are "room temperature" which is generally
20-22.degree. C. However, ambient temperature of a "warm room" (for
bacteriological growth) can be 37.degree. C. Thus, ambient
temperature is readily determined from the context in which it is
used and is well understood by those of skill in the art.
[0054] Formation of Delivery Systems
[0055] The derivatized carbohydrates provided herein can be used to
form a biodegradable delivery system, optionally with a substance
incorporated therein, such as a therapeutic substance. The
derivatized carbohydrates are referred to herein as the "vehicle"
used to form the delivery system. As used herein, the term
"delivery system" refers to any form of the substituted
carbohydrate having a substance incorporated therein. Preferably,
the delivery system is in the form of a solid matrix having the
substance incorporated therein. The matrix can be designed to have
a desired release rate of the substance incorporated therein, by
selection of the material forming the matrix, selection of the
conditions of forming the matrix, and by the addition of other
substances which can modify the rate of release.
[0056] The derivatized carbohydrates readily form glasses either
from a quenched melt or an evaporated organic solvent. Examples of
methods of forming amorphous carbohydrate glass matrices are
described in "Pharmaceutical Dosage Forms," Vol. 1 (H. Lieberman
and L. Lachman, Eds.) 1982.
[0057] The derivatized carbohydrates and substance or substances to
be incorporated can be intimately mixed together in the appropriate
molar ratios and melted until clear. Suitable melting conditions
include, but are not limited to, melting in open glass flasks at
about 30-250.degree. C. for about 1-2 minutes. This results in a
fluid melt which can be allowed to cool slightly before dissolving
the substance in the melt, if required, and quenching to glass for
instance by pouring over a brass plate or into a metal mould for
shaped delivery vehicles. The melts can also be quenched by any
methods including spray chilling. Melt temperature can be carefully
controlled and substances can be incorporated into the derivatized
carbohydrates either in the pre-melted formulation, or stirred into
the cooling melt before quenching.
[0058] The melts are thermally stable and allow the incorporation
of molecules without denaturation, or suspension of core particles
without alteration of their physical nature. The glass melts can be
used also to coat micron-sized particles. This is particularly
important in the formulation of non-hygroscopic powders containing
hygroscopic actives for by-inhalation administration of therapeutic
agents. Compositions made by this process are also encompassed by
this invention.
[0059] Alternatively, delivery systems can be formed by evaporation
of the derivatized carbohydrates and substance to be incorporated
in solution in a solvent or mixture thereof. Suitable organic
solvents include, but are not limited to, dichloromethane,
chloroform, dimethylsulfoxide, dimethylformamide, ethyl acetate,
acetone and alcohols. The type of solvent is immaterial as it is
completely removed on formation of the delivery system. Preferably,
both the substituted carbohydrate and substance to be incorporated
are soluble in the solvent. However, the solvent can dissolve the
substituted carbohydrate and allow a suspension of the substance to
be incorporated in the matrix. In one embodiment, on concentrating
the solvent, crystallization of the derivatized carbohydrates does
not occur. Instead, a vitreous solid is produced, which has similar
properties to the quenched glass. Alternatively, solid matrices
which are partially, substantially or fully crystalline can be
formed. Substances can be incorporated easily either in solution or
as a particle suspension.
[0060] In one embodiment, a solution of the substance to be
incorporated, containing a sufficient quantity of substituted
carbohydrate to form a glass on drying, can be dried by any method
known in the art, including, but not limited to, freeze drying,
lyophilization, vacuum, spray, belt, air or fluidized-bed drying.
Another suitable method of drying, exposing a syrup to a vacuum
under ambient temperature, is described in PCT GB96/01367. After
formation of a glass containing homogeneously distributed substance
in solid solution or fine suspension in the glass, the glasses can
then be milled and/or micronized to give microparticles of
homogeneous defined size.
[0061] Different dosing schemes can also be achieved by the
delivery system formulated. The delivery system can permit a quick
release or flooding dose of the incorporated substance after
administration, upon dissolving and release of the substance from
the delivery system. Coformulations of vehicles with slowly
water-soluble glasses and plastics such as phosphate, nitrate or
carboxylate glasses and lactide/glycolide, glucuronide or
polyhydroxybutyrate plastics and polyesters, provide more slowly
dissolving vehicles for a slower release and prolonged dosing
effect. Optionally, a substance can be incorporated into the
vitreous matrix which retards recrystallization of the matrix, such
as polyvinylpyrolidone, or a hydrophobic substance, to modify the
release rate of the active agent, such as a water insoluble wax or
a fatty acid. These are described in PCT WO 93/10758.
[0062] The delivery systems can also be coformulated with a
hydrophobically-derivatized carbohydrate (HDC) glass forming
material. Suitable HDC glass forming materials include, but are not
limited to, those described in PCT WO 96/03978. As used herein, HDC
refers to a wide variety of hydrophobically derivatized
carbohydrates where at least one hydroxyl group is substituted with
a hydrophobic moiety. Examples of suitable HDCs and their syntheses
are described in Developments in Food Carbohydrate--2 ed. C. K.
Lee, Applied Science Publishers, London (1980). Other syntheses are
described for instance, in Akoh et al. (1987) J. Food Sci. 52:1570;
Khan et al. (1993) Tet. Letts 34:7767; Khan (1984) Pure & Appl.
Chem. 56:833-844; and Khan et al. (1990) Carb. Res.
198:275-283.
[0063] The delivery of more than one bioactive material can also be
achieved using a delivery system including multiple coatings or
layers loaded with different materials or mixtures thereof.
Administration of the solid dose delivery systems of the present
invention can be used in conjunction with other conventional
therapies and coadministered with other therapeutic, prophylactic
or diagnostic substances. Compositions such as these are
encompassed by the invention.
[0064] The solid delivery systems can be used to deliver
therapeutic agents by any means including, but not limited to,
topical, transdermal, transmucosal, oral, gastrointestinal,
intraperitoneal, subcutaneous, ocular, intramuscular, intravenous
and by-inhalation (naso-pharyngeal and pulmonary, including
transbronchial and transalveolar).
[0065] Topical administration is, for instance, by a dressing or
bandage having dispersed therein a delivery system, or by direct
administration of a delivery system into incisions or open wounds.
Creams or ointments having dispersed therein slow release bead or
microspheres of a delivery system are suitable for use as topical
ointments or wound filling agents.
[0066] Compositions for transdermal administration are preferably
powders of delivery systems in the form of preferably homogeneously
sized microneedles or microbeads. Larger, macroscopic needle and
bead forms of the delivery systems are also provided for subdermal
implantation and extended drug delivery. The particle sizes should
be small enough so that they cause only minimal skin damage upon
administration. The powders can be prepackaged in single-dose,
sealed, sterile formats. Suitable methods of transdermal
administration include, but are not limited to, direct impact,
ballistic, trocar and liquid jet delivery.
[0067] The delivery systems suitable for transmucosal delivery
include, but are not limited to, mucoadhesive wafers, films or
powders, lozenges for oral delivery, pessaries, and rings and other
devices for vaginal or cervical delivery.
[0068] Compositions suitable for gastrointestinal administration
include, but are not limited to, pharmaceutically acceptable
powders, tablets, capsules and pills for ingestion and
suppositories for rectal administration.
[0069] Compositions suitable for subcutaneous administration
include, but are not limited to, various implants. Preferably the
implants are macroscopic discoid, spherical or cylindrical shapes
for ease of insertion and can be either fast or slow release. Since
the entire implant is dissolved in the body fluids, removal of the
implant is not necessary. Furthermore, the implants do not contain
synthetic polymers and are biodegradable.
[0070] Compositions suitable for ocular administration include, but
are not limited to, microsphere and macrosphere formulations and
saline drops, creams and ointments containing these and round-ended
shaped rods which fit comfortably in the lower conjunctival fornix
beneath the lower eyelid.
[0071] Compositions suitable for by-inhalation administration
include, but are not limited to, powder forms of the delivery
systems. There are a variety of devices suitable for use in
by-inhalation delivery of powders. See, e.g., Lindberg (1993)
Summary of Lecture at Management Forum Dec. 6-7 1993 "Creating the
Future for Portable Inhalers." Additional devices suitable for use
herein include, but are not limited to, those described in
WO9413271, WO9408552, WO9309832 and U.S. Pat. No. 5,239,993.
[0072] The delivery systems are preferably biodegradable and
release substances incorporated therein over a desired time period,
depending on the particular application, and the composition of the
system. As used herein, the term "biodegradable" refers to the
ability to degrade under the appropriate conditions of use, such as
outdoors, or in the body, for example by dissolution,
devitrification, hydrolysis or enzymatic reaction.
[0073] Substances Incorporated in the Delivery Systems
[0074] Substances which can be incorporated into the delivery
systems include, but are not limited to, medicinal or agricultural
bioactive materials suitable for use in vivo and in vitro. Suitable
bioactive materials include, but are not limited to, pharmaceutical
agents, therapeutic and prophylactic agents, and agrochemicals such
as pesticides and pheromones.
[0075] Suitable therapeutic and prophylactic agents include, but
are not limited to, any therapeutically effective biological
modifier. Such modifiers include, but are not limited to,
pharmaceutical actives, subcellular compositions, cells, bacteria,
viruses and molecules including, but not limited to, lipids,
organics, proteins and peptides (synthetic and natural), peptide
mimetics, hormones (peptide, steroid and corticosteroid), D and L
amino acid polymers, saccharides including oligosaccharides and
polysaccharides, nucleotides, oligonucleotides and nucleic acids,
including DNA and RNA, protein-nucleic acid hybrids, small
molecules and physiologically active analogs thereof. Further, the
modifiers can be derived from natural sources or made by
recombinant or synthetic means and include analogs, agonists and
homologs.
[0076] As used herein "protein" refers also to peptides and
polypeptides. Such proteins include, but are not limited to,
enzymes, biopharmaceuticals, growth hormones, growth factors,
insulin, monoclonal antibodies, interferons, interleukins and
cytokines.
[0077] Organic compounds include, but are not limited to,
pharmaceutically active chemicals. For instance, representative
organic compounds include, but are not limited to, vitamins,
neurotransmitters, antimicrobials, antihistamines, analgesics,
.beta.-agonists, .beta.-antagonists, .beta.-blockers,
corticosteroids, and immunosuppressants.
[0078] Compositions comprising solid dose delivery systems
containing prophylactic bioactive materials and carriers therefore
are further encompassed by the invention. Preferable compositions
include immunogens such as for use in vaccines. Preferably, the
compositions contain an amount of the immunogen effective for
either immunization or booster inoculation.
[0079] The invention will be further understood by the following
non-limiting examples.
EXAMPLE 1
[0080] Synthesis and Physical Properties of Derivatized
Carbohydrates
[0081] The carbohydrate derivatives were routinely synthesized by
standard esterification of the carbohydrate with the chloride of
the desired hydrocarbon side chain under anhydrous conditions and
the resulting derivatives purified by standard techniques of
solvent extraction and re-crystallization. For example, trehalose
octa-3,3-dimethylbutyrate was synthesized by reacting
3,3,-dimethylbutyroyl chloride with trehalose in anhydrous
pyridine, followed by extraction with ether, hydrochloric acid,
potassium carbonate solution and water and finally re-crystallized
twice from alcohol to yield colorless, needle-like crystals
(.about.80% yield) of m.pt 138-140.degree. C., .alpha..sub.D
112.degree.. Trehalose hexa-3,3-dimethylbutyrate (THEX) can be
prepared by protecting the 6,6'-hydroxy group of trehalose with a
bulky group such as trityl or t-butyldiphenylsilyl, for example by
heating trehalose and trityl chloride in pyridine. The
6,6'-ditrityltrehalose can be acylated with 3,3-dimethylbutyroyl
chloride in pyridine to give 6,6'-ditritylhexa-3,3-d-
imethylbutyryltrehalose. The trityl group can be removed by strong
acid, for example hydrogen bromide in acetic acid, to give THEX.
TACT can be prepared by acylating THEX with acetic anhydride in
pyridine. Suitable work-up yields the HDC in crystalline form. The
physical characteristics, melting points and glass transition
temperatures (Tg, .degree.C.) of selected carbohydrate derivatives
are shown in Tables 1-5.
[0082] It was found that advantageously compounds could be made
which melted, then quenched to glasses with high Tgs
(>40.degree. C.). Table 1 shows examples of fully substituted
pivalate and tertbutyl acetate derivatives which show Tgs of up to
81.degree. C., much higher than the equivalent straight chain
derivatives (butyrate and valerate) which form oily syrups instead
of glassy solids. This unusual property of branched-chain
derivatives enables more hydrophobic derivatives (compared to the
acetates) to be prepared, which permits further reduction of drug
release rates for longer term applications.
[0083] Table 2 illustrates that mixed straight and branched chain
ester derivatives of trehalose resulted in glasses with lower water
solubilities, yet useful high Tgs. Interestingly, several of these
derivatives failed to crystallize during the purification steps,
thus illustrating that selected mixed ester derivatives can be
difficult to crystallize. Preferred derivatives are those that form
stable hydrophobic glasses with high Tgs (greater than about
40.degree. C.), yet have a degree of instability that produces a
defined, even crystal growth as the HDC glass interacts with water.
The mixed ester derivatives offer a combination of both glass
stability and increased hydrophobicity, which are useful to delay
drug release.
[0084] Partially substituted trehalose derivatives, as shown in
Tables 3, show surprising characteristics of very high Tgs, and in
some cases a reluctance to also crystallize. These derivatives also
fail to crystallize when immersed in water. For example, trehalose
hexa-3,3-dimethylbutyrate (THEX) is stable in the glassy state when
immersed in saline medium at 37.degree. C. When the hydroxyl groups
are replaced with acetates, as with trehalose diacetate hexa
3,3-dimethylbutyrate (TACT), the glass stability is reduced, though
both these glasses are more stable than trehalose octa 3,3
dimethylbutyrate (TOCT). These compounds are thus useful for
controlling the release rate of drugs formulated within the
respective glasses. To extend this, blends of two or more HDCs
permit further variations in controlling the rate of
devitrification and hence drug release. For example, the pure
.alpha., .beta. anomers of lactose isobutyrate heptaacetate
crystallize from solution; however, when a small amount of the
corresponding anomer is added, the blend fails to crystallize.
Thus, using combinations of HDCs and/or anomers thereof, the rate
of drug release can be controlled.
[0085] Table 4 illustrates some selected properties of other
disaccharide ester derivatives. Cellobiose octaisobutyrate has a
surprisingly high melting temperature, yet is very hard to quench
to glass. Lactose and cellobiose derivatives tend to have higher
Tgs than trehalose and sucrose derivatives. Lactose derivatives
were found to devitrify much more slowly than their corresponding
trehalose derivatives despite their similar Tgs. For example,
lactose isobutyrate heptaacetate is very stable in the glassy
state, when immersed in water. It also has a very high Tg (Table
4).
1TABLE 1 Effect of branched versus straight chains Derivatized
Carbohydrate M.P.(.degree. C.) Tg(.degree. C.) COMMENT Trehalose
octaacetate 135.9 55 C2 straight chain Trehalose octapropionate 47
3 C3 straight chain. Glass not stable above ambient temperature
Trehalose octabutyrate syrup syrup C4 straight chain. No glass
formation Trehalose octaisobutyrate 78 7 C4 branched chain. Glass
formed, but not stable above ambient temperature Trehalose
octavalerate syrup syrup C5 straight chain. No glass formation
Trehalose octapivalate 188 81 C5 branched chain. Glass formed now
stable above ambient temperature
[0086]
2TABLE 2 Formation of mixed branched and straight chain derivatives
Derivatized Carbohydrate M.P.(.degree. C.) Tg(.degree. C.) COMMENT
Trehalose 6,6'di-(2,2- amorphous 47 Material not dimethylbutyrate)
hexaacetate isolated in crystalline form Trehalose 6,6'-di-(3,3-
165 50 dimethylbutyrate) hexaacetate Trehalose 6,6'-diaacetate 140
44 hexa-3,3-dimethylbutyrate Trehalose 6,6'-di-(2- 63 30
ethylbutyrate) hexaacetate Trehalose 6,6'-diisobutyrate 87 42
hexaacetate Trehalose 4,4'-diisobutyrate 123 41 hexaacetate
Trehalose 6,6'-dipropionate amorphous 43 Material not hexaactetate
isolated in crystalline form Trehalose 4,4'-dipropionate amorphous
42 Material not hexaactetate isolated in crystalline form Trehalose
6,6'dipivalate 159 56 hexaacetate
[0087]
3TABLE 3 Effect of partially derivatization with branched chains
Derivatized Carbohydrate M.P.(.degree. C.) Tg(.degree. C.) COMMENT
Trehalose octapivalate 188 81 Very hydrophobic, most resistant to
devitrification in aqueous environ- ment Trehalose heptapivalate
182 73 Trehalose hexapivalate 203 86 Trehalose pentapivalate
amorphous 81 Material not isolated in crystalline form Trehalose
tetrapivalate 301 96 Most hydrophilic, least resistant to
devitrification in aqueous environ- ment Trehalose octa-3,3- 139 42
dimethylbutyrate Trehalose hexa-3,3- amorphous 64 Material not
isolated dimethylbutyrate in crystalline form Trehalose tetra-3,3-
237 82 dimethylbutyrate
[0088]
4TABLE 4 Effect of changing carbohydrate backbone Derivatized
Carbohydrate M.P.(.degree. C.) Tg(.degree. C.) COMMENT .alpha.,
.beta.-Lactose 147 67 Undefined anomeric ratio octaacetate
.alpha.-Lactose 119 70 octaacetate .beta.-Lactose 87 63 octaacetate
Lactose isobutyrate amorphous 60 1:1 ratio of .alpha. and .beta.
heptaacetate anomers .beta.-Lactose amorphous 60 Mixed straight and
isobutyrate branched chain derivative heptaacetate .alpha.-Lactose
3-acetyl- 128 48 Mixed straight and hepta-3,3- branched chain
derivative dimethylbutyrate .alpha.-Lactose octa-3,3- 149 53 C5
branched chain. Glass dimethyl-butyrate stable above ambient
temperature .beta.-Lactose 168 88 C5 branched chain. Glass
octapivalate stable well above ambient temperature
.alpha.-Cellobiose 224 65 Poor glass former octaacetate
.beta.-Cellobiose 193 53 Good glass former octaacetate
.beta.-Cellobiose methyl 186 77 Mixed straight chains heptaacetate
derivative .beta.-Cellobiose ethyl 182 52 Longer straight chain
heptaacetate (C2) gives lowers Tg .beta.-Cellobiose syrup 15 C3
straight chain. Glass octapropionate not stable above ambient
temperature Raffinose undeca- 83 15 Branched chain isobutyrate
derivative of trisaccharide
EXAMPLE 3
[0089] Incorporation of Active Into Single and Composite
Formulations of Derivatized Carbohydrates and Controlled Release in
vitro
[0090] a. Formulation and controlled release of a model hydrophilic
drug
[0091] The model hydrophilic drug, diltiazem hydrochloride
("hydrophilic active"), was incorporated (10% loading) into solid
vehicles of the single straight chain HDC trehalose octaacetate or
the branched chain HDCs trehalose octa-3,3, dimethylbutyrate and
trehalose octapivalate as well as composite formulations (1:1
ratio) of the two branched-chain HDCs or the straight chain HDC
trehalose octaacetate and the branched chain HDC trehalose
octapivalate, by quenching from the melt. Release of the active
from the HDC solid dose delivery vehicle was assessed using an in
vitro USP (volume 23) type 2 dissolution test in saline containing
0.1% sodium cholate as the dissolution medium. The much slower
release of HDC formulated active from a solid vehicle of the single
branched chain HDC trehalose octa-3,3, dimethylbutyrate as compared
to the formulation of a single straight chain HDC, trehalose
octaacetate (FIG. 1) reflects the greater stability of the branched
chain HDC formulation to devitrification in aqueous media. The
composite formulation of the two branched chain HDCs (trehalose
octa-3,3, dimethylbutyrate and trehalose octapivalate) showed a Tg
of 61.degree. C. (Table 5) and a much slower release of active as
compared to the composite formulation of a mix of straight and
branched chain HDCs (trehalose octaacetate and trehalose
octapivalate) (FIG. 2).
[0092] The model hydrophilic drug diltiazem hydrochloride was also
incorporated (5% loading) into solid vehicles of the single
branched chain HDCs trehalose diisobutyrate hexaacetate and
trehalose octapivalate and composite formulations (1:1 ratio) of
the two branched-chain HDCs by solvent removal by rotary
evaporation, in a Buchi Rotavapor R-124, of a 20% solution of
active plus HDCs in a dichloromethane: acetone mixed solvent (9:1
ratio) system. The composite HDC formulation of active showed a Tg
of 52.7.degree. C. compared to Tgs of 46.5.degree. C. (trehalose
diisobutyrate hexaacetate) and 83.7.degree. C. (trehalose
octapivalate) of the single branched-chain HDC formulations of
active.
[0093] b. Formulation and controlled release of a model hydrophobic
active
[0094] The model hydrophobic steroid fluticasone propionate
("hydrophobic active") was incorporated (5% loading) into solid
vehicles of the single straight chain HDC trehalose octaacetate or
the branched chain HDCs trehalose octa-3,3, dimethylbutyrate and
trehalose dipropanoate hexaacetate and composite formulations (1:1
ratio) of the two branched-chain HDCs by either quenching from the
melt or solvent evaporation by rotary evaporation. Melt
incorporation was carried out by melting the HDCs at
150-170.degree. C. and dissolving the active in the melt at
120-140.degree. C. Rotary evaporation was carried out using a Buchi
Rotavapor R-124 using a 20% solution of active plus HDCs in a
dichloromethane: acetone mixed solvent (9:1 ratio) system. The
hydrophobic active was also incorporated into solid vehicles of the
branched chain HDCs, trehalose octapivalate, trehalose
diisobutyrate hexaacetate and lactose isobutyrate heptaacetate,
either by quenching from the melt or solvent evaporation by rotary
evaporation. The Tgs for various examples of the branched chain HDC
formulations containing hydrophobic active are shown in Table 5.
Release of hydrophobic active from the HDC solid dose delivery
vehicle was assessed using an in vitro USP (volume 23) type 2
dissolution test in saline containing 0.1% sodium cholate as the
dissolution medium. The formulation of the single branched chain
HDC, trehalose octapivalate (Q2), showed a much slower release of
active as compared to the formulation of a single straight chain
HDC, trehalose octaacetate (Q1), reflecting the greater stability
of the branched chain HDC formulation to devitrification in aqueous
media (FIG. 3).
[0095] c. Formulation of a bioactive polypeptide
[0096] As an example of a polypeptide drug, the polypeptide hormone
insulin ("polypeptide active") was incorporated (10% loading) into
solid vehicles of the single branched chain HDCs trehalose
diisobutyrate hexaacetate and trehalose hexapivalate and composite
formulations of the branched chain HDCs trehalose diisobutyrate
hexaacetate and trehalose octapivalate (8:1 ratio) by solvent
removal by lyophilization of a 20% solution of insulin plus HDCs in
dimethylsulfoxide. The Tgs for the trehalose diisobutyrate
hexaacetate, trehalose hexapivalate and composite (trehalose
diisobutyrate hexaacetate: trehalose octapivalate) formulations
were 50.1.degree. C., 76.5.degree. C. and 45.degree. C.
respectively (Table 5). Release of active from the HDC solid dose
delivery vehicle was assessed using an in vitro USP (volume 23)
type 2 dissolution test in saline containing 0.1% sodium cholate as
the dissolution medium. The composite branched chain HDC
formulation (trehalose diisobutyrate hexaacetate:trehalose
octapivalate) showed a much slower release of active than the
single straight chain HDC formulation (trehalose octaacetate), with
57% and 88% release of active respectively, after 1 hour in the
dissolution assay.
5TABLE 5 Incorporation of actives in single branched chain
derivative formulations Method Derivatized Active of incor-
Carbohydrate Tg(.degree. C.) incorporated Tg(.degree. C.) poration
Trehalose octaacetate 50 hydrophobic 53 Melt, active Solvent
Trehalose 38 hydrophobic 44 Melt, dipropanoate active Solvent
hexaacetate Trehalose octapivalate 80 hydrophobic 80 Melt active
Trehalose octa 3,3 46 hydrophobic 45 Melt, dimethylbutyrate active
Solvent Trehalose n.d. hydrophobic 39 Melt, dipropanoate active
Solvent hexaacetate/ trehalose octa 3,3 dimethylbutyrate (1:1)
Trehalose 42 hydrophobic 50 Melt, diisobutyrate active Solvent
hexaacetate Lactose isobutyrate 60 hydrophobic 59 Melt heptaacetate
active Trehalose 42 hydrophilic 46.5 Melt, diisobutyrate active
Solvent hexaacetate Trehalose octapivalate 80 hydrophilic 83.7 Melt
active Trehalose n.d. hydrophilic 52.7 Melt, diisobutyrate active
Solvent hexaacetate:trehalose octapivalate (8:1) Trehalose octa
3,3- n.d hydrophilic 61 Melt dimethylbutyrate: active trehalose
octapivalate (1:1) Trehalose 42 polypeptide 50.1 Solvent
diisobutyrate active hexaacetate Trehalose hexapivalate 86
polypeptide 76.5 Solvent active Trehalose octapivalate: n.d
polypeptide 45 Solvent trehalose diisobutyrate active hexaacetate
(8:1)
[0097] Although the foregoing invention has been described in some
detail by way of illustration and example for purposes of clarity
and understanding, it will be apparent to those skilled in the art
that certain changes and modifications can be practiced. Therefore,
the description and examples should not be construed as limiting
the scope of the invention, which is delineated by the appended
claims.
* * * * *