U.S. patent application number 10/953841 was filed with the patent office on 2005-02-24 for semi-solid delivery vehicle and pharmaceutical compositions.
This patent application is currently assigned to A.P. PHARMA, INC.. Invention is credited to Heller, Jorge, Ng, Steven Y., Shen, Hui Rong.
Application Number | 20050042194 10/953841 |
Document ID | / |
Family ID | 36119607 |
Filed Date | 2005-02-24 |
United States Patent
Application |
20050042194 |
Kind Code |
A1 |
Ng, Steven Y. ; et
al. |
February 24, 2005 |
Semi-solid delivery vehicle and pharmaceutical compositions
Abstract
A semi-solid delivery vehicle contains a polyorthoester and an
excipient, and a semi-solid pharmaceutical composition contains an
active agent and the delivery vehicle. The pharmaceutical
composition may be a topical, syringable, or injectable
formulation; and is suitable for local delivery of the active
agent. Methods of treatment are also disclosed.
Inventors: |
Ng, Steven Y.; (San
Francisco, CA) ; Shen, Hui Rong; (Fremont, CA)
; Heller, Jorge; (Woodside, CA) |
Correspondence
Address: |
HELLER EHRMAN WHITE & MCAULIFFE LLP
275 MIDDLEFIELD ROAD
MENLO PARK
CA
94025-3506
US
|
Assignee: |
A.P. PHARMA, INC.
Redwood City
CA
|
Family ID: |
36119607 |
Appl. No.: |
10/953841 |
Filed: |
September 28, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10953841 |
Sep 28, 2004 |
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10765768 |
Jan 26, 2004 |
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10765768 |
Jan 26, 2004 |
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10409408 |
Apr 7, 2003 |
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6790458 |
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10409408 |
Apr 7, 2003 |
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09854180 |
May 11, 2001 |
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6613355 |
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60325790 |
May 11, 2000 |
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Current U.S.
Class: |
424/78.3 |
Current CPC
Class: |
A61K 9/0014 20130101;
A61K 45/06 20130101; A61K 8/85 20130101; A61P 39/02 20180101; A61K
31/445 20130101; A61K 8/86 20130101; A61P 23/02 20180101; A61P
29/00 20180101; A61Q 19/00 20130101; A61K 31/573 20130101; A61P
23/00 20180101; A61K 9/06 20130101; A61K 9/0019 20130101; A61K
9/0024 20130101; A61K 9/1647 20130101; A61K 47/34 20130101; A61K
31/439 20130101; A61Q 15/00 20130101; A61Q 17/04 20130101; A61K
47/10 20130101; A61K 31/765 20130101; A61P 1/08 20180101 |
Class at
Publication: |
424/078.3 |
International
Class: |
A61K 031/765 |
Claims
What is claimed is:
1. A pharmaceutical composition comprising: (A) semi-solid delivery
vehicle, comprising: (i) a polyorthoester of formula I or formula
II 23where: R is a bond, --(CH.sub.2).sub.a--, or
--(CH.sub.2).sub.b--O--(CH- .sub.2).sub.c--; where a is an integer
of 1 to 10, and b and c are independently integers of 1 to 5; R* is
a C.sub.1-4 alkyl; n is an integer of at least 5; and A is R.sup.1,
R.sup.2, R.sup.3, or R.sup.4, where R.sup.1 is: 24where: p is an
integer of 1 to 20; R.sup.5 is hydrogen or C.sub.1-4 alkyl; and
R.sup.6 is: 25where: s is an integer of 0 to 30; t is an integer of
2 to 200; and R.sup.7 is hydrogen or C.sub.1-4 alkyl; R.sup.2 is:
26R.sup.3 is: 27where: x is an integer of 0 to 30; y is an integer
of 2 to 200; R.sup.8 is hydrogen or C.sub.1-4 alkyl; R.sup.9 and
R.sup.10 are independently C.sub.1-12 alkylene; R.sup.11 is
hydrogen or C.sub.1-6 alkyl and R.sup.12 is C.sub.1-6 alkyl; or
R.sup.11 and R.sup.12 together are C.sub.3-10 alkylene; and R.sup.4
is the residue of a diol containing at least one functional group
independently selected from amide, imide, urea, and urethane
groups; in which at least 0.01 mol percent of the A units are of
the formula R.sup.1; and (ii) a pharmaceutically acceptable,
polyorthoester-compatibl- e liquid excipient selected from
polyethylene glycol ether derivatives having a molecular weight
between 200 and 4000, polyethylene glycol copolymers having a
molecular weight between 400 and 4000, mono-, di-, or
tri-glycerides of a C.sub.2-19 aliphatic carboxylic acid or a
mixture of such acids, alkoxylated tetrahydrofurfuryl alcohols and
their C.sub.1-4 alkyl ethers and C.sub.2-19 aliphatic carboxylic
acid esters, and biocompatible oils; and (B) an antiemetic agent,
and/or an anesthetic agent.
2. The semi-solid delivery vehicle of claim 1 where the
concentration of the polyorthoester ranges from 1% to 99% by
weight.
3. The semi-solid delivery vehicle of claim 1 where the
polyorthoester has a molecular weight between 1,000 and 20,000.
4. The semi-solid delivery vehicle of claim 1 where the fraction of
the A units that are of the formula R.sup.1 is between 1 and 90 mol
percent.
5. The semi-solid delivery vehicle of claim 1 where the
polyorthoester is of formula I, where: none of the units have A
equal to R.sup.2; R.sup.3is: 28where: x is an integer of 0 to 10; y
is an integer of 2 to 30; and R.sup.6is: 29where: s is an integer
of 0 to 10; t is an integer of 2 to 30; and R.sup.5, R.sup.7, and
R.sup.8 are independently hydrogen or methyl.
6. The semi-solid delivery vehicle of claim 5 where: R.sup.3 and
R.sup.6 are both
--(CH.sub.2--CH.sub.2--O).sub.2--(CH.sub.2--CH.sub.2)--; R.sup.5 is
methyl; and p is 1 or 2.
7. The semi-solid delivery vehicle of claim 5 where: R.sup.3 and
R.sup.6 are both
--(CH.sub.2--CH.sub.2--O).sub.9--(CH.sub.2--CH.sub.2)--; R.sup.5 is
methyl; and p is 1or2.
8. The pharmaceutical composition of claim 1 where the anesthetic
agent is selected from the group consisting of bupivacaine,
lidocaine, mepivacaine, pyrrocaine and prilocaine.
9. The pharmaceutical composition of claim 8, wherein the
concentration of the anesthetic agent in the composition is about
1-5 wt. %.
10. The pharmaceutical composition of claim 1 where the antiemetic
agent is granisetron.
11. The pharmaceutical composition of claim 1 where the fraction of
the antiemetic agent is from 0.1% to 80% by weight of the
composition.
12. The pharmaceutical composition of claim 11 where the fraction
of the antiemetic agent is from 1% to 5% by weight of the
composition.
13. The pharmaceutical composition of claim 10 where the
composition is in topical, syringable, or injectable form.
14. The pharmaceutical composition of claim 1 where the antiemetic
agent is selected from the group consisting of 5-HT.sub.3
antagonists, a dopamine antagonists, an anticholinergic agents, a
GABA.sub.B receptor agonists, an NK.sub.1 receptor antagonists, and
a GABA.sub.A.alpha..sub.2 and/or .alpha..sub.3 receptor
agonists.
15. The pharmaceutical composition of claim 14 where the antiemetic
agent is a 5-HT.sub.3 antagonist.
16. The pharmaceutical composition of claim 15 where the 5-HT.sub.3
antagonist is selected from the group consisting of ondansetron,
granisetron and tropisetron.
17. The pharmaceutical composition of claim 16 further comprising a
second antiemetic agent to form a combination composition.
18. The pharmaceutical composition of claim 17 where the second
antiemetic agent is selected from the group consisting of alpha-2
adrenoreceptor agonists, a dopamine antagonist, an anticholinergic
agent, a GABA.sub.B receptor agonist, an NK.sub.1 receptor
antagonist, and a GABA.sub.A.alpha..sub.2 and/or .alpha..sub.3
receptor agonist.
19. The pharmaceutical composition of claim 18 where the alpha-2
adrenoreceptor agonists is selected from the group consisting of
clonidine, apraclonidine, para-aminoclonidine, brimonidine,
naphazoline, oxymetazoline, tetrahydrozoline, tramazoline,
detomidine, medetomidine, dexmedetomidine, B-HT 920, B-HIT 933,
xylazine, rilmenidine, guanabenz, guanfacine, labetalol,
phenylephrine, mephentermine, metaraminol, methoxamine and
xylazine.
20. A method for the treatment of emesis induced by a
chemotherapeutic agent, by radiation-induced nausea and vomiting,
and/or by post operative induced nausea and vomiting in a patient
in need thereof which comprises administering to the patient the
composition comprising the 5-HT.sub.3 antagonist of claim 15.
21. The method of claim 20 wherein the 5-HT.sub.3 antagonist is
selected from the group consisting of ondansetron, granisetron and
tropisetron.
22. The method of claim 20 wherein the patient is a human.
23. The method of claim 22 wherein the administration comprises the
deposition of the composition comprising the 5-HT.sub.3 antagonist
into a surgical site.
24. A method for the prevention of emesis induced by a
chemotherapeutic agent in a patient in need thereof which comprises
administering to the patient the composition comprising the
5-HT.sub.3 antagonist of claim 15.
25. The method of claim 24 wherein the 5-HT.sub.3 antagonist is
selected from the group consisting of ondansetron, granisetron and
tropisetron.
26. The method of claim 24 wherein the patient is a human.
27. A method for ameliorating the symptoms attendant to emesis
induced by a chemotherapeutic agent, by radiation-induced nausea
and vomiting, and/or by post operative induced nausea and vomiting
in a patient comprising administering to the patient in need
thereof the composition comprising the 5-HT.sub.3 antagonist of
claim 15.
28. The method of claim 27 wherein the 5-HT.sub.3 antagonist is
selected from the group consisting of ondansetron, granisetron and
tropisetron.
29. The method of claim 27 wherein the patient is a human.
30. A method for the prevention of emesis induced by a
chemotherapeutic agent, by radiation-induced nausea and vomiting,
and/or by post operative induced nausea and vomiting in a patient
in need thereof which comprises administering to the patient the
composition comprising the 5-HT.sub.3 antagonist of claim 15, and a
second antiemetic agent.
31. The method of claim 30 wherein the second antiemetic agent is a
compound selected from the group consisting of alpha-2
adrenoreceptor agonists, a dopamine antagonist, an anticholinergic
agent, a GABA.sub.B receptor agonist, an NK.sub.1 receptor
antagonist, and a GABA.sub.A.alpha.2 and/or .alpha..sub.3 receptor
agonist.
32. A process for the preparation of the delivery vehicle of claim
1, comprising mixing the components (A) and (B) in the absence of a
solvent, at a temperature between about 20 and 150.degree. C.
33. A process for the preparation of the pharmaceutical composition
of claim 1 where the antiemetic agent and/or anesthetic agent is in
solid form, comprising: (1) optionally milling the active agent to
reduce the particle size of the active agent; (2) mixing the active
agent and the delivery vehicle; and (3) optionally milling the
composition to reduce the particle size of the active agent.
34. A process for the preparation of the pharmaceutical composition
of claim 1 where the antiemetic agent and/or the anesthetic agent
is in solid form, comprising: (1) warming the polyorthoester to
70.degree. C.; (2) dissolving the active agent in the excipient at
120-150.degree. C.; and (3) mixing the 70.degree. C. polyorthoester
into the 120.degree. C. solution of the active agent in the
excipient with an agitator under the following conditions to obtain
a homogeneous distribution of the components: (a) under an inert
atmosphere (b) optionally warming the mixing vessel to 70.degree.
C.; or (c) optionally allowing the temperature of the mixture to
equilibrate under ambient conditions during the mixing process.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation-in-part of application
Ser. No. 10/765,768, filed Jan. 26, 2004, which is a continuation
of application Ser. No. 10/409,408, filed Apr. 7, 2003, which is a
divisional of 09/854,180, filed Jun. 11, 2001 (U.S. Pat. No.
6,613,355), which claims the benefit of U.S. Provisional
Application No. 60/325,790, filed Jun. 11, 2000.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to semi-solid delivery vehicles
comprising a polyorthoester and an excipient, and to controlled
release pharmaceutical compositions comprising the delivery vehicle
and an active agent. The pharmaceutical compositions may be in the
form of a topical, syringable, or injectable formulation for local
controlled delivery of the active agent.
[0004] 2. Description of the Prior Art
[0005] A large class of active agents such as antibiotics,
antiseptics, corticosteroids, antineoplastics, and local
anesthetics may be administered to the skin or mucous membrane by
topical application, or by injection. The active agent may act
locally or systemically. Topical delivery may be accomplished
through the use of compositions such as ointments, creams,
emulsions, solutions, suspensions and the like. Injections for
delivery of the active agents include solutions, suspensions and
emulsions. All of these preparations have been extensively used for
delivery of active agents for years. However, these preparations
suffer the disadvantage that they are short-acting and therefore
they often have to be administered several times in a day to
maintain a therapeutically effective dose level in the blood stream
at the sites where the activity/treatment is required.
[0006] In recent years, a great deal of progress has been made to
develop dosage forms which, after their administration, provide a
long-term therapeutic response. These products may be achieved by
microencapsulation, such as liposomes, microcapsules, microspheres,
microparticles and the like. For this type of dosage forms, the
active agents are typically entrapped or encapsulated in
microcapsules, liposomes or microparticles which are then
introduced into the body via injection or in the form of an
implant. The release rate of the active agent from this type of
dosage forms is controlled which eliminates the need for frequent
dosing. However their manufacture is cumbersome which often results
in high costs. In addition, they, in many cases, have low
reproducibility and consequently lack of reliability in their
release patterns. Furthermore, if an organic solvent is used in the
manufacturing process, there could be organic solvent residues in
the compositions which may be highly toxic. The use of an organic
solvent is also undesirable for environmental and fire hazard
reasons.
[0007] Interest in synthetic biodegradable polymers for the
delivery of therapeutic agents began in the early 1970's with the
work of Yolles et al., Polymer News, 1, 9-15 (1970) using
poly(lactic acid). Since that time, numerous other polymers have
been prepared and investigated as bioerodible matrices for the
controlled release of active agents. U.S. Pat. Nos. 4,079,038,
4,093,709, 4,131,648, 4,138,344, 4,180,646, 4,304,767, 4,946,931,
and 5,968,543 disclose various types of biodegradable or
bioerodible polymers which may be used for controlled delivery of
active agents. Many of these polymers may appear in the form of a
semi-solid. However the semi-solid polymer materials are often too
sticky. As a result, the active agents frequently cannot be easily
and reliably released from the semi-solid polymer materials.
SUMMARY OF THE INVENTION
[0008] A first objective of the present invention is to provide a
semi-solid delivery vehicle which comprises a polyorthoester and an
excipient. The excipient is readily miscible with the
polyorthoester and the resulting semi-solid delivery vehicle has a
smooth and flowable texture. The polyorthoesters suitable for the
invention are represented by formula I and formula II below.
[0009] Another objective of the present invention is to provide a
controlled release semi-solid pharmaceutical composition for local
controlled delivery of an active agent. The composition comprises
an active agent and the semi-solid delivery vehicle.
[0010] A further objective of the present invention is to provide a
semi-solid syringable or injectable composition for the controlled
delivery of locally acting active agents, in particular local
anesthetics.
[0011] The polyorthoester can be homogeneously mixed with the
excipient at room temperature without the use of a solvent. In
another variation of the process, the polyorthoester can be
homogeneously mixed with the excipient at between about 5 and
200.degree. C., more preferably between about 20 and 150.degree.
C., and most preferably between about 25 and 100.degree. C. In one
variation, the polyorthoester can be at one temperature, for
example at about 70.degree. C., and the excipient can be at a
different temperature, for example at about 120.degree. C., and the
two components are mixed to attain a final temperature that is
above room temperature. The desired temperatures for each of the
two components will be based on the type of the polyorthoester and
the excipient selected. The resulting semi-solid delivery vehicle
and controlled-release pharmaceutical compositions have a useful
texture and viscosity, and the release rate of the active agent
from the compositions can also be conveniently and reliably
adjusted to accommodate the desired therapeutic effect.
[0012] Thus, in a first aspect, this invention provides a
semi-solid delivery vehicle, comprising:
[0013] (a) a polyorthoester of formula I or formula II 1
[0014] where:
[0015] R is a bond, --(CH.sub.2).sub.a--, or
--(CH.sub.2).sub.b--O--(CH.su- b.2).sub.c--; where a is an integer
of 1 to 10, and b and c are independently integers of 1 to 5;
[0016] R* is a C.sub.1-4 alkyl;
[0017] n is an integer of at least 5; and
[0018] A is R.sup.1, R.sup.2, R.sup.3, or R.sup.4, where
[0019] R.sup.1 is: 2
[0020] where:
[0021] p is an integer of 1 to 20;
[0022] R.sup.5 is hydrogen or C.sub.1-4 alkyl; and
[0023] R6 is: 3
[0024] where:
[0025] s is an integer of 0 to 30;
[0026] t is an integer of 2 to 200; and
[0027] R.sup.7 is hydrogen or C.sub.1-4 alkyl;
[0028] R.sup.2 is: 4
[0029] R.sup.3 is: 5
[0030] where:
[0031] x is an integer of 0 to 30;
[0032] y is an integer of 2 to 200;
[0033] R.sup.8 is hydrogen or C.sub.1-4 alkyl;
[0034] R.sup.9 and R.sup.10 are independently C.sub.1-2
alkylene;
[0035] R.sup.11 is hydrogen or C.sub.1-6 alkyl and R.sup.12 is
C.sub.1-6 alkyl; or R.sup.11 and R.sup.12 together are C.sub.3-10
alkylene; and
[0036] R.sup.4 is a diol containing at least one functional group
independently selected from amide, imide, urea, and urethane
groups;
[0037] in which at least 0.01 mol percent of the A units are of the
formula R.sup.1, and
[0038] (b) a pharmaceutically acceptable, polyorthoester-compatible
liquid excipient selected from polyethylene glycol ether
derivatives having a molecular weight between 200 and 4000,
polyethylene glycol copolymers having a molecular weight between
400 and 4000, mono-, di-, or tri-glycerides of a C.sub.2-19
aliphatic carboxylic acid or a mixture of such acids, alkoxylated
tetrahydrofurfuryl alcohols and their C.sub.1-4 alkyl ethers and
C.sub.2-19 aliphatic carboxylic acid esters, and biocompatible
oils.
[0039] In a second aspect, this invention provides a controlled
release semi-solid pharmaceutical composition comprising:
[0040] (a) an active agent; and
[0041] (b) as a delivery vehicle, the semi-solid delivery vehicle
described above.
[0042] In a third aspect, this invention provides a method of
treating a disease state treatable by controlled release local
administration of an active agent, in particular treating pain by
administration of a local anesthetic, comprising locally
administering a therapeutically effective amount of the active
agent in the form of the pharmaceutical composition described
above.
[0043] In a fourth aspect, this invention provides a method of
treating a disease state treatable by controlled release local
administration of an active agent, in particular treating or
preventing of nausea and/or emesis by administration of a
antiemetic agent, comprising locally administering a
therapeutically effective amount of the active agent in the form of
the pharmaceutical composition described above.
DETAILED DESCRIPTION OF THE INVENTION
[0044] Definitions
[0045] Unless defined otherwise in this specification, all
technical and scientific terms are used herein according to their
conventional definitions as they are commonly used and understood
by those of ordinary skill in the art of synthetic chemistry,
pharmacology and cosmetology.
[0046] "Active agent" includes any compound or mixture of compounds
which produces a beneficial or useful result. Active agents are
distinguishable from such components as vehicles, carriers,
diluents, lubricants, binders and other formulating aids, and
encapsulating or otherwise protective components. Examples of
active agents and their pharmaceutically acceptable salts, are
pharmaceutical, agricultural or cosmetic agents. Suitable
pharmaceutical agents include locally or systemically acting
pharmaceutically active agents which may be administered to a
subject by topical or intralesional application (including, for
example, applying to abraded skin, lacerations, puncture wounds,
etc., as well as into surgical incisions) or by injection, such as
subcutaneous, intradermal, intramuscular, intraocular, or
intra-articular injection. Examples of these agents include, but
not limited to, anti-infectives (including antibiotics, antivirals,
fungicides, scabicides or pediculicides), antiseptics (e.g.,
benzalkonium chloride, benzethonium chloride, chlorhexidine
gluconate, mafenide acetate, methylbenzethonium chloride,
nitrofurazone, nitromersol and the like), steroids (e.g.,
estrogens, progestins, androgens, adrenocorticoids, and the like),
therapeutic polypeptides (e.g. insulin, erythropoietin, morphogenic
proteins such as bone morphogenic protein, and the like),
analgesics and anti-inflammatory agents (e.g., aspirin, ibuprofen,
naproxen, ketorolac, COX-1 inhibitors, COX-2 inhibitors, and the
like), cancer chemotherapeutic agents (e.g., mechlorethamine,
cyclophosphamide, fluorouracil, thioguanine, carmustine, lomustine,
melphalan, chlorambucil, streptozocin, methotrexate, vincristine,
bleomycin, vinblastine, vindesine, dactinomycin, daunorubicin,
doxorubicin, tamoxifen, and the like), narcotics (e.g., morphine,
meperidine, codeine, and the like), local anesthetics (e.g., the
amide- or anilide-type local anesthetics such as bupivacaine,
dibucaine, mepivacaine, procaine, lidocaine, tetracaine, and the
like), antiemetic agents such as ondansetron, granisetron,
tropisetron, metoclopramide, domperidone, scopolamine, and the
like, antiangiogenic agents (e.g., combrestatin, contortrostatin,
anti-VEGF, and the like), polysaccharides, vaccines, antigens, DNA
and other polynucleotides, antisense oligonucleotides, and the
like. The present invention may also be applied to other locally
acting active agents, such as astringents, antiperspirants,
irritants, rubefacients, vesicants, sclerosing agents, caustics,
escharotics, keratolytic agents, sunscreens and a variety of
dermatologics including hypopigmenting and antipruritic agents. The
term "active agents" further includes biocides such as fungicides,
pesticides, and herbicides, plant growth promoters or inhibitors,
preservatives, disinfectants, air purifiers and nutrients.
Pro-drugs of the active agents are included within the scope of the
present invention.
[0047] "Alkyl" denotes a linear saturated hydrocarbyl having from
one to the number of carbon atoms designated, or a branched or
cyclic saturated hydrocarbyl having from three to the number of
carbon atoms designated (e.g., C.sub.1-4 alkyl). Examples of alkyl
include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl,
t-butyl, cyclopropylmethyl, and the like.
[0048] "Alkylene" denotes a straight or branched chain divalent,
trivalent or tetravalent alkylene radical having from one to the
number of carbon atoms designated, or a branched or cyclic
saturated cycloalkylenyl having from three to the number of carbon
atoms designated (e.g., C.sub.1-4 alkylenyl, or C.sub.3-7
cycloalkylenyl), and include, for example 1,2-ethylene,
1,3-propylene, 1,2-propylene, 1,4-butylene, 1,5-pentylene,
1,6-hexylene, 1,2,5-hexylene, 1,3,6-hexylene, 1,7-heptylene, and
the like.
[0049] "Bioerodible" and "bioerodibility" refer to the degradation,
disassembly or digestion of the polyorthoester by action of a
biological environment, including the action of living organisms
and most notably at physiological pH and temperature. A principal
mechanism for bioerosion of the polyorthoesters of the present
invention is hydrolysis of linkages between and within the units of
the polyorthoester.
[0050] "Comprising" is an inclusive term interpreted to mean
containing, embracing, covering or including the elements listed
following the term, but not excluding other unrecited elements.
[0051] "Controlled release", "sustained release", and similar terms
are used to denote a mode of active agent delivery that occurs when
the active agent is released from the delivery vehicle at an
ascertainable and controllable rate over a period of time, rather
than dispersed immediately upon application or injection.
Controlled or sustained release may extend for hours, days or
months, and may vary as a function of numerous factors. For the
pharmaceutical composition of the present invention, the rate of
release will depend on the type of the excipient selected and the
concentration of the excipient in the composition. Another
determinant of the rate of release is the rate of hydrolysis of the
linkages between and within the units of the polyorthoester. The
rate of hydrolysis in turn may be controlled by the composition of
the polyorthoester and the number of hydrolyzable bonds in the
polyorthoester. Other factors determining the rate of release of an
active agent from the present pharmaceutical composition include
particle size, solubility of the active agent, acidity of the
medium (either internal or external to the matrix) and physical and
chemical properties of the active agent in the matrix.
[0052] "Delivery vehicle" denotes a composition which has the
functions including transporting an active agent to a site of
interest, controlling the rate of access to, or release of, the
active agent by sequestration or other means, and facilitating the
application of the agent to the region where its activity is
needed.
[0053] "Matrix" denotes the physical structure of the
polyorthoester or delivery vehicle which essentially retains the
active agent in a manner preventing release of the agent until the
polyorthoester erodes or decomposes.
[0054] "Polyorthoester-compatible" refers to the properties of an
excipient which, when mixed with the polyorthoester, forms a single
phase and does not cause any physical or chemical changes to the
polyorthoester.
[0055] "Pro-drug" denotes a pharmacologically inactive or less
active form of a compound which must be changed or metabolized in
vivo, e.g., by biological fluids or enzymes, by a subject after
administration into a pharmacologically active or more active form
of the compound in order to produce the desired pharmacological
effect. Prodrugs of a compound can be prepared by modifying one or
more functional group(s) present in the compound in such a way that
the modification(s) may be cleaved in vivo to release the parent
compound. Prodrugs include compounds wherein a hydroxy, amino,
sulfhydryl, carboxy or carbonyl group in a compound is bonded to
any group that can be cleaved in vivo to regenerate the free
hydroxyl, amino, sulfhydryl, carboxy or carbonyl group
respectively. Examples of prodrugs include, but are not limited to,
esters (e.g. acetate, dialkylaminoacetates, formates, phosphates,
sulfates and benzoate derivatives) and carbamates of hydroxy
functional groups (e.g. N,N-dimethylcarbonyl), esters of carboxyl
functional groups (e.g. ethyl esters, morpholinoethanol esters),
N-acyl derivatives (e.g. N-acetyl), N-Mannich bases, Schiff bases
and enaminones of amino functional groups, oximes, acetals, ketals,
and enol esters of ketones and aldehyde functional groups in a
compound, and the like.
[0056] "Semi-solid" denotes the mechano-physical state of a
material that is flowable under moderate stress. More specifically,
the semi-solid material should have a viscosity between about
10,000 and 3,000,000 cps, especially between about 50,000 and
500,000 cps. Preferably the formulation is easily syringable or
injectable, meaning that it can readily be dispensed from a
conventional tube of the kind well known for topical or ophthalmic
formulations, from a needleless syringe, or from a syringe with a
16 gauge or smaller needle, such as 16-25 gauge.
[0057] "Sequestration" is the confinement or retention of an active
agent within the internal spaces of a polyorthoester matrix.
Sequestration of an active agent within the matrix may limit the
toxic effect of the agent, prolong the time of action of the agent
in a controlled manner, permit the release of the agent in a
precisely defined location in an organism, or protect unstable
agents against the action of the environment.
[0058] A "therapeutically effective amount" means the amount that,
when administered to an animal for treating a disease, is
sufficient to effect treatment for that disease.
[0059] "Treating" or "treatment" of a disease includes preventing
the disease from occurring in an animal that may be predisposed to
the disease but does not yet experience or exhibit symptoms of the
disease (prophylactic treatment), inhibiting the disease (slowing
or arresting its development), providing relief from the symptoms
or side-effects of the disease (including palliative treatment),
and relieving the disease (causing regression of the disease). For
the purposes of this invention, a "disease" includes pain.
[0060] A "unit" denotes an individual segment of a polyorthoester
chain, which consists of the residue of a diketene acetal molecule
and the residue of a polyol.
[0061] An ".alpha.-hydroxy acid containing" unit denotes a unit
where A is R.sup.1, i.e. in which the polyol is prepared from an
.alpha.-hydroxy acid or cyclic diester thereof and a diol of the
formula HO--R.sup.5--OH. The fraction of the polyorthoester that is
.alpha.-hydroxy acid containing units affects the rate of
hydrolysis (or bioerodibility) of the polyorthoester, and in turn,
the release rate of the active agent.
[0062] Polyorthoesters
[0063] The polyorthoesters are of formula I or formula II 6
[0064] where:
[0065] R is a bond, --(CH.sub.2).sub.a--, or
--(CH.sub.2).sub.b--O--(CH.su- b.2).sub.c--; where a is an integer
of 1 to 10, and b and c are independently integers of 1 to 5;
[0066] R* is a C.sub.1-4 alkyl;
[0067] n is an integer of at least 5; and
[0068] A is R.sup.1, R.sup.2, R.sup.3, or R.sup.4, where
[0069] R.sup.1 is: 7
[0070] where:
[0071] p is an integer of 1 to 20;
[0072] R.sup.5 is hydrogen or C.sub.1-4 alkyl; and
[0073] R.sup.6 is: 8
[0074] where:
[0075] s is an integer of 0 to 30;
[0076] t is an integer of 2 to 200; and
[0077] R.sup.7 is hydrogen or C.sub.1-4 alkyl;
[0078] R.sup.2 is: 9
[0079] R.sup.3 is: 10
[0080] where:
[0081] x is an integer of 0 to 30;
[0082] y is an integer of 2 to 200;
[0083] R.sup.8 is hydrogen or C.sub.1-4 alkyl;
[0084] R.sup.9 and R.sup.10 are independently C.sub.1-12
alkylene;
[0085] R.sup.11 is hydrogen or C.sub.1-6 alkyl and R.sup.12 is
C.sub.1-6 alkyl; or R.sup.11 and R.sup.12 together are C.sub.3-10
alkylene; and
[0086] R.sup.4 is a the residue of a diol containing at least one
functional group independently selected from amide, imide, urea,
and urethane groups;
[0087] in which at least 0.01 mol % of the A units are of the
formula R.sup.1.
[0088] The structure of the polyorthoester useful for the present
invention, as shown in formula I and formula II, is one of
alternating residues of a diketene acetal and a diol, with each
adjacent pair of diketene acetal residues being separated by the
residue of one polyol, preferably a diol.
[0089] In the presence of water, the .alpha.-hydroxy acid
containing units are readily hydrolyzed at a body temperature of
37.degree. C. and a physiological pH, to produce the corresponding
hydroxyacids. These hydroxyacids then act as acidic catalysts to
control the hydrolysis rate of the polyorthoester without the
addition of exogenous acid. When the polyorthoester is used as a
delivery vehicle or matrix entrapping an active agent, the
hydrolysis of the polyorthoester causes release of the active
agent.
[0090] Polyorthoesters having a higher mole percentage of the
".alpha.-hydroxy acid containing" units will have a higher rate of
bioerodibility. Preferred polyorthoesters are those in which the
mole percentage of the ".alpha.-hydroxy acid containing" units is
at least 0.01 mole percent, in the range of about 0.01 to about 50
mole percent, more preferably from about 0.05 to about 30 mole
percent, for example from about 0.1 to about 25 mole percent,
especially from about 1 to about 20 mole percent. The mole
percentage of the ".alpha.-hydroxy acid containing" units
appropriate to achieve the desired composition will vary from
formulation to formulation.
[0091] Preferred polyorthoesters are those where:
[0092] n is an integer of 5 to 1000;
[0093] the polyorthoester has a molecular weight of 1000 to 20,000,
preferably 1000 to 10,000, more preferably 1000 to 8000;
[0094] R.sup.5 is hydrogen or methyl;
[0095] R.sup.6 is: 11
[0096] where s is an integer of 0 to 10, especially 1 to 4; t is an
integer of 2 to 30, especially 2 to 10; and R.sup.7 is hydrogen or
methyl;
[0097] R.sup.3 is: 12
[0098] where x is an integer of 0 to 10, especially 1 to 4; y is an
integer of 2 to 30, especially 2 to 10; and R.sup.8 is hydrogen or
methyl;
[0099] R.sup.4 is selected from the residue of an aliphatic diol of
2 to 20 carbon atoms, preferably 2 to 10 carbon atoms, interrupted
by one or two amide, imide, urea, or urethane groups;
[0100] the proportion of units in which A is R.sup.1 is about
0.01-50 mol %, preferably 0.05-30 mol %, more preferably 0.1-25 mol
%;
[0101] the proportion of units in which A is R.sup.2 is less than
20%, preferably less than 10%, especially less than 5%, and
[0102] the proportion of units in which A is R.sup.4 is less than
20%, preferably less than 10%, especially less than 5%.
[0103] While the presence of any of these preferences results in a
polyorthoester that is more preferred than the same polyorthoester
in which the preference is not met, the preferences are generally
independent, and polyorthoesters in which a greater number of
preferences is met will generally result in a polyorthoester that
is more preferred than that in which a lesser number of preferences
is met.
[0104] Preparation of the Polyorthoesters
[0105] The polyorthoesters are prepared according to the methods
described in U.S. Pat. Nos. 4,549,010 and 5,968,543. Specifically,
the polyorthoesters are prepared by the reaction of a diketene
acetal of formula III or formula IV: 13
[0106] where L is hydrogen or a C.sub.1-3 alkyl,
[0107] with a diol of the formula HO--R.sup.1--OH and at least one
diol of the formulae HO--R.sup.2--OH, HO--R.sup.3--OH, or
HO--R.sup.4--OH.
[0108] To form the polyorthoester using a mixture of the two types
of the diols, the mixture is formed with selected proportions based
on the desired characteristics of the polyorthoester. The use of
increasing amounts of diols in which A is R.sup.1 increases the
bioerodibility of the polyorthoester, and the use of such diols in
which R.sup.6 is a polyethyleneoxide moiety or an alkane increases
the softness of the polymer; the use of increasing amounts of diols
in which A is R.sup.2 increases the hardness of the polyorthoester
(and is therefore not generally desirable, though it may be useful
in special circumstances); and the use of diols in which A is
R.sup.3 increases the softness of the polyorthoester, especially
when these diols are low molecular weight polyethylene glycols or
aliphatic diols. The use of diols in which A is R.sup.4 also
generally increases the hardness of the polyorthoester because of
the hydrogen bonding between adjacent chains of the polyorthoester,
and may or may not be desirable depending on the other diols
used.
[0109] The preparation of the diketene acetals of the types of
formula III and formula IV is disclosed in U.S. Pat. Nos.
4,304,767, 4,532,335, and 5,968,543; and will be known to a person
of ordinary skill in the art. A typical method is the condensation
of a bis(diol) of formula V (i.e. pentaerythritol) or formula VI:
14
[0110] with two equivalents of a 2-halocarboxaldehyde dialkyl
acetal, such as 2-bromoacetaldehyde diethyl acetal, followed by
dehydrohalogenation to give the diketene acetal. The condensation
of a glycol with diethylbromoacetals is described in Roberts et
al., J. Am. Chem. Soc., 80, 1247-1254 (1958), and
dehydrohalogenation is described in Beyerstedt et al., J. Am. Chem.
Soc., 58, 529-553 (1936).
[0111] The diketene acetals may also be prepared by the
isomerization of divinyl acetals. Thus, for example,
3,9-di(ethylidene)-2,4,8,10-tetraoxas- piro[5.5]undecane (DETOSU)
may be prepared by the isomerization of
3,9-divinyl-2,4,8,10-tetraoxaspiro[5.5]undecane, using
n-butyllithium in ethylenediamine. The isomerization of the double
bond is described in Corey et al., J. Org. Chem., 38, 3224 (1973).
The divinyl acetals may be prepared by the condensation of the
bis(diol) of formula V or formula VI with two equivalents of a
vinylic aldehyde, such as acrolein or crotonaldehyde, or their
dialkyl acetals, such as acrolein dimethyl acetal, and such
condensation reactions are well known.
[0112] The bis(diol) of formula VI where R is a bond is erythritol.
The bis(diol) of formula VI where R is --(CH.sub.2).sub.a-- may be
prepared by the oxidation of an .alpha.,.omega.-diene, such as
1,3-butadiene or 1,5-hexadiene, with an oxidizing reagent such as
osmium tetroxide/hydrogen peroxide, or by other methods known in
the art, to give the bis(diol). The bis(diol) of formula VI where R
is --(CH.sub.2).sub.b--O--(CH.sub.2).sub.c-- may be prepared by the
reaction of an .omega.-hydroxy-.alpha.-olefin, such as allyl
alcohol, with an .omega.-haloalkyloxirane, such as epichlorohydrin,
to form an .omega.-epoxy-.alpha.-olefin with the backbone
interrupted by an oxygen atom, such as 2-allyloxymethyloxirane,
which is then oxidized with an oxidizing reagent such as osmium
tetroxide/hydrogen peroxide, or by other methods known in the art,
to give the bis(diol).
[0113] The diols of the formulae HO--R.sup.1--OH, HO--R.sup.2--OH,
HO--R.sup.3--OH, and HO--R.sup.4--OH are prepared according to
methods known in the art, and as described, for example, in U.S.
Pat. Nos. 4,549,010 and 5,968,543. Some of the diols are
commercially available. The diol of the formula HO--R.sup.1--OH
that comprises a polyester moiety may be prepared by reacting a
diol of the formula HO--R.sup.6--OH with between 0.5 and 10 molar
equivalents of a cyclic diester of an .alpha.-hydroxy acid, such as
lactide or glycolide, and allowing the reaction to proceed at
100-200.degree. C. for about 12 hours to about 48 hours. Although
particular solvents are not required for this reaction, organic
solvents such as dimethylacetamide, dimethyl sulfoxide,
dimethylformamide, acetonitrile, pyrrolidone, tetrahydrofuran, and
methylbutyl ether may be used. The preparation of diols, in
particular the diol of the formula HO--R.sup.3--OH is generally
disclosed in Heller et al., J. Polymer Sci., Polymer Letters Ed.
18:293-297 (1980), by reacting an appropriate divinyl ether with an
excess of an appropriate diol. Diols of the formula HO--R.sup.4--OH
include diols where R.sup.4 is R'CONR"R' (amide), R'CONR"COR'
(imide), R'NR"CONR.DELTA.R' (urea), and R'OCONR"R' (urethane),
where each R' is independently an aliphatic, aromatic, or
aromatic/aliphatic straight or branched chain hydrocarbyl,
especially a straight or branched chain alkyl of 2 to 22 carbon
atoms, especially 2 to 10 carbon atoms, and more especially 2 to 5
carbon atoms, and R" is hydrogen or C.sub.1-6 alkyl, especially
hydrogen or methyl, more especially hydrogen. Some representative
diols of the formula HO--R.sup.4--OH include
N,N'-bis-(2-hydroxyethyl)-terephthalamide,
N,N'-bis-(2-hydroxyethyl)pyromellitic diimide,
1,1'-methylenedi(p-phenyle- ne)-bis-[3-(2-hydroxyethyl)urea],
N,N'-bis-(2-hydroxyethyl)oxamide, 1,3-bis(2-hydroxyethyl)urea,
3-hydroxy-N-(2-hydroxyethyl)propionamide,
4-hydroxy-N-(3-hydroxypropyl)butyramide, and
bis(2-hydroxyethyl)ethylened- icarbamate. These diols are known to
the art in reported syntheses and may are commercially available.
Representative diols of the formula
HO--(CH.sub.2).sub.n--NHCO--(CH.sub.2).sub.m--OH where n is an
integer of 2 to 6 and m is an integer of 2 to 5 are made by the
reaction of 2-aminoethanol, 3-aminopropanol, 4-aminobutanol,
5-aminopentanol, or 6-aminohexanol with .beta.-propiolactone,
.gamma.-butyrolactone, .delta.-valerolactone, or
.epsilon.-caprolactone. Representative diols of the formula
HO--(CH.sub.2).sub.n--NHCOO--(CH.sub.2).sub.m--OH where n and m are
each integers of 2 to 6 are made by the reaction of the same
aminoalcohols just mentioned with cyclic carbonates of the formula
15
[0114] such as ethylene carbonate. Bis-amide diols of the formula
HO--A--NHCO--B--CONH--A--OH are prepared by the reaction of a
diacid, optionally in activated form, such as the diacyldihalide,
with two equivalents of a hydroxy-amine. Other methods of
preparation of the diols of the formula HO--R.sup.4--OH are known
in the art.
[0115] Once made, the diol of the formula HO--R.sup.1--OH and the
diol(s) of the formulae HO--R.sup.2--OH, HO--R.sup.3--OH, and
HO--R.sup.4--OH in the desired proportions are mixed with the
diketene acetal of formula III or formula IV, in a slightly less
than 1:1 (e.g. 0.5:1-0.9:1) ratio of total number of moles of
diketene acetal to total number of moles of diols, in a suitable
solvent at ambient temperature. The condensation reaction between
the diketene acetal and the diols is carried out under conditions
which are described in, for example, U.S. Pat. Nos. 4,304,767,
4,549,010, and 5,968,543, and are well known to those skilled in
the art; and will also be readily apparent from the structures of
the reactants themselves. Suitable solvents are aprotic solvents,
such as dimethylacetamide, dimethyl sulfoxide, dimethylformamide,
acetonitrile, acetone, ethyl acetate, pyrrolidone, tetrahydrofuran,
and methylbutyl ether, and the like. Catalysts are not required for
this reaction, but when used, suitable catalysts are iodine in
pyridine, p-toluenesulfonic acid; salicylic acid, Lewis acids (such
as boron trichloride, boron trifluoride, boron trichloride
etherate, boron trifluoride etherate, stannic oxychloride,
phosphorous oxychloride, zinc chloride, phosphorus pentachloride,
antimony pentafluoride, stannous octoate, stannic chloride, diethyl
zinc, and mixtures thereof); and Br.o slashed.nsted catalysts (such
as polyphosphoric acid, crosslinked polystyrene sulfonic acid,
acidic silica gel, and mixtures thereof). A typical amount of
catalyst used is about 0.2% by weight relative to the diketene
acetal. Smaller or larger amounts can also be used, such as 0.005%
to about 2.0% by weight relative to the diketene acetal. Once the
reaction is complete, the reaction mixture is allowed to cool and
concentrated by rotoevaporation under vacuum. The concentrated
mixture may be further dried under vacuum at an elevated
temperature.
[0116] The polyorthoesters may also be prepared by reaction of the
diketene acetal with the chosen diol(s) under similar reaction
conditions, but in the presence of a "chain stopper" (a reagent
that terminates polyorthoester chain formation). Suitable chain
stoppers are C.sub.5-20 alkanols, especially C.sub.10-20 alkanols.
The chain stopper is preferably present in from 1-20 mol % based on
the diketene acetal. The polyorthoesters thus prepared have low
molecular weights with a lower molecular weight dispersion than
those prepared by the reaction of the diketene acetals with only
diols, and are therefore especially suitable for this
invention.
[0117] The Excipients
[0118] The excipients suitable for the present invention are
pharmaceutically acceptable and polyorthoester-compatible
materials. They are liquid at room temperature, and are readily
miscible with the polyorthoesters.
[0119] Suitable excipients include poly(ethylene glycol) ether
derivatives having a molecular weight of between 200 and 4,000,
such as poly(ethylene glycol) mono- or di-alkyl ethers, preferably
poly(ethylene glycol)monomethyl ether 550 or poly(ethylene
glycol)dimethyl ether 250; poly(ethylene glycol)copolymers having a
molecular weight of between 400 and 4,000 such as poly(ethylene
glycol-co-polypropylene glycol); propylene glycol mono- or
di-esters of a C.sub.2-19 aliphatic carboxylic acid or a mixture of
such acids, such as propylene glycol dicaprylate or dicaprate;
mono-, di- or tri-glycerides of a C.sub.2-19 aliphatic carboxylic
acid or a mixture of such acids, such as glyceryl caprylate,
glyceryl caprate, glyceryl caprylate/caprate, glyceryl
caprylate/caprate/laurate, glycofurol and similar ethoxylated
tetrahydrofurfuryl alcohols and their C.sub.1-4 alkyl ethers and
C.sub.2-19 aliphatic carboxylic acid esters; and biocompatible oils
such as sunflower oil, sesame oil and other non- or
partially-hydrogenated vegetable oils.
[0120] Most of these materials are commercially available, for
example, from Aldrich Chemical Company (Milwaukee, Wis.) and from
Abitec Corporation (Columbus, Ohio), LIPO Chemicals Inc. (Paterson,
N.J.), and Jarchem Industries, Inc. (Newark, N.J.).
[0121] The Delivery Vehicle
[0122] The delivery vehicle comprises a polyorthoester and an
excipient selected from those described in preceding sections.
[0123] The concentrations of the polyorthoester and the excipient
in the delivery vehicle may vary. For example, the concentration of
the excipient in the vehicle may be in the range of 1-99% by
weight, preferably 5-80% weight, especially 20-60% by weight of the
vehicle.
[0124] While the singular form is used to describe the
polyorthoester and excipient in this application, it is understood
that more than one polyorthoesters and excipients selected from the
groups described above may be used in the delivery vehicle.
[0125] The delivery vehicle is prepared by mixing or blending
together the polyorthoester and the excipient. The mixing or
blending can be performed by any methods at a temperature less than
about 50.degree. C., e.g. at room temperature, in the absence of
solvents, using any suitable devices to achieve a homogeneous,
flowable and non-tacky semi-solid blend at room temperature. In
another aspect of the invention, the mixing or blending can be
performed by any methods at a temperature of about between 5 to
200.degree. C., more preferably about between 20 to 150.degree. C.,
and more preferably about between 25 and 100.degree. C., depending
on the nature of the starting material selected, as noted above, to
achieve a homogeneous, flowable and tacky or non-tacky semi-solid
blend at room temperature.
[0126] Semi-Solid Pharmaceutical Compositions
[0127] If the active agent is itself a liquid or semi-solid, it may
be mixed with the delivery vehicle in the same manner as the
delivery vehicle was formed, i.e. conventional blending of
semi-solid formulations. Such blending is carried out in a manner
suitable to obtain a homogeneous distribution of the components
throughout the formulation, by mixing the components in any order
necessary to achieve such homogeneity. However, the active agent is
typically a solid. It is desirable that the particle size of the
active agent be sufficiently small (for example, 1-100 .mu.m,
especially 5-50 .mu.m) so that the resulting composition is smooth.
Therefore, unless the active agent is already in micron-sized
powder form, it is generally first milled into fine particles
preferably less than 100 .mu.m and sieved before mixing with the
other ingredients. The mechanical mixing process is performed at
room temperature, preferably under vacuum in order to avoid air
bubbles. In another aspect of the process, the mechanical mixing
process may be performed at room temperature or above room
temperature without the use of any vacuum. If desired, further size
reduction of the size of the particles of the active agent can be
carried out by passing the semi-solid mixture through a ball mill
or roller mill to achieve a homogeneous and uniform pharmaceutical
composition.
[0128] The active agent may be mixed with the delivery vehicle
already formed or directly mixed together with the polyorthoester
and the excipient. In another aspect of the invention, the active
agent, delivery vehicle, polyorthoester and excipient may be mixed
together in any suitable order to obtain the product which is
homogeneous and with the desired characteristics.
[0129] The active agent is present in the composition in an amount
which is effective to provide a desired biological or therapeutic
effect. Because of the sustained release nature of the
compositions, the active agent usually is present in an amount
which is greater than the conventional single dose. The
concentration of the active agent in the semi-solid polyorthoester
composition can vary over a wide range (e.g., 0.1-80 wt. %,
preferably 0.3-60 wt. %, more preferably 0.5-40 wt. %, such as 1-30
wt. %, based on the composition as a whole) depending on a variety
of factors, such as the release profile of the composition, the
therapeutically effective dose of the active agent, and the desired
length of the time period during which the active agent is
released. In one aspect of the invention, the concentration of the
active agent in the semi-solid polyorthoester composition is
between about 1-5 wt. %, more preferably between about 2-3 wt.
%.
[0130] The concentration of the polyorthoester may be 1-99 wt. %,
preferably 5-40 wt. %, of the composition. The total concentration
of the excipient is 1-90 wt. %, preferably 5-60 wt. %, more
preferably 10-50 wt. %, of the composition.
[0131] It is also understood that while not required, other
pharmaceutically acceptable inert agents such as coloring agents
and preservatives may also be incorporated into the
composition.
[0132] The semi-solid pharmaceutical composition of the present
invention has an improved texture which is non-tacky and flowable.
In another aspect of the invention, the semi-solid pharmaceutical
composition of the present invention has an improved texture which
is tacky and also flowable. As used herein, the term "tacky" refers
to a physical property of the composition in which the composition
is sticky when lightly touched. The composition therefore can be
conveniently applied to the skin or mucous membrane in the manner
of a conventional cream or gel. Preferably the formulation is
easily syringable or injectable, meaning that it can readily be
dispensed from a conventional tube of the kind well known for
topical or ophthalmic formulations, from a needleless syringe, or
from a syringe with a 16 gauge or smaller needle (such as 16-25
gauge), and injected subcutaneously, intradermally or
intramuscularly. The formulation may be applied using various
methods known in the art, including by syringe, injectable or tube
dispenser, for example, directly or indirectly to the skin or a
wound.
[0133] After topical application, administration by injection, or
any other routes of administration, including surface or
subcutaneous application to open wounds, the active agent is
released from the composition in a sustained and controlled manner.
The rate of release may be regulated or controlled in a variety of
ways to accommodate the desired therapeutic effect. The rate may be
increased or decreased by altering the mole percentage of the
.alpha.-hydroxy acid containing units in the polyorthoester, or by
selecting a particular excipient, or by altering the amount of the
selected excipient, or the combination thereof.
[0134] The compositions are also stable. The release rates of the
active agent are not affected by irradiation for sterilization.
[0135] Particular Compositions and Their Uses
[0136] Exemplary compositions of this invention, and their uses,
include:
[0137] (1) compositions containing local anesthetics, optionally in
combination with glucocorticosteroids such as dexamethasone,
cortisone, hydrocortisone, prednisone, prednisolone,
beclomethasone, betamethasone, flunisolide, fluocinolone acetonide,
fluocinonide, triamcinolone, including deposition of the
compositions into surgical sites, and the like, for the prolonged
relief of local pain or a prolonged nerve blockade. This use is
discussed further below;
[0138] (2) compositions containing cancer chemotherapeutic agents,
such as those listed above under "Active Agents", for deposition by
syringe or by injection into tumors or operative sites from which a
tumor has been ablated, for tumor control or treatment and/or the
suppression of regrowth of the tumor from residual tumor cells
after ablation of the tumor;
[0139] (3) compositions containing progestogens, such as
flurogestone, medroxyprogesterone, norgestrel, norgestimate,
norethindrone, and the like, for estrus synchronization or
contraception;
[0140] (4) compositions containing antimetabolites such as
fluorouracil and the like, as an adjunct to glaucoma filtering
surgery; compositions containing antiangiogenic agents such as
combrestatin, for the treatment of macular degeneration and retinal
angiogenesis; and other compositions for the controlled release of
ophthalmic drugs to the eye;
[0141] (5) compositions containing therapeutic polypeptides
(proteins), such as insulin, LHRH antagonists, and the like, for
the controlled delivery of these polypeptides, avoiding the need
for daily or other frequent injection;
[0142] (6) compositions containing anti-inflammatory agents such as
the NSAIDs, e.g. ibuprofen, naproxen, COX-1 or COX-2 inhibitors,
and the like, or glucocorticosteroids, for intra-articular
application or injection;
[0143] (7) compositions containing antibiotics, for the prevention
or treatment of infection, especially for deposition into surgical
sites to suppress post-operative infection, or into or on wounds,
for the suppression of infection (e.g. from foreign bodies in the
wound);
[0144] (8) compositions containing morphogenic proteins such as
bone morphogenic protein;
[0145] (9) compositions containing DNA or other polynucleotides,
such as antisense oligonucleotides;
[0146] (10) compositions containing antiemetic agents;
[0147] (11) compositions containing antigens in vaccines; and
[0148] (12) compositions comprising a combination of two or more of
the above active agents for concurrent therapeutic
applications.
[0149] Delivery of Controlled-release Antiemetic Agents
[0150] The present invention further relates to a method for the
treatment or prevention of emesis in a patient which comprises
administering an 5-HT.sub.3 antagonist, wherein the 5-HT.sub.3
antagonist minimize the side effects of nausea and/or emesis
associated with other pharmacological agents.
[0151] In a further aspect of the present invention, there is
provided a pharmaceutical composition for the treatment or
prevention of emesis comprising an HT.sub.3 antagonist, together
with at least one pharmaceutically acceptable carrier or
excipient.
[0152] As used herein, the term "emesis" include nausea and
vomiting. The HT.sub.3 antagonists in the semi-solid injectable
form of the present invention are beneficial in the therapy of
acute, delayed or anticipatory emesis, including emesis induced by
chemotherapy, radiation, toxins, viral or bacterial infections,
pregnancy, vestibular disorders (e.g. motion sickness, vertigo,
dizziness and Meniere's disease), surgery, migraine, and variations
in intracranial pressure. The HT.sub.3 antagonist of use in the
invention are of particular benefit in the therapy of emesis
induced by radiation and/or by chemotherapy, for example during the
treatment of cancer, or radiation sickness; and in the treatment of
post-operative nausea and vomiting. The HT.sub.3 antagonists in the
semi-solid injectable form of the invention are beneficial in the
therapy of emesis induced by antineoplastic (cytotoxic) agents
including those routinely used in cancer chemotherapy, and emesis
induced by other pharmacological agents, for example, alpha-2
adrenoceptor antagonists, such as yohimbine, MK-912 and MK-467, and
type IV cyclic nucleotide phosphodiesterase (PDE4) inhibitors, such
as RS14203, CT-2450 and rolipram.
[0153] Particular examples of chemotherapeutic agents are
described, for example, by D. J. Stewart in Nausea and Vomiting:
Recent Research and Clinical Advances, ed. J. Kucharczyk et al.,
CRC Press Inc., Boca Raton, Fla., USA, 1991, pages 177-203, see
page 188. Examples of commonly used chemotherapeutic agents include
cisplatin, dacarbazine (DTIC), dactinomycin, mechlorethamine
(nitrogen mustard), streptozocin, cyclophosphamide, carmustine
(BCNU), lomustine (CCNU), doxorubicin (adriamycin), daunorubicin,
procarbazine, mitomycin, cytarabine, etoposide, methotrexate,
5-fluorouracil, vinblastine, vincristine, bleomycin and
chlorambucil (see R. J. Gralle et al. in Cancer Treatment Reports,
1984, 68, 163-172).
[0154] Many of the antiemetic agents are conventionally used in the
form of their acid addition salts, as this provides solubility in
aqueous injection media. However, because the presence of the large
amount of acid within such a local antiemetic acid addition salt
will result in more rapid degradation of the polyorthoesters and
rapid release of the antiemetic agent, it is generally desirable to
use the antiemetic agent in the free base form. Alternatively, the
antiemetic may be used with only a small proportion of the acid
addition salt present (addition of small quantities of the acid
addition salt may provide enhanced release if desired).
[0155] The semi-solid injectable form of an antiemetic agent of the
present invention is prepared by incorporating the antiemetic agent
into the delivery vehicle in a manner as described above. The
concentration of the antiemetic agent may vary from about 0.1-80
wt. %, preferably from about 0.2-60 wt. %, more preferably from
about 0.5-40 wt. %, most preferably from about 1-5 wt. %, for
example, about 2-3 wt. %. The semi-solid composition is then filled
into a syringe with a 16-25 gauge needle, and injected into sites
that have been determined to be most effective. The semi-solid
injectable composition of the present invention can be used for
controlled delivery of both slightly soluble and soluble antiemetic
agents.
[0156] Suitable classes of antiemetic agents employed in the
present invention include, for example, a 5-HT.sub.3 antagonist
such as ondansetron, granisetron or tropisetron; a dopamine
antagonist such as metoclopramide or domperidone; an
anticholinergic agent such as scopolamine; a GABA.sub.B receptor
agonist such as baclofen; an NK.sub.1 receptor antagonist as
described, for example, in WO 97/49710; or a
GABA.sub.A.alpha..sub.2 and/or .alpha..sub.3 receptor agonist as
described in WO 99/67245.
[0157] The 5-HT.sub.3 antagonists employed in the present invention
are also useful for the treatment of or prevention of emesis in
conjunction with the use of other antiemetic agents known in the
art.
[0158] In one particular aspect, suitable classes of other
antiemetic agents of use in conjunction with the present invention
include, for example, alpha-2 adrenoreceptor agonists including for
example, clonidine, apraclonidine, para-aminoclonidine,
brimonidine, naphazoline, oxymetazoline, tetrahydrozoline,
tramazoline, detomidine, medetomidine, dexmedetomidine, B-HT 920,
B-HIT 933, xylazine, rilmenidine, guanabenz, guanfacine, labetalol,
phenylephrine, mephentermine, metaraminol, methoxamine and
xylazine.
[0159] As noted, the compounds or agents employed in the present
invention are also useful for the treatment of or prevention of
emesis in conjunction with another antiemetic agents known in the
art, such as a 5-HT.sub.3 antagonist, a dopamine antagonist, an
anticholinergic agent, a GABA.sub.B receptor agonist, an NK.sub.1
receptor antagonist, and a GABA.sub.A.alpha..sub.2 and/or
.alpha..sub.3 receptor agonist.
[0160] In another aspect of the invention, the antiemetic agents as
a single agent or as a combination, may be used independently in
the form of a salt or salts or mixtures of the agent and the salt
of the agent. Suitable pharmaceutically acceptable salts of the
compounds of use in the present invention include acid addition
salts which may, for example, be formed by mixing a solution of the
compound with a solution of a pharmaceutically acceptable non-toxic
acid such as hydrochloric acid, iodic acid, fumaric acid, maleic
acid, succinic acid, acetic acid, citric acid, tartaric acid,
carbonic acid, phosphoric acid, sulfuric acid and the like. Salts
of amine groups may also comprise the quaternary ammonium salts in
which the amino nitrogen atom carries an alkyl, alkenyl, alkynyl or
aralkyl group. Where the compound carries an acidic group, for
example a carboxylic acid group, the present invention also
contemplates salts thereof, preferably non-toxic pharmaceutically
acceptable salts thereof, such as the sodium, potassium and calcium
salts thereof. 72 It will be appreciated that when using a
combination of the present invention, the 5-HT.sub.3 antagonists
and the other antiemetic agent will be administered to a patient
together in the semi-solid injectable form of the invention. In one
aspect of the invention, the compounds may be in the same
pharmaceutically acceptable carrier and therefore administered
simultaneously.
[0161] When administered in combination, either as a single product
in the semi-solid injectable form or as separate pharmaceutical
compositions, the 5-HT.sub.3 antagonists and the other antiemetic
medicament are to be presented in a ratio which is consistent with
the manifestation of the desired effect. In particular, the ratio
by weight of the 5-HT.sub.3 antagonists and the other antiemetic
agent will suitably be between 0.001 to 1 and 1000 to 1, and
especially between 0.01 to l and 100 to 1.
[0162] The present invention is further directed to a method for
ameliorating the symptoms attendant to emesis in a patient
comprising administering to the patient an 5-HT.sub.3 antagonists.
In accordance with the present invention the 5-HT.sub.3 antagonists
is administered to a patient in a quantity sufficient to treat or
prevent the symptoms and/or underlying etiology associated with
emesis in the patient.
[0163] Delivery of Controlled-Release Local Anesthetics
[0164] Local anesthetics induce a temporary nerve conduction block
and provide pain relief which lasts from a few minutes to a few
hours. They are frequently used to prevent pain in surgical
procedures, dental manipulations or injuries.
[0165] The synthetic local anesthetics may be divided into two
groups: the slightly soluble compounds and the soluble compounds.
Conventionally, the soluble local anesthetics can be applied
topically and by injection, and the slightly soluble local
anesthetics are used only for surface application. The local
anesthetics conventionally administered by injection can also be
divided into two groups, esters and non-esters. The esters include
(1) benzoic acid esters (piperocaine, meprylcaine and isobucaine);
(2) para-aminobenzoic acid esters (procaine, tetracaine,
butethamine, propoxycaine, chloroprocaine); (3) meta-aminobenzoic
acid esters (metabutethamine, primacaine); and (4)
para-ethoxybenzoic acid ester (parethoxycaine). The non-esters are
anilides (amides or nonesters) which include bupivacaine,
lidocaine, mepivacaine, pyrrocaine and prilocaine.
[0166] Many of the local anesthetics are conventionally used in the
form of their acid addition salts, as this provides solubility in
aqueous injection media. However, because the presence of the large
amount of acid within such a local anesthetic acid addition salt
will result in more rapid degradation of the polyorthoesters and
release of the local anesthetic, it is generally desirable to use
the local anesthetics in free base form, or with only a small
proportion of the acid addition salt present (addition of small
quantities of the acid addition salt may provide enhanced release
if desired).
[0167] The semi-solid injectable form of a local anesthetic of the
present invention is prepared by incorporating the local anesthetic
into the delivery vehicle in a manner as described above. The
concentration of the local anesthetic may vary from about 0.1-80
wt. %, preferably from about 1-60 wt. %, more preferably from about
0.5-40 wt. %, most preferably from about 1-5 wt. %, for example,
about 2-3 wt. %. The semi-solid composition can be administered
directly into surgical incision sites or sub-cutaneously via a
suitable sized needle. In another aspect, the semi-solid
composition is then filled into a syringe with a 16-25 gauge
needle, and injected into sites that are painful or to be subjected
to surgical procedures. The semi-solid injectable composition of
the present invention can be used for controlled delivery of both
slightly soluble and soluble local anesthetics.
[0168] Because the duration of action of a local anesthetic is
proportional to the time during which it is in actual contact with
nervous tissues, the present injectable delivery system can
maintain localization of the anesthetic at the nerve for an
extended period of time which will greatly prolong the effect of
the anesthetic.
[0169] A number of authors, including Berde et al., U.S. Pat. No.
6,046,187 and related patents, have suggested that the
co-administration of a glucocorticosteroid may prolong or otherwise
enhance the effect of local anesthetics, especially
controlled-release local anesthetics; and formulations containing a
local anesthetic and a glucocorticosteroid, and their uses for
controlled release local anesthesia, are within the scope of this
invention.
ASPECTS OF THE INVENTION
[0170] In one aspect of the invention, there is provided a
pharmaceutical composition comprising:
[0171] (A) semi-solid delivery vehicle, comprising:
[0172] (i) a polyorthoester of formula I or formula II 16
[0173] where:
[0174] R is a bond, --(CH.sub.2).sub.a--, or
--(CH.sub.2).sub.b--O--(CH.su- b.2).sub.c--; where a is an integer
of 1 to 10, and b and c are independently integers of 1 to 5;
[0175] R* is a C.sub.1-4 alkyl;
[0176] n is an integer of at least 5; and
[0177] A is R.sup.1, R.sup.2, R.sup.3, or R.sup.4, where
[0178] R.sup.1 is: 17
[0179] where:
[0180] p is an integer of 1 to 20;
[0181] R.sup.5 is hydrogen or C.sub.1-4 alkyl; and
[0182] R.sup.6 is: 18
[0183] where:
[0184] s is an integer of 0 to 30;
[0185] t is an integer of 2 to 200; and
[0186] R.sup.7 is hydrogen or C.sub.1-4 alkyl;
[0187] R.sup.2 is: 19
[0188] R.sup.3 is: 20
[0189] where:
[0190] x is an integer of 0 to 30;
[0191] y is an integer of 2 to 200;
[0192] R.sup.8 is hydrogen or C.sub.1-4 alkyl;
[0193] R.sup.9 and R.sup.10 are independently C.sub.1-12
alkylene;
[0194] R.sup.11 is hydrogen or C.sub.1-6 alkyl and R.sup.12 is
C.sub.1-6 alkyl; or R.sup.11 and R.sup.12 together are C.sub.3-10
alkylene; and
[0195] R.sup.4 is the residue of a diol containing at least one
functional group independently selected from amide, imide, urea,
and urethane groups;
[0196] in which at least 0.01 mol percent of the A units are of the
formula R.sup.1; and
[0197] (ii) a pharmaceutically acceptable,
polyorthoester-compatible liquid excipient selected from
polyethylene glycol ether derivatives having a molecular weight
between 200 and 4000, polyethylene glycol copolymers having a
molecular weight between 400 and 4000, mono-, di-, or
iri-glycerides of a C.sub.2-19 aliphatic carboxylic acid or a
mixture of such acids, alkoxylated tetrahydrofurfuryl alcohols and
their C.sub.1-4 alkyl ethers and C.sub.2-19 aliphatic carboxylic
acid esters, and biocompatible oils; and
[0198] (B) an antiemetic agent, and/or an anesthetic agent.
[0199] In another aspect of the invention, there is provided the
semi-solid delivery vehicle above where the concentration of the
polyorthoester ranges from 1% to 99% by weight. In one variation,
the polyorthoester has a molecular weight between 1,000 and 20,000.
In another aspect, the fraction of the A units that are of the
formula R.sup.1 is between 1 and 90 mol percent.
[0200] In one aspect of the invention, the polyorthoester is of
formula I, where none of the units have A equal to R.sup.2, R.sup.3
is: 21
[0201] where x is an integer of 0 to 10; y is an integer of 2 to
30; and R.sup.6 is: 22
[0202] where s is an integer of 0 to 10, t is an integer of 2 to
30, and R.sup.5, R.sup.7, and R.sup.8 are independently hydrogen or
methyl. In one variation, R.sup.3 and R.sup.6 are both
--(CH.sub.2--CH.sub.2--O).sub- .2--(CH.sub.2--CH.sub.2)--, R.sup.5
is methyl, and p is 1 or 2. In another variation, R.sup.3 and
R.sup.6 are both --(CH.sub.2--CH.sub.2--O).sub.9---
(CH.sub.2--CH.sub.2)--, R.sup.5 is methyl, and p is 1 or 2.
[0203] In one aspect of the invention, there is provided a
pharmaceutical composition of wherein the anesthetic agent is
selected from the group consisting of bupivacaine, lidocaine,
mepivacaine, pyrrocaine and prilocaine. In one variation, the
concentration of the anesthetic agent in the composition is about
1-5 wt. %.
[0204] In one aspect of the invention, there is provided the above
composition wherein the antiemetic agent is granisetron. In one
variation, the fraction of the antiemetic agent is from 0.1% to 80%
by weight of the composition. In another variation, the fraction of
the antiemetic agent is from 1% to 5% by weight of the
composition.
[0205] In another aspect of the invention, the composition is in
topical, syringable, or injectable form.
[0206] In yet another aspect of the invention, there is provided a
composition wherein the antiemetic agent is selected from the group
consisting of 5-HT.sub.3 antagonists, a dopamine antagonists, an
anticholinergic agents, a GABA.sub.B receptor agonists, an NK.sub.1
receptor antagonists, and a GABA.sub.A.alpha..sub.2 and/or
.alpha..sub.3 receptor agonists. In one variation, the antiemetic
agent is a 5-HT.sub.3 antagonist. In another variation, the
5-HT.sub.3 antagonist is selected from the group consisting of
ondansetron, granisetron and tropisetron.
[0207] In yet another aspect, there is provided the above
pharmaceutical composition further comprising a second antiemetic
agent to form a combination composition. In one variation, the
second antiemetic agent is selected from the group consisting of
alpha-2 adrenoreceptor agonists, a dopamine antagonist, an
anticholinergic agent, a GABA.sub.B receptor agonist, an NK.sub.1
receptor antagonist, and a GABA.sub.A.alpha..sub.2 and/or
.alpha..sub.3 receptor agonist. In another variation, the alpha-2
adrenoreceptor agonists is selected from the group consisting of
clonidine, apraclonidine, paraaminoclonidine, brimonidine,
naphazoline, oxymetazoline, tetrahydrozoline, tramazoline,
detomidine, medetomidine, dexmedetomidine, B-HT 920, B-HIT 933,
xylazine, rilmenidine, guanabenz, guanfacine, labetalol,
phenylephrine, mephentermine, metaraminol, methoxamine and
xylazine.
[0208] In another aspect of the invention, there is provided a
method for the treatment of emesis induced by a chemotherapeutic
agent, by radiation-induced nausea and vomiting, and/or by post
operative induced nausea and vomiting in a patient in need thereof
which comprises administering to the patient the above composition
comprising the 5-HT.sub.3 antagonist of the invention. In one
variation of the above method, the 5-HT.sub.3 antagonist is
selected from the group consisting of ondansetron, granisetron and
tropisetron. In another variation of the above method, the patient
is a human. In yet another variation of the method, the
administration comprises the deposition of the 5-HT.sub.3
antagonist into a surgical site.
[0209] In another aspect of the invention, there is provided a
method for the prevention of emesis induced by a chemotherapeutic
agent in a patient in need thereof which comprises administering to
the patient the above composition comprising the 5-HT.sub.3
antagonist. In one variation, the 5-HT.sub.3 antagonist is selected
from the group consisting of ondansetron, granisetron and
tropisetron. In another variation of the above method, the patient
is a human.
[0210] In another aspect, there is provided a method for
ameliorating the symptoms attendant to emesis induced by a
chemotherapeutic agent, by radiation-induced nausea and vomiting,
and/or by post operative induced nausea and vomiting in a patient
comprising administering to the patient in need thereof a
composition of the invention comprising an 5-HT.sub.3 antagonist.
In one variation, the 5-HT.sub.3 antagonist is selected from the
group consisting of ondansetron, granisetron and tropisetron. In
one variation of the above method, the patient is a human.
[0211] In another aspect of the invention, there is provided a
method for the prevention of emesis induced by a chemotherapeutic
agent, by radiation-induced nausea and vomiting, and/or by post
operative induced nausea and vomiting in a patient in need thereof
which comprises administering to the patient a composition of the
invention comprising a 5-HT.sub.3 antagonist, and a second
antiemetic agent. In one variation, the second antiemetic agent is
a compound selected from the group consisting of alpha-2
adrenoreceptor agonists, a dopamine antagonist, an anticholinergic
agent, a GABA.sub.B receptor agonist, an NK.sub.1 receptor
antagonist, and a GABA.sub.A.alpha..sub.2 and/or .alpha..sub.3
receptor agonist.
[0212] In yet another aspect of the invention, there is provided a
process for the preparation of the delivery vehicle of the present
invention, comprising mixing the components (A) and (B) in the
absence of a solvent, at a temperature between about 20 and
150.degree. C.
[0213] In yet another aspect, there is provided a process for the
preparation of the pharmaceutical composition above where the
antiemetic agent is in solid form, comprising: (1) optionally
milling the active agent to reduce the particle size of the active
agent; (2) mixing the active agent and the delivery vehicle; and
(3) optionally milling the composition to reduce the particle size
of the active agent.
[0214] In yet another aspect,. there is provided a process for the
preparation of the pharmaceutical composition of the present
invention where the antiemetic agent and/or the anesthetic agent is
in solid form, comprising: (1) warming the polyorthoester to
70.degree. C.; (2) dissolving the active agent in the excipient at
120-150.degree. C.; and (3) mixing the 70.degree. C. polyorthoester
into the 120.degree. C. solution of the active agent in the
excipient with an agitator under the following conditions to obtain
a homogeneous distribution of the components: (a) under an inert
atmosphere, such as an argon or nitrogen atmosphere (b) optionally
warming the mixing vessel to 70.degree. C.; or (c) optionally
allowing the temperature of the mixture to equilibrate under
ambient conditions during the mixing process.
EXAMPLES
Example 1
[0215] Preparation of Polyorthoesters
[0216] The following syntheses illustrate the preparation of
representative polyorthoesters. The starting materials are either
commercially available or may be prepared as described in the
preceding sections and in U.S. Pat. Nos. 4,549,010 and
5,968,543.
[0217] 1(a) The polyorthoester in this example was prepared from
3,9-di(ethylidene)-2,4,8,10-tetraoxaspiro[5.5]undecane (DETOSU),
triethylene glycol (TEG), and triethyleneglycol monoglycolide
(TEG-mGL). The molar ratio of the three components
(DETOSU:TEG:TEG-mGL) was 65:95:5.
[0218] Under rigorously anhydrous conditions, DETOSU (6.898 g, 32.5
mmol), TEG (7.133 g, 47.5 mmol) and TEG-mGL (0.521 g, 2.5 mmol)
were weighed into a 250 mL round bottom flask, and the mixture
dissolved in anhydrous ethyl acetate (16 mL). To this solution was
added a salicylic acid solution in ethyl acetate (12 drops, 10
mg/mL) to initiate the polymerization. The solution came to a boil
within a few minutes. The solution was allowed to cool to room
temperature, then concentrated by rotoevaporation at 40-50.degree.
C. The flask was transferred to a vacuum oven, and dried at
40.degree. C. for 2 hours followed by drying at 70.degree. C. for
additional 3 hours. The material was semi-solid with a molecular
weight of about 4000.
[0219] 1(b) The polyorthoester in this example was prepared from
DETOSU, TEG, and triethyleneglycol diglycolide (TEG-diGL). The
molar ratio of the three components (DETOSU:TEG:TEG-diGL) was
65:80:20. Following the procedure of Example 1(a), DETOSU (6.898 g,
32.5 mmol), TEG (6.007 g, 40 mmol) and TEG-diGL (2.662 g, 10 mmol)
were allowed to react. The reaction yielded a semi-solid material
having a molecular weight of about 2000.
[0220] 1(c) The polyorthoester in this example was prepared from
DETOSU, TEG, and TEG-diGL. The molar ratio of the three components
(DETOSU:TEG:TEG-diGL) was 60:70:30. Following the procedure of
Example 1(a), DETOSU (25.470 g, 120 mmol), TEG (21.024 g, 140 mmol)
and TEG-diGL (15.973 g, 60 mmol) were allowed to react. The
reaction yielded a semi-solid material having a molecular weight of
about 2000.
[0221] Other polyorthoesters, e.g. those containing diketene
acetals of formula IV and/or those containing other diols of
formulae HO--R.sup.1--OH, HO--R.sup.2--OH, HO--R.sup.3--OH, and
HO--R.sup.4--OH, are prepared by similar methods.
[0222] 1(d) The polyorthoester in this example was prepared from
DETOSU, TEG and TEG-diGL. The molar ratio of the three components
(DETOSU:TEG:TEG-diGL) was 90:80:20. Under rigorously anhydrous
conditions, DETOSU (114.61 g, 540 mmol) was dissolved in a 2 L
flask in 450 mL anhydrous THF and TEG (72.08 g, 480 mmol) and
TEG-diGL (31.95 g, 120 mmol) was weighed into a 500 mL round bottom
flask, and dissolved in anhydrous THF (50 mL). The TEG-diGL
solution was added to the solution of DETOSU and TEG to initiate
the polymerization. The solution came to a boil within a few
minutes. The solution was allowed to cool to room temperature, then
concentrated by rotary evaporation at 50.degree. C., followed by
rotary evaporation at 80.degree. C. The material was semi-solid
with a molecular weight of about 6,500.
Example 2
[0223] Preparation of Pharmaceutical Compositions
[0224] 2(a) Semi-solid pharmaceutical compositions with bupivacaine
as the active agent were prepared by first milling the bupivacaine
into fine particles and sieving, before mixing with selected
amounts of a polyorthoester and an excipient. The mixing process
was performed at room temperature under vacuum. Further size
reduction of the bupivacaine particles was carried out by passing
the semi-solid composition through a ball mill.
[0225] A. 60 wt. % polyorthoester (DETOSU/TEG/TEG-mGL 60:95:5)
[0226] 40 wt. % bupivacaine. (control)
[0227] B. 40 wt. % polyorthoester (DETOSU/TEG/TEG-mGL 60:95:5)
[0228] 40 wt. % bupivacaine
[0229] 20 wt. % polyethylene glycol monomethyl ether 550.
[0230] C. 60 wt. % polyorthoester (DETOSU/TEG/TEG-diGL
60:80:20)
[0231] 40 wt. % bupivacaine. (control)
[0232] D. 40 wt. % polyorthoester (DETOSU/TEG/TEG-diGL
60:80:20)
[0233] 40 wt. % bupivacaine
[0234] 20% wt. % polyethylene glycol monomethyl ether 550.
[0235] E. 20% wt. % polyorthoester (DETOSU/TEG/TEG-diGL
60:70:30)
[0236] 40% wt. % bupivacaine
[0237] 40% wt. % polyethylene glycol monomethyl ether.
[0238] Compositions B, D, and E had non-tacky, flowable texture.
Compositions A and C had very sticky texture, were difficult to
handle and showed poor syringability.
[0239] 2(b) Semi-solid pharmaceutical compositions with mepivacaine
as the active agent were prepared by dissolving the mepivacaine in
the excipient ether 550 at a temperature between 120.degree. C. and
150.degree. C. in one vessel and mixing in the specified amount of
the polyorthoester that was previously warmed to 70.degree. C. to
make it flowable in a separate vessel. The formulation was
additionally transferred once between the two vessels to ensure
complete transfer of all components into a single vessel, and
further mixed under an argon or nitrogen environment. This mixing
may be carried out with or without warming the mixing vessel at
70.degree. C. in order to maintain the flow characteristics
necessary for a homogeneous distribution of all the components
throughout the formulation. An example of a composition of such a
formulation is shown below:
[0240] 77.6 weight % polyorthoester (molar ratio of
DETOSU:TEG:TEG-diGL/90:80:20)
[0241] 19.4 weight % polyethylene glycol monomethyl ether 550
[0242] 3.0 weight % mepivacaine.
[0243] 2(c) Semi-solid pharmaceutical compositions with granisetron
as the active agent were prepared as described in Example 2(b) to
obtain the following composition:
[0244] 78.4 weight % polyorthoester (molar ratio of
DETOSU:TEG:TEG-diGL/90:80:20)
[0245] 19.6 weight % polyethylene glycol monomethyl ether 550
[0246] 2.0 weight % granisetron.
[0247] 2(d) A semi-solid delivery vehicle was prepared in a manner
similar to that described in Example 2(b), with the omission of the
step to dissolve the active pharmaceutical ingredient in the
excipient. An example of a composition of a semi-solid delivery
vehicle is shown below:
[0248] 80 weight % polyorthoester (molar ratio of
DETOSU:TEG:TEG-diGL/90:8- 0:20)
[0249] 20 weight % polyethylene glycol monomethyl ether 550.
[0250] Other compositions containing other polyorthoesters, e.g.
those containing diketene acetals of formula IV and those
containing other diols of formulae HO--R.sup.1--OH,
HO--R.sup.2--OH, HO--R.sup.3--OH, and HO--R.sup.4--OH, and
different active agents, and/or in different proportions are
prepared in a similar manner.
Example 3
[0251] Release Profiles of the Pharmaceutical Compositions
[0252] The semi-solid compositions of Example 2 were weighed,
placed into bottles with screw caps. 100 mL of 50mM PBS (pH 7.4)
was added to each bottle. The test bottles were transferred to a
37.degree. C. incubator and placed on top of a rotor shaker (36
rpm). At various time points, bottles were removed from the
incubator and samples of about 5 mL were removed and analyzed for
bupivacaine content by HPLC at 263 nm. The remaining volume of
buffer was removed and replaced with 100 mL fresh buffer.
[0253] Composition B had an increased rate of release over the
control Composition A.
[0254] Composition D had a similar release rate as the control
Composition C.
[0255] These test results demonstrated that the pharmaceutical
compositions of the present invention have the advantage that the
release rates of the composition may be adjusted and controlled in
a variety of ways. The rates of release can be adjusted to
accommodate a desired therapeutic effect by either altering the
mole percentage of the .alpha.-hydroxyacid containing units in the
polyorthoester as disclosed in U.S. Pat. No. 5,968,543, or by
selecting a particular excipient, or by altering the concentration
of the excipient in the composition, or the combination of all
these factors.
[0256] The compositions can be irradiated, and the release rate of
Composition E before and after irradiation showed no significant
difference over twelve days using the test described above.
[0257] The foregoing is offered primarily for purposes of
illustration. It will be readily apparent to those skilled in the
art that the molecular structures, proportions of the various
components in the delivery vehicle or pharmaceutical composition,
method of manufacture and other parameters of the invention
described herein may be further modified or substituted in various
ways without departing from the spirit and scope of the invention.
For example, effective dosages other than the particular dosages as
set forth herein above may be applicable as a consequence of
variations in the responsiveness of the mammal being treated for
any of the indications with the compounds of the invention
indicated above. Likewise, the specific pharmacological responses
observed may vary according to and depending upon the particular
active compounds selected or whether there are present
pharmaceutical carriers, as well as the type of formulation and
mode of administration employed, and such expected variations or
differences in the results are contemplated in accordance with the
objects and practices of the present invention. It is intended,
therefore, that the invention be defined by the scope of the claims
which follow and that such claims be interpreted as broadly as is
reasonable.
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