U.S. patent application number 12/639892 was filed with the patent office on 2010-10-14 for pharmaceutical formulation.
This patent application is currently assigned to Progenics Pharmaceuticals, Inc.. Invention is credited to Thomas A. Boyd, Suketu P. Sanghvi.
Application Number | 20100261746 12/639892 |
Document ID | / |
Family ID | 33299842 |
Filed Date | 2010-10-14 |
United States Patent
Application |
20100261746 |
Kind Code |
A1 |
Sanghvi; Suketu P. ; et
al. |
October 14, 2010 |
PHARMACEUTICAL FORMULATION
Abstract
Stable pharmaceutical compositions useful for administering
methylnaltrexone are described, as are methods for making the same.
Kits, including these pharmaceutical compositions, also are
provided.
Inventors: |
Sanghvi; Suketu P.; (Kendall
Park, NJ) ; Boyd; Thomas A.; (Grandview, NY) |
Correspondence
Address: |
WOLF GREENFIELD & SACKS, P.C.
600 ATLANTIC AVENUE
BOSTON
MA
02210-2206
US
|
Assignee: |
Progenics Pharmaceuticals,
Inc.
|
Family ID: |
33299842 |
Appl. No.: |
12/639892 |
Filed: |
December 16, 2009 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10821811 |
Apr 8, 2004 |
|
|
|
12639892 |
|
|
|
|
60461611 |
Apr 8, 2003 |
|
|
|
Current U.S.
Class: |
514/282 |
Current CPC
Class: |
A61K 47/02 20130101;
A61K 47/183 20130101; A61P 7/10 20180101; A61K 9/19 20130101; A61P
7/08 20180101; A61P 17/00 20180101; A61P 1/12 20180101; A61P 3/00
20180101; A61K 45/06 20130101; A61P 17/04 20180101; A61P 19/02
20180101; A61P 25/04 20180101; A61P 37/04 20180101; A61K 9/0019
20130101; A61K 47/18 20130101; A61P 13/00 20180101; A61K 31/195
20130101; A61K 47/12 20130101; A61P 7/06 20180101; A61P 1/08
20180101; A61P 1/14 20180101; A61P 9/00 20180101; A61P 9/02
20180101; A61K 31/047 20130101; A61P 1/04 20180101; A61P 1/18
20180101; A61P 1/10 20180101; A61P 25/06 20180101; A61P 25/22
20180101; A61P 43/00 20180101; A61P 1/16 20180101; A61K 31/485
20130101; A61P 13/02 20180101; A61P 37/06 20180101; A61P 1/00
20180101; A61P 31/18 20180101; A61P 35/00 20180101; A61P 1/06
20180101; A61P 25/28 20180101; A61P 29/00 20180101; A61K 31/047
20130101; A61K 2300/00 20130101; A61K 31/195 20130101; A61K 2300/00
20130101; A61K 31/485 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/282 |
International
Class: |
A61K 31/485 20060101
A61K031/485; A61P 1/04 20060101 A61P001/04; A61P 1/08 20060101
A61P001/08; A61P 1/10 20060101 A61P001/10; A61P 13/00 20060101
A61P013/00; A61P 17/04 20060101 A61P017/04; A61P 25/22 20060101
A61P025/22; A61P 37/06 20060101 A61P037/06 |
Claims
1-187. (canceled)
188. A pharmaceutical preparation comprising a solution of
methylnaltrexone or salt thereof, wherein the solution further
comprises a chelating agent.
189-315. (canceled)
316. The pharmaceutical preparation of claim 188, wherein the
chelating agent is selected from the group consisting of EDTA and
derivatives thereof, citric acid and derivatives thereof,
niacinamide and derivatives thereof, and sodium desoxycholate and
derivatives thereof.
317. The pharmaceutical preparation of claim 189, wherein the
chelating agent is EDTA or derivative thereof.
318. The pharmaceutical preparation of claim 188, wherein the
concentration of methylnaltrexone or salt thereof ranges from 0.01
to 100 mg/ml.
319. The pharmaceutical preparation of claim 318, wherein the
concentration of methylnaltrexone or salt thereof ranges from 1.0
to 50.0 mg/ml.
320. The pharmaceutical preparation of claim 319, wherein the
concentration of methylnaltrexone or salt thereof is about 20
mg/ml.
321. The preparation of claim 319, wherein the preparation is
stable to storage for 6 months at about room temperature.
322. The pharmaceutical preparation of claim 319, wherein the
preparation is stable to storage for 12 months at about room
temperature.
323. The pharmaceutical preparation of claim 320, wherein the
preparation is stable to storage for 24 months at about room
temperature.
324. The pharmaceutical preparation of claim 319, further
comprising a preservative.
325. The preparation of claim 324, wherein the preparation is
stable to storage for 6 months at about room temperature.
326. The pharmaceutical preparation of claim 325, wherein the
preparation is stable to storage for 12 months at about room
temperature.
327. The pharmaceutical preparation of claim 326, wherein the
preparation is stable to storage for 24 months at about room
temperature.
328. The pharmaceutical preparation of claim 324, wherein the
solution is provided in a vial with a septum or a syringe.
329. The pharmaceutical preparation of claim 319, further
comprising an isotonicity agent.
330. The preparation of claim 329, wherein the preparation is
stable to storage for 6 months at about room temperature.
331. The pharmaceutical preparation of claim 330, wherein the
preparation is stable to storage for 12 months at about room
temperature.
332. The pharmaceutical preparation of claim 331, wherein the
preparation is stable to storage for 24 months at about room
temperature.
333. The pharmaceutical preparation of claim 329, wherein the
solution is provided in a vial with a septum or a syringe.
334. The pharmaceutical preparation of claim 329, further
comprising an isotonicity agent.
335. The preparation of claim 334, wherein the preparation is
stable to storage for 6 months at about room temperature.
336. The pharmaceutical preparation of claim 335, wherein the
preparation is stable to storage for 12 months at about room
temperature.
337. The pharmaceutical preparation of claim 336, wherein the
preparation is stable to storage for 24 months at about room
temperature.
338. The pharmaceutical preparation of claim 329, wherein the
solution is provided in a vial with a septum or a syringe.
339. The pharmaceutical preparation of claim 317, wherein the EDTA
or derivative thereof concentration ranges from about 0.001 to
about 100 mg/ml.
340. The pharmaceutical preparation of claim 339, wherein the EDTA
or derivative concentration ranges from about 0.1 to about 25.0
mg/ml.
341. The pharmaceutical preparation of claim 340, wherein the EDTA
or derivative concentration is about 0.4 mg/ml.
342. The pharmaceutical preparation of claim 340, wherein the
concentration of methylnaltrexone or salt thereof ranges from 1.0
to 50.0 mg/ml.
343. The pharmaceutical preparation of claim 342, further
comprising a preservative.
344. The pharmaceutical preparation of claim 342, further
comprising an isotonicity agent.
345. The preparation of claim 342, wherein the preparation is
stable to storage for 6 months at about room temperature.
346. The pharmaceutical preparation of claim 345, wherein the
preparation is stable to storage for 12 months at about room
temperature.
347. The pharmaceutical preparation of claim 346, wherein the
preparation is stable to storage for 24 months at about room
temperature.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 10/821,811, filed Apr. 8, 2004, entitled
"PHARMACEUTICAL FORMULATION," which claims priority under 35 U.S.C.
.sctn.119(e) to U.S. Provisional Application Ser. No. 60/461,611,
entitled "PHARMACEUTICAL FORMULATION," filed on Apr. 8, 2003, the
contents of which applications are incorporated herein by reference
in their entirety.
FIELD OF THE INVENTION
[0002] This invention relates to methylnaltrexone pharmaceutical
preparations, methylnaltrexone formulations, methylnaltrexone kits,
and methods of making the same.
BACKGROUND OF THE INVENTION
[0003] Quaternary amine opioid antagonist derivatives have been
shown to have utility in a number of contexts. They are considered
peripherally acting only, and, therefore, find particular utility
in reducing the side-effects of opioids without reducing the
analgesic effect of opioids. Such side effects include nausea,
emesis, dysphoria, pruritis, urinary retention, bowel hypomotility,
constipation, gastric hypomotility, delayed gastric emptying and
immune suppression. The utility of these peripherally acting opioid
antagonists is not limited to reducing side-effects stemming from
opioid analgesic treatment. Instead, these derivatives also have
utility in circumstances where endogenous opioids alone (or in
conjunction with exogenous opioid treatment) cause undesirable
conditions such as ileus and other such conditions including, but
not limited to, those mentioned above.
[0004] Methylnaltrexone is a quaternary amine opioid antagonist
derivative, discovered in the mid-70s. Methylnaltrexone and some of
its uses are described in U.S. Pat. Nos. 4,176,186, 4,719,215,
4,861,781, 5,102,887, 5,972,954, and 6,274,591. Stable formulations
of methylnaltrexone, however, have heretofore not existed.
Methylnaltrexone apparently was assumed to have a structure that
was inherently stable. The stability of a pharmaceutical
composition in solution, however, is not necessarily predictable
either over time when stored at room temperature or when
autoclaved.
[0005] Naloxone is an opioid antagonist that acts both centrally
and peripherally. It differs structurally from methylnaltrexone and
would be expected to have a different stability in solution. An
allegedly stable formulation of naloxone is described in U.S. Pat.
No. 5,866,154.
[0006] Surprisingly, it has been discovered that methylnaltrexone
is unusually unstable. It further has been discovered that
methylnaltrexone has certain degradation products different from
those of naloxone. It also has been discovered that critical
parameters and conditions are required for stable formulations of
methylnaltrexone.
SUMMARY OF THE INVENTION
[0007] In one aspect, the invention provides a composition or
preparation that is a solution of methylnaltrexone or a salt
thereof, wherein the preparation after autoclaving has a
concentration of methylnaltrexone degradation products that does
not exceed 2% of the methylnaltrexone or salt thereof in the
preparation. Preferably, the concentration of such degradation
products does not exceed 1.5%, 1%, 0.5%, 0.25%, or even 0.125% of
the methylnaltrexone or salt thereof in the preparation. The
composition or preparation can contain one of, any combination of,
or all of a chelating agent, a buffering agent, an anti-oxidant, a
cryoprotecting agent, an isotonicity agent and an opioid. The
preferred chelating agent is disodium edetate or a derivative
thereof. The disodium edetate preferably is at a concentration
ranging from between 0.001 and 100 mg/ml, more preferably 0.05 to
25.0 mg/ml, and even more preferably, 0.1 to 2.5 mg/ml. A preferred
buffering agent is citrate buffer. The citrate buffer typically is
in a concentration ranging from 0.001 to 100.0 mM, preferably from
0.1 to 10 mM, and more preferably, 0.1 to 5.0 mM. A preferred
cryoprotecting agent is mannitol.
[0008] The composition or preparation preferably has a pH that does
not exceed 4.25. More preferably, the pH ranges from 2.0 to 4.0,
3.0 to 4.0, and most preferably, from 3.0 to 3.5.
[0009] According to another aspect of the invention, a composition
or preparation is provided, which includes a solution of
methylnaltrexone or a salt thereof, wherein the preparation after
storage at about room temperature for six months has a
concentration of methylnaltrexone degradation products that does
not exceed 2% of the methylnaltrexone in the preparation. The
concentration of the methylnaltrexone degradation products
preferably does not exceed 1.5%, 1.0%, 0.5%, 0.25%, and even 0.125%
of the methylnaltrexone in the preparation. The composition or
preparation can contain one of, any combination of, or all of a
chelating agent, a buffering agent, an anti-oxidant, a
cryoprotecting agent, an isotonicity agent and an opioid. The
preferred chelating agent and concentrations are as described
above. The preferred buffering agent and concentrations are as
described above. Preferably, the composition or preparation has a
pH that does not exceed 4.25. The preferred pHs and ranges are as
described above.
[0010] According to another aspect of the invention, a stable
composition or preparation is provided. The composition or
preparation is a solution of methylnaltrexone or a salt thereof
wherein the pH is below 4.25. Preferably, the pH is between 2.75
and 4.25, more preferably, between 3.0 and 4.0, and most
preferably, between 3.0 and 3.5. According to conventional
procedures, pH can be adjusted with an acid. Examples of acids
useful for this purpose include hydrochloric acid, citric acid,
sulfuric acid, acetic acid, and phosphoric acid. The stable
composition or preparation can also include any one of, any
combination of, or all of a chelating agent, a buffering agent, an
isotonicity agent, an antioxidant, a cryogenic agent, and an
opioid.
[0011] According to another aspect of the invention, a stable
composition or preparation is provided. The composition or
preparation is a solution of methylnaltrexone or salt thereof,
wherein the solution further comprises a chelating agent in an
amount sufficient to inhibit degradation of the methylnaltrexone or
salt thereof, whereby the amount is such that the composition or
preparation after autoclaving has a concentration of
methylnaltrexone degradation products that does not exceed 0.5%,
0.25% or even 0.125% of the methylnaltrexone or salt thereof in the
composition or preparation. The composition or preparation can
further include any one of, any combination of, or all of a
buffering agent, an isotonicity agent, an antioxidant and an
opioid. Preferred chelating agents, buffering agents and pHs are as
described above.
[0012] According to another aspect of the invention, a composition
or preparation is provided. The composition or preparation is a
solution of methylnaltrexone or salt thereof in at least one
methylnaltrexone degradation inhibiting agent. The agent can be any
one of, any combination of, or all of a chelating agent, a
buffering agent, and an antioxidant, provided that the solution has
a pH ranging from 2.0 to 6.0. The degradation inhibiting agent is
present in an amount sufficient to render the composition or
preparation stable, wherein the composition or preparation is
processed under at least one sterilization technique, and wherein
the composition or preparation is substantially free of
methylnaltrexone degradation products. The composition or
preparation can be stable to storage for at least six months, at
least twelve months, or at least twenty-four months, at about room
temperature. Preferably, the composition or preparation is stable
after autoclaving. The composition or preparation further may
include either or both of an isotonicity agent and an opioid.
Preferably, the pH of the solution is between 2.75 and 4.25, more
preferably, between 3.0 and 4.0, and most preferably, between 3.0
and 3.5.
[0013] In any one of the foregoing aspects of the invention, the
composition or preparation can be a pharmaceutical composition.
[0014] In any one of the foregoing aspects of the invention, the
methylnaltrexone can be present in a therapeutically effective
amount. In some embodiments, the concentration of methylnaltrexone
ranges from 0.01 to 100 mg/ml. In other embodiments, the
methylnaltrexone concentration ranges between 0.1 and 100.0 mg/ml.
In other embodiments, the methylnaltrexone ranges between 1.0 and
50.0 mg/ml.
[0015] In any one of the foregoing embodiments, the
methylnaltrexone can be present in an amount sufficient to treat
nausea, emesis, dysphoria, pruritus, urinary retention, ileus,
post-operative ileus, post-partum ileus, paralytic ileus, bowel
hypomotility, constipation, gastric hypomotility, delayed gastric
emptying, decreased biliary secretion, decreased pancreatic
secretion, biliary spasm, increased sphincter tone, cutaneous
flushing, impaction, sweating, inhibition of gastrointestinal
motility, inhibition of gastric emptying, gastrointestinal
dysfunction, incomplete evacuation, bloating, abdominal distention,
increased gastroesophageal reflux, hypotension, bradycardia,
irritable bowel syndrome, or immunosuppression.
[0016] In any of the foregoing embodiments, the methylnaltrexone
can be present in an amount sufficient to accelerate discharge from
hospital post-surgery (including abdominal surgeries such as rectal
resection, colectomy, stomach, esophageal, duodenal, appendectomy,
hysterectomy, or non-abdominal surgeries such as orthopedic, trauma
injuries, thoracic or transplantation), for example, by
accelerating bowel sounds after surgery, or speeding the time to
first food intake or first bowel movement. In other important
embodiments, the amount is sufficient to induce laxation. This has
particular application where the subject is a chronic opioid
user.
[0017] In any one of the foregoing embodiments, the solution of
methylnaltrexone or salt thereof may be contained in a sealed
container such as a bottle, an infusion bag, a syringe, a vial, a
vial with a septum, an ampoule, an ampoule with a septum, or a
syringe. The container may include indicia indicating that the
solution has been autoclaved or otherwise subjected to a
sterilization technique.
[0018] According to another aspect of the invention, any of the
foregoing embodiments is lyophilized, preferably in the presence of
a cryoprotecting agent. The invention therefore provides a
lyophilized preparation of methylnaltrexone. Preferably, the
lyophilized preparation is a stable preparation, containing less
than 1%, less than 0.5%, less than 0.25% and even less than 0.125%
methylnaltrexone degradation product. The preparation can contain a
cryoprotecting agent, which preferably is neutral or acidic in
water.
[0019] According to another aspect of the invention, a product is
provided. The product is a stable lyophilized formulation of
methylnaltrexone, wherein the formulation upon reconstitution and
water at a concentration of 20 mg/ml has a pH of between 2 and 6.
In some embodiments, the formulation upon reconstitution has a pH
of about 2, about 3, about 4, about 5, or about 6. The formulation
can include a cryoprotecting agent present in amounts sufficient to
render the formulation stable. The cryoprotecting agent in
important embodiments are polymerized carbohydrates. A preferred
cryoprotecting agent is mannitol. Any one of the foregoing
solutions described above can be lyophilized. It therefore is an
aspect of the invention that such materials include one or any
combination of a buffering agent, a chelating agent, an
antioxidant, and an isotonicity agent. Preferred materials are as
described above.
[0020] According to still another aspect of the invention, a
product is provided that includes methylnaltrexone and the
degradation inhibiting agent selected from the group consisting of
a chelating agent, a buffering agent, an antioxidant, and
combinations thereof, wherein the degradation inhibiting agent is
present in an amount sufficient to render stable the solution of
the product containing a concentration of 20 mg/ml methylnaltrexone
in water. Preferably, the product when in solution at a
concentration of 20 mg/ml methylnaltrexone yields a pH of between 2
and 6.
[0021] According to another aspect of the invention, a
pharmaceutical preparation is provided. The pharmaceutical
preparation contains methylnaltrexone, sodium chloride, citric
acid, trisodium citrate, and disodium edetate. In one important
embodiment, the methylnaltrexone is present between 20 and 40
mg/ml, the sodium chloride is present between 2 and 6 mg/ml, the
citric acid is present between 0.05 and 0.1 mg/ml, the trisodium
citrate is present between 0.025 and 0.075 mg/ml, and the disodium
edetate is present between 0.5 and 1.0 mg/ml.
[0022] The buffering agent may be any pharmaceutically acceptable
buffering agent. Common buffering agents include citric acid,
sodium citrate, sodium acetate, acetic acid, sodium phosphate and
phosphoric acid, sodium ascorbate, tartaric acid, maleic acid,
glycine, sodium lactate, lactic acid, ascorbic acid, imidazole,
sodium bicarbonate and carbonic acid, sodium succinate and succinic
acid, histidine, and sodium benzoate and benzoic acid. The
preferred buffering agent is a citrate buffering agent.
[0023] The chelating agent may be any pharmaceutically acceptable
chelating agent. Common chelating agents include
ethylenediaminetetraacetic acid (EDTA) and derivatives thereof,
citric acid and derivatives thereof, niacinamide and derivatives
thereof, and sodium desoxycholate and derivatives thereof. The
preferred chelating agent is disodium edetate.
[0024] The antioxidant may be any pharmaceutically acceptable
antioxidant. Common antioxidants include those selected from the
group consisting of an ascorbic acid derivative, butylated hydroxy
anisole, butylated hydroxy toluene, alkyl gallate, sodium
meta-bisulfite, sodium bisulfite, sodium dithionite, sodium
thioglycollic acid, sodium formaldehyde sulfoxylate, tocopherol and
derivatives thereof, monothioglycerol, and sodium sulfite. The
preferred antioxidant is monothioglycerol.
[0025] The cryoprotecting agent may be any pharmaceutically
acceptable cryoprotecting agent. Common cryoprotecting agents
include histidine, polyethylene glycol, polyvinyl pyrrolidine,
lactose, sucrose, and mannitol. Improtant cryoprotecting agents are
polyols. The preferred cryoprotecting agent of the invention is
mannitol.
[0026] The opioid can be any pharmaceutically acceptable opioid.
Common opioids are those selected from the group consisting of
alfentanil, anileridine, asimadoline, bremazocine, burprenorphine,
butorphanol, codeine, dezocine, diacetylmorphine (heroin),
dihydrocodeine, diphenoxylate, fedotozine, fentanyl,
funaltrexamine, hydrocodone, hydromorphone, levallorphan,
levomethadyl acetate, levorphanol, loperamide, meperidine
(pethidine), methadone, morphine, morphine-6-glucoronide,
nalbuphine, nalorphine, opium, oxycodone, oxymorphone, pentazocine,
propiram, propoxyphene, remifentanyl, sufentanil, tilidine,
trimebutine, and tramadol.
[0027] The isotonicity agent can be any pharmaceutically acceptable
isotonicity agent. Common isotonicity agents include those selected
from the group consisting of sodium chloride, mannitol, lactose,
dextrose, glycerol, and sorbitol. The preferred isotonicity agent
is mannitol.
[0028] The pharmaceutical preparation may optionally comprise a
preservative. Common preservatives include those selected from the
group consisting of chlorobutanol, parabens, thimerosol, benzyl
alcohol, and phenol.
[0029] According to another aspect of the invention, a method is
provided for preparing an autoclaved preparation of a solution of
methylnaltrexone or salts thereof, whereby the autoclaved
preparation has a concentration of methylnaltrexone degradation
products that does not exceed 2% of the methylnaltrexone or salt
thereof in the preparation. The method involves providing a
solution, having a pH of 4.25 or less, of methylnaltrexone or a
salt thereof, and being substantially free of methylnaltrexone
degradation products, and autoclaving the solution. The solution
can contain, optionally, any one of, any combination of, or all of
a chelating agent, an isotonicity agent, a buffering agent, an
antioxidant, a cryoprotecting agent, and an opioid. Preferably, the
pH of the solution ranges from 2.0 to 4.0. More preferably, from
3.0 to 4.0, and most preferably from 3.0 to 3.5. Preferred
chelating agents, isotonicity agents, buffering agents,
antioxidants, cryoprotecting agents, and opioids are as described
above. Preferred concentrations of methylnaltrexone, likewise, are
as described above.
[0030] According to another aspect of the invention, a method is
provided for preparing an autoclaved preparation. The preparation
has a concentration of methylnaltrexone degradation products that
does not exceed 2% of the methylnaltrexone or salt thereof in the
preparation. The method involves providing a solution containing
methylnaltrexone or salt thereof and a chelating agent, the
solution being substantially free of methylnaltrexone degradation
products, and then autoclaving the solution. The chelating agent is
present in an amount sufficient to protect the preparation against
substantial unwanted degradation of methylnaltrexone or its salt,
and maintain the solution to be substantially free of
methylnaltrexone degradation products. Preferred chelating agents
and concentrations thereof are as described above. The preparation
may include, optionally, any one of, any combination of, or all of
a buffering agent, an isotonicity agent, an antioxidant, a
cryoprotecting agent, and an opioid. Preferred buffering agents,
isotonicity agents, antioxidants and opioids, as well as
concentrations, are as described above. Preferred pHs of the
solution likewise are as described above. Preferably, the
degradation products after autoclaving do not exceed 1.5%, 1%,
0.5%, 0.25% or even 0.125%.
[0031] According to another aspect of the invention, a method is
provided for inhibiting the formation of methylnaltrexone
degradation products in a preparation that is a solution of
methylnaltrexone or salts thereof. The method involves preparing an
aqueous solution containing at least one methylnaltrexone
degradation inhibiting agent selected from the group consisting of
a chelating agent, a buffering agent, an antioxidant, a
cryoprotecting agent, and combinations thereof. A powdered source
of methylnaltrexone or salt thereof is dissolved into the solution
to form the preparation. The preparation has or is adjusted without
addition of a pH-adjusting base to have a pH of between 2 and 6.
More preferably, the pharmaceutical preparation is adjusted to have
a pH ranging from 3 to 5, more preferably, 3 to 4, and most
preferably, 3.0 to 3.5. An isotonicity agent may be added to the
solution. Likewise, an opioid may be added to the solution.
[0032] In any one of the foregoing aspects of the invention, the
preparation can be a pharmaceutical preparation.
[0033] According to another aspect of the invention, a method is
provided for preparing a stable pharmaceutical preparation that is
an aqueous solution of methylnaltrexone or salts thereof to inhibit
formation of methylnaltrexone degradation products. A solution is
provided containing methylnaltrexone or salts thereof and at least
one methylnaltrexone degradation inhibiting agent. The solution is
processed under at least one sterilization technique prior to
and/or after terminal filling the solution in a sealable container
to form the stable pharmaceutical preparation, wherein the method
is carried out without the addition of pH-adjusting base to the
solution. The methylnaltrexone degradation inhibiting agent can be
selected from the group consisting of a chelating agent, a
buffering agent, an antioxidant, and combinations thereof. An
isotonicity agent can be added. A cryoprotecting agent can also be
added. Likewise, an opioid can be added. Preferred chelating
agents, buffering agents, antioxidants, isotonicity agents,
cryoprotecting agents, and opioids are as described above.
Preferred concentrations are as described above. The solution may
be processed to adjust the pH. This is preferably done using an
acid. Most preferably, the solution is adjusted to a range between
a pH of 2 and 6, more preferably, between 3 and 5, 3 and 4, and
most preferably between 3.0 and 3.5. The material can be contained
in a sealed container. The container can be purged with nitrogen
and/or sparged to eliminate oxygen.
[0034] In some embodiments of the invention, parenteral
formulations are provided. In one embodiment, the formulation made
by dissolving methylnaltrexone diluted in water, to which mannitol
is added. The solution is then filter sterilized followed by
lyophilization. Therefore, the product may be provided in
lyophilized form, and in combination with certain cryoprotectants
such as mannitol or lactose. Optionally, a reconstituting diluent
is provided, such as a physiological saline diluent.
[0035] According to another aspect of the invention, a kit is
provided. The kit is a package containing a sealed container
comprising any one of the preparations described above, together
with instructions for use. The kit can also include a diluent
container containing a pharmaceutically acceptable diluent. The kit
can further comprise instructions for mixing the preparation and
the diluent. The diluent can be any pharmaceutically acceptable
diluent. Well known diluents include 5% dextrose solution and
physiological saline solution. The container can be an infusion
bag, a sealed bottle, a vial, a vial with a septum, an ampoule, an
ampoule with a septum, an infusion bag or a syringe. The kit
further can contain an opioid container containing an opioid. The
containers can optionally include indicia indicating that the
containers have been autoclaved or otherwise subjected to
sterilization techniques. The kit can include instructions for
administering the various solutions contained in the containers to
subjects.
[0036] The invention also involves methods of treatment. According
to another aspect of the invention, a method is provided for
treating a subject in need of such treatment with an effective
amount of methylnaltrexone or a salt thereof. The method involves
administering to the subject an effective amount of
methylnaltrexone or salt thereof in any one of the pharmaceutical
preparations described above, detailed herein, and/or set forth in
the claims. In one aspect, the method is a method for inhibiting a
peripheral opioid receptor in a human subject. In another aspect,
the method is for reducing a side-effect of opioid treatment. In
another aspect, the method is for treating any one of a condition
selected from the group consisting of nausea, emesis, dysphoria,
pruritus, urinary retention, ileus, post-operative ileus,
post-partumileus, parallytic ileus, bowel hypomotility,
constipation, gastric hypomotility, delayed gastric emptying,
decreased biliary secretion, decreased pancreatic secretion,
biliary spasm, increased sphincter tone, cutaneous flushing,
impaction, sweating, inhibition of gastrointestinal motility,
inhibition of gastric emptying, gastrointestinal dysfunction,
incomplete evacuation, bloating, abdominal distention, increased
gastroesophageal reflux, hypotension, bradycardia, irritable bowel
syndrome, or immunosuppression.
[0037] In any of the foregoing embodiments, the methylnaltrexone
can be present in an amount sufficient to accelerate discharge from
hospital post-surgery, accelerate bowel sounds after surgery, or
induce laxation.
[0038] The subject can be any subject in need of such treatment.
Important subjects include those receiving opioids including
opioids for pain, cancer or surgical patients, or immunosuppressed
or immunocompromised patients (including HIV infected patients),
patients with advanced medical illness, terminally ill patients,
patients with neuropathies, patients with rheumatoid arthritis,
patients with osteoarthritis, patients with chronic pack pain,
patients with spinal cord injury, patients with chronic abdominal
pain, patients with chronic pancreatic pain, patients with
pelvic/perineal pain, patients with fibromyalgia, patients with
chronic fatigue syndrome, patients with migraine or tension
headaches, patients on hemodialysis, and patients with sickle cell
anemia.
[0039] In the foregoing description, applicants have described the
invention in connection with methylnaltrexone or salts thereof.
Such salts include, but are not limited to, bromide salts, chloride
salts, iodide salts, carbonate salts, and sulfate salts. It should
be understood, however, that methylnaltrexone is a member of a
class of compounds known as quaternary derivatives of
noroxymorphone, as disclosed in U.S. Pat. No. 4,176,186, the entire
disclosure of which is incorporated herein by reference. It is
believed that the invention extends to any such quaternary
derivative of noroxymorphone, and the invention is intended to
embrace pharmaceutical preparations, methods and kits containing
such derivatives. Another aspect of the invention then embraces the
foregoing summary but read in each aspect as if any such derivative
is substituted wherever "methylnaltrexone" appears. Likewise, the
invention also embraces each and every claim read as if the term
"quaternary derivative of noroxymorphone" were substituted whenever
"methylnaltrexone" appears.
BRIEF DESCRIPTION OF THE DRAWINGS
[0040] FIG. 1 is a graph depicting methylnaltrexone degradation
products eluting from a column at time zero (peak Nos. 1, 2 and 4
are degradation products; peak No 4 is methylnaltrexone; peak no 5.
O-methylnaltrexone bromide).
[0041] FIG. 2 is a graph depicting methylnaltrexone degradation
products eluting from a column at 12 months (peak Nos. 1, 2 and 4
are degradation products; peak No 4 is methylnaltrexone; peak no 5.
O-methylnaltrexone bromide).
[0042] FIG. 3 is a schematic representation of a kit according to
the invention containing the formulations described herein.
DETAILED DESCRIPTION OF THE INVENTION
[0043] Applicants have discovered that during the autoclaving
process, methylnaltrexone in aqueous solution tends to degrade to a
surprising extent. The amount of degradation resulting from simple
autoclaving (122.degree. C., 15 lbs. pressure for 20 min.) can be
as high as 10%. The degradation products are depicted in FIG. 1,
and appear to include at least two predominant degradants having
relative retention times (RRT) of 0.72 (2.828 minutes) and 0.89
(3.435 minutes) and, with other minor forms as can be observed. The
degradant identified by the 0.72 RRT peak appears in small amounts,
0.074, immediately upon dissolving the methylnaltrexone into
solution and increases overtime with storage or autoclaving 0.25%.
The degradant identified by the 0.89 RRT peak appears only after
storage over time or after autoclaving (<0.05% and 0.724%,
respectively). Applicants also have discovered that
methylnaltrexone is unstable in aqueous solutions when stored at
room temperature or even at 4.degree. C. for significant (but
commercially necessary) periods of time such as 6 months, 12 months
or even two years. Degradation occurs without regard to whether the
aqueous solution was previously autoclaved or filter sterilized. It
would be desirable to stabilize formulations of methylnaltrexone
such that following the autoclaving process or following storage
(or both autoclaving and storage), the amount of the total
degradation products would be less than 2.0%, 1.5%, 1.0%, 0.5%,
0.25%, and even 0.125%.
[0044] The invention provides stable formulations of
methylnaltrexone. By stable solutions of methylnaltrexone, it is
meant that following autoclaving at 122.degree. C., 15 lbs.
pressure for 20 minutes, the methylnaltrexone degradation products
resulting from such conditions are not more than 2% of the total
methylnaltrexone present in a given solution. By stable solution of
methylnaltrexone, it also is meant that following storage of an
unautoclaved solution at room temperature for twelve months, the
methylnaltrexone degradation products resulting from such
conditions are not more than 2% of the total methylnaltrexone
present in a given solution. By stable solutions of
methylnaltrexone, it is also meant that following storage of an
unautoclaved solution at room temperature for two months, the
methylnaltrexone degradation products resulting from such
conditions are not more than 1.0% of the total methylnaltrexone
present in a given solution. By stable lyophilized formulations of
methylnaltrexone, it is meant that following lyophilization and
storage at room temperature of methylnaltrexone for two months, and
their reconstitution in water the methylnaltrexone degradation
products resulting from such conditions are not more than 1.0% of
the total methylnaltrexone present in a given solution.
[0045] It was surprisingly discovered that pH alone can solve the
problem of excessive methylnaltrexone degradation products. In
particular, it was discovered that when the pH of a
methylnaltrexone solution containing 2 mg/mL of methylnaltrexone
was at about 4.25 pH or less, there was a steep drop-off in the
amount of methylnaltrexone degradation products following
autoclaving. When the pH of the solution containing
methylnaltrexone was adjusted to between 3.5 and 4.0, then the
total percentage of degradants fell below 2%, and in certain
instances even below 1.39%. When the pH was adjusted to between 3.0
and 3.5, the percentage of total degradants dropped to about 0.23%
after autoclaving. It was also noted that there was a significant
drop, before a plateau, when the pH of the methylnaltrexone
solution was brought to below 6.0 prior to autoclaving. Adjusting
pHs to between 4.25 and 6 was not sufficient to produce stable
formulations of methylnaltrexone (through the adjustment of pH
alone). As will be seen below, however, manipulating other
parameters in concert with pH resulted in stable formulations of
methylnaltrexone anywhere in a range from a pH of 2.0 to 6.0. The
benefits of a low pH on the stability of methylnaltrexone
formulations persisted in the presence of chelating agents,
isotonicity agents, buffering agents, and antioxidants. Thus, the
invention in one aspect provides stable formulations of
methylnaltrexone in solution, wherein the pH is below 4.25,
preferably between 3.0 and 4.0, and most preferably between 3.0 and
3.5.
[0046] Applicants also noted that despite setting the pH of a
methylnaltrexone solution at points between 3.0 and 6.0 using a
pH-adjusting acid or pH-adjusting base prior to autoclaving and
despite the benefits obtained from lower pH, the pH of the
autoclaved sample drifted almost immediately to about 7.0. It was
therefore tested, in particular, whether buffering agents could
eliminate the pH drift that resulted from autoclaving without
negatively affecting the ability to protect against heat
degradation resulting from autoclaving. Applicants discovered that
buffering agents indeed could be employed to stabilize the pH of
methylnaltrexone solutions throughout the autoclaving process
without permitting degradation products to exceed acceptable
minimums. Buffers were used in concentrations ranging from 0.25 mM
to 25 mM. Acceptable levels of degradation products were obtained
at all buffer concentrations tested. It was noted, however, that
citrate buffer had properties more desirable than those of acetate
buffer. In particular, the addition of citrate buffer did not seem
to alter in any material respects the amount of degradation
products resulting from autoclaving the methylnaltrexone solution,
resulting in less than 0.23% of degradation products at pH of 3.5.
The addition of acetate buffer, however, appeared to increase
somewhat the amount of methylnaltrexone degradation products,
although not to unacceptable levels, resulting in less than 1.39%
of degradation products at pH of 3.6. Nonetheless, citrate buffer
surprisingly is preferable to acetate buffer. The preferred citrate
buffer range is between about 2 and 5 mM.
[0047] Buffers in general are well known to those of ordinary skill
in the art. Buffer systems include citrate buffers, acetate
buffers, borate buffers, and phosphate buffers. Examples of buffers
include citric acid, sodium citrate, sodium acetate, acetic acid,
sodium phosphate and phosphoric acid, sodium ascorbate, tartartic
acid, maleic acid, glycine, sodium lactate, lactic acid, ascorbic
acid, imidazole, sodium bicarbonate and carbonic acid, sodium
succinate and succinic acid, histidine, and sodium benzoate and
benzoic acid.
[0048] Applicants also discovered, surprisingly, that a chelating
agent alone was capable of reducing the amount of degradation
products to acceptable levels. In particular, pH was not adjusted
and disodium edetate was added at concentrations of 0.01, 0.1,
0.25, 0.5, 0.75, and 1.0 mg/mL. The disodium edetate stabilized
methylnaltrexone against heat degradation in a
concentration-dependent manner. As little as 0.01 mg/mL had a
substantial effect on the amount of degradants, yielding
approximately 2.3% total degradants. A concentration of 0.1 mg/mL
resulted in under 1.5% total degradants. There was a critical point
at approximately 0.3-0.4 mg/mL where the total degradants became
slightly under 0.5% and leveled off with increasing amounts of
disodium edetate. Thus, disodium edetate alone was sufficient to
render stable an unbuffered solution of methylnaltrexone with no
adjustment to pH. This was a surprising result.
[0049] Applicants believe that the result is not limited to
disodium edetate. Instead, other chelating agents well known to
those of ordinary skill in the art will be useful according to the
invention. Chelating agents are chemicals which form water soluble
coordination compounds with metal ions in order to trap or remove
the metal irons from solution, thereby avoiding the degradative
effects of the metal ions. Chelating agents include
ethylenediaminetetraacetic acid (also synonymous with EDTA, edetic
acid, versene acid, and sequestrene), and EDTA derivatives, such as
dipotassium edetate, disodium edetate, edetate calcium disodium,
sodium edetate, trisodium edetate, and potassium edetate. Other
chelating agents include citric acid and derivatives thereof.
Citric acid also is known as citric acid monohydrate. Derivatives
of citric acid include anhydrous citric acid and
trisodiumcitrate-dihydrate. Still other chelating agents include
niacinamide and derivatives thereof and sodium desoxycholate and
derivatives thereof. A synergistic effect of pH and disodium
edetate was also observed. At pH 3-3.5, in the presence of citrate
buffer (25 mM), and 0.01 mg/mL disodium edetate, the total
degradants after autoclaving amounted to less than 0.4%. Under the
same conditions, except increasing the concentration of disodium
edetate to 1 mg/mL, there was no detectable difference. That is,
the degradants were on the order of approximately 0.4% after
autoclaving. The circumstance, however, differed when pH was
adjusted upwardly to between 6.0 and 7.0 in an unbuffered system.
In particular, at a pH adjusted upwardly to between 6.0 and 7.0,
the total degradants were above 3-6% at a concentration of 0.01
mg/mL disodium edetate and approximately 2.8% at 1.0 mg/mL disodium
edetate. This at first glance appears anomalous with the results
described above, where disodium edetate alone was sufficient to
bring total degradants under 0.5% at concentrations above
approximately 0.3 disodium edetate mg/mL. It was discovered,
however, that the increase in degradation was due to the addition
of a pH-adjusting base to the solution containing methylnaltrexone
to upwardly adjust the pH to 6.0-7.0. Therefore, it was discovered
unexpectedly that the addition of a pH-adjusting base, such as
sodium hydroxide, to a solution containing methylnaltrexone should
be avoided in order to minimize the presence of degradants.
[0050] The same results were achieved through a combination of
acetate buffer and disodium edetate at 0.01 mg/mL and 1.0 mg/mL,
although, once again, citrate buffer seemed to work surprisingly
better than acetate buffer in protecting methylnaltrexone from heat
degradation. Higher levels of disodium edetate in the presence of
acetate buffer could compensate, however, for the differential
effect that was observed when using citrate buffer versus acetate
buffer. It is to be noted that citrate buffer also is a chelating
agent, which might contribute to its apparent superior properties.
However, there was no concentration-dependent stabilization due to
citrate buffer and it would appear that the chelating effect of
citrate is not wholly responsible for the differential effects
observed between citrate buffer and acetate buffer.
[0051] Applicants also believe that antioxidants will be useful
according to the invention. Antioxidants are substances capable of
inhibiting oxidation by removing free radicals from solution.
Antioxidants are well known to those of ordinary skill in the art
and include materials such as ascorbic acid, ascorbic acid
derivatives (e.g., ascorbylpalmitate, ascorbylstearate, sodium
ascorbate, calcium ascorbate, etc.), butylated hydroxy anisole,
buylated hydroxy toluene, alkylgallate, sodium meta-bisulfate,
sodium bisulfate, sodium dithionite, sodium thioglycollic acid,
sodium formaldehyde sulfoxylate, tocopherol and derivatives
thereof, (d-alpha tocopherol, d-alpha tocopherol acetate, dl-alpha
tocopherol acetate, d-alpha tocopherol succinate, beta tocopherol,
delta tocopherol, gamma tocopherol, and d-alpha tocopherol
polyoxyethylene glycol 1000 succinate) monothioglycerol, and sodium
sulfite. Such materials are typically added in ranges from 0.01 to
2.0%.
[0052] The pharmaceutical preparations of the invention also may
include isotonicity agents. This term is used in the art
interchangeably with iso-osmotic agent, and is known as a compound
which is added to the pharmaceutical preparation to increase the
osmotic pressure to that of 0.9% sodium chloride solution, which is
iso-osmotic with human extracellular fluids, such as plasma.
Preferred isotonicity agents are sodium chloride, mannitol,
sorbitol, lactose, dextrose and glycerol.
[0053] Optionally, the pharmaceutical preparations of the invention
may further comprise a preservative. Suitable preservatives include
but are not limited to: chlorobutanol (0.3-0.9% W/V), parabens
(0.01-5.0%), thimerosal (0.004-0.2%), benzyl alcohol (0.5-5%),
phenol (0.1-1.0%), and the like.
[0054] In view of the success achieved with disodium edetate alone
in an unbuffered system, it would have been expected that stable
formulations could be prepared at virtually any pH simply by
optimizing the various potential methylnaltrexone degradation
inhibiting agents. Such agents include those as described above,
that is, chelating agents, buffering agents, antioxidants, and the
like. It was discovered, however, that stable formulations of
methylnaltrexone in solution could not be obtained with such
degradation inhibiting agents at pHs above 6. Thus, in one aspect
of the invention, stable pharmaceutical preparations containing
methylnaltrexone in solution are permitted, wherein the solution
further includes an agent selected from the group consisting of a
chelating agent, a buffering agent, an antioxidant, and
combinations thereof, provided that the solution has a pH ranging
from between 2 to 6.
[0055] The stable pharmaceutical preparations of the invention are
stable not only to heat degradation resulting from autoclaving, but
also to other sterilization processes used during manufacturing.
Sterilization processes or techniques as used herein include
aseptic techniques such as one or more filtration (0.45 or 0.22
micron filters) steps, autoclaving, and a combination of filtration
and autoclaving. They also are stable to long term storage. The
stable formulations of the invention are stable for at least six
months at temperatures of 30.degree. C. or less, preferably a range
from 5.degree. C. to 30.degree. C., and, more preferably, they are
stable at a temperature above 15.degree. C. for at least six
months. More particularly, the stable pharmaceutical preparations
are stable for periods of at least six months, at least twelve
months, and even at least twenty-four months at about room
temperature or 25.degree. C. Such preparations remain substantially
free of methylnaltrexone degradation products, that is, such
solutions contain less than 2% methylnaltrexone degradation
products compared to the total amount of methylnaltrexone in the
solution.
[0056] Applicants also discovered, surprisingly, that lyophilizing
conditions could dramatically affect the amount of methylnaltrexone
degradation products. The pharmaceutical preparations of the
invention therefore may advantageously include cryoprotective
agents, which protect methylnaltrexone from the harmful effects of
freezing. Such agents also can prevent caking and flaking, which
can be problematic in reconstituting a solution and in
manufacturing processing. Important cryoprotecting agents are
mannitol, lactose, sucrose, polyethylene glycol and polyvinyl
pyrrolidine. Most preferred is mannitol. It is believed that
cryoprotecting agents which result in a reconstitution pH of 6.0
and higher or which are basic will contribute also to degradation
of methylnaltrexone due to pH effects discussed above. Thus,
preferred cryoprotecting agents are those which, together with the
other components of the formulation, result in a pH in the
preferred ranges described above. Preferably, the cryoprotecting
agent is neutral or acidic.
[0057] The amount of methylnaltrexone in the solution is effective
to treat completely, ameliorate, or even prevent conditions
associated with activation of endogenous opioid receptors, in
particular, peripheral opioid receptors such as mu opioid
receptors. Such conditions include nausea, emesis, dysphoria,
pruritus, urinary retention, ileus, post-operative ileus,
post-partumileus, parallytic ileus, bowel hypomotility,
constipation, gastric hypomotility, delayed gastric emptying,
decreased biliary secretion, decreased pancreatic secretion,
biliary spasm, increased sphincter tone, cutaneous flushing,
impaction, sweating, inhibition of gastrointestinal motility,
inhibition of gastric emptying, gastrointestinal dysfunction,
incomplete evacuation, bloating, abdominal distention, increased
gastroesophageal reflux, hypotension, bradycardia, irritable bowel
syndrome, or immunosuppression. One important use is in the
treatment of constipation, i.e., less than one bowel movement in 3
days or less than 3 bowel movements in a week.
[0058] In any of the foregoing embodiments, the methylnaltrexone
can be present in an amount sufficient to accelerate discharge from
hospital post-surgery, accelerate bowel sounds after surgery, or
induce laxation. Such amounts are well known to those of ordinary
skill in the art and are described in the literature, including the
patents listed in the background of the invention. The
methylnaltrexone may also be in a salt form, including the bromide,
chloride, iodide, carbonate, and sulfate salts of
methylnaltrexone.
[0059] Patients treatable with the formulations of the invention
include those receiving opioids including opioids for pain, cancer
or surgical patients, immunosuppressed or immunocompromised
patients (including HIV infected patients), patients with advanced
medical illness, terminally ill patients, patients with
neuropathies, patients with rheumatoid arthritis, patients with
osteoarthritis, patients with chronic pack pain, patients with
spinal cord injury, patients with chronic abdominal pain, patients
with chronic pancreatic pain, patients with pelvic perineal pain,
patients with fibromyalgia, patients with chronic fatigue syndrome,
patients with migraine or tension headaches, patients on
hemodialysis, and patients with sickle cell anemia.
[0060] The pharmaceutical preparations of the invention also can
include an opioid. The therapeutic use of opioids is well known
and, again, is described in both the literature and the patents
mentioned above. Opioids include alfentanil, anileridine,
asimadoline, bremazocine, burprenorphine, butorphanol, codeine,
dezocine, diacetylmorphine (heroin), dihydrocodeine, diphenoxylate,
fedotozine, fentanyl, funaltrexamine, hydrocodone, hydromorphone,
levallorphan, levomethadyl acetate, levorphanol, loperamide,
meperidine (pethidine), methadone, morphine,
morphine-6-glucoronide, nalbuphine, nalorphine, opium, oxycodone,
oxymorphone, pentazocine, propiram, propoxyphene, remifentanyl,
sufentanil, tilidine, trimebutine, and tramadol.
[0061] It should be understood that the pharmaceutical preparations
of the invention will typically be held in bottles, vials,
ampoules, infusion bags, and the like, any one of which may be
sparged to eliminate oxygen or purged with nitrogen. In some
embodiments, the bottles vials and ampoules are opaque, such as
when amber in color. Such sparging and purging protocols are well
known to those of ordinary skill in the art and should contribute
to maintaining the stability of the pharmaceutical preparations.
The pharmaceutical preparations also, in certain embodiments, are
expected to be contained within syringes.
[0062] According to another aspect of the invention, kits also are
provided. Referring to FIG. 3, a kit 10 is depicted. The kit 10
includes a pharmaceutical preparation vial 12, a pharmaceutical
preparation diluent vial 14, an opioid vial 16, and an opioid
diluent vial 18. The kit also includes instructions 20. The vial 14
containing the diluent for the pharmaceutical preparation is
optional. The vial 14 contains a diluent such as physiological
saline for diluting what could be a concentrated solution of
methylnaltrexone contained in vial 12. The instructions can include
instructions for mixing a particular amount of the diluent with a
particular amount of the concentrated pharmaceutical preparation,
whereby a final formulation for injection or infusion is prepared.
The instructions may include instructions for use in a patient
controlled analgesia (PCA) device. Likewise, the kit optionally
contains an opioid in the opioid vial 16, which also optionally may
be in a concentrated form. The optional vial 18 contains a diluent
for a concentrated opioid. The instructions also may include
instructions for mixing the opioid with the pharmaceutical
preparation and/or diluting the opioid with the opioid diluent
contained in the opioid diluent vial 18. The instructions,
therefore, would take a variety of forms depending on the presence
or absence of diluent and opioid. The instructions 20 can include
instructions for treating a patient with an effective amount of
methylnaltrexone. It also will be understood that the containers
containing the pharmaceutical preparation, whether the container is
a bottle, a vial with a septum, an ampoule with a septum, an
infusion bag, and the like, can contain indicia such as
conventional markings which change color when the pharmaceutical
preparation has been autoclaved or otherwise sterilized.
[0063] The pharmaceutical preparations of the invention, when used
in alone or in cocktails, are administered in therapeutically
effective amounts. A therapeutically effective amount will be
determined by the parameters discussed below; but, in any event, is
that amount which establishes a level of the drug(s) effective for
treating a subject, such as a human subject, having one of the
conditions described herein. An effective amount means that amount
alone or with multiple doses, necessary to delay the onset of,
inhibit completely or lessen the progression of or halt altogether
the onset or progression of the condition being treated. When
administered to a subject, effective amounts will depend, of
course, on the particular condition being treated; the severity of
the condition; individual patient parameters including age,
physical condition, size and weight; concurrent treatment;
frequency of treatment; and the mode of administration. These
factors are well known to those of ordinary skill in the art and
can be addressed with no more than routine experimentation. It is
preferred generally that a maximum dose be used, that is, the
highest safe dose according to sound medical judgment.
[0064] The pharmaceutical preparations of the present invention may
include or be diluted into a pharmaceutically-acceptable carrier.
The term "pharmaceutically-acceptable carrier" as used herein means
one or more compatible solid, or semi-solid or liquid fillers,
diluants or encapsulating substances which are suitable for
administration to a human or other mammal such as a dog, cat,
horse, cow, sheep, or goat. The term "carrier" denotes an organic
or inorganic ingredient, natural or synthetic, with which the
active ingredient is combined to facilitate the application. The
carriers are capable of being commingled with the preparations of
the present invention, and with each other, in a manner such that
there is no interaction which would substantially impair the
desired pharmaceutical efficacy or stability. Carriers suitable for
oral, subcutaneous, intravenous, intramuscular, etc. formulations
can be found in Remington's Pharmaceutical Sciences, Mack
Publishing Company, Easton, Pa.
[0065] A variety of administration routes are available. The
particular mode selected will depend of course, upon the particular
drug selected, the severity of the disease state being treated and
the dosage required for therapeutic efficacy. The methods of this
invention, generally speaking, may be practiced using any mode of
administration that is medically acceptable, meaning any mode that
produces effective levels of the active compounds without causing
clinically unacceptable adverse effects. Such modes of
administration include oral, rectal, sublingual, topical, nasal,
transdermal or parenteral routes. The term "parenteral" includes
subcutaneous, intravenous, intramuscular, or infusion.
[0066] Dosage may be adjusted appropriately to achieve desired drug
levels, locally or systemically. Generally, daily oral doses of
active compounds will be from about 0.1 mg/kg per day to 30 mg/kg
per day. It is expected that IV doses in the range of 0.01-1.00
mg/kg will be effective. In the event that the response in a
subject is insufficient at such doses, even higher doses (or
effective higher doses by a different, more localized delivery
route) may be employed to the extent that patient tolerance
permits. Continuous IV dosing over, for example, 24 hours or
multiple doses per day also are contemplated to achieve appropriate
systemic levels of compounds. Preferred subcutaneous doses for
chronic opioid users to induce laxation are 0.1-0.3 mg/kg, and
preferred oral doses for the same patient population are 1.0-3.0
mg/kg. Preferred IV doses to treat post operative ileus are 0.15
mg/kg.
[0067] The invention also involves methods for preparing autoclaved
pharmaceutical preparations that have concentrations of
methylnaltrexone degradation products that do not exceed 2% of the
methylnaltrexone or salt thereof in the preparation. Aqueous
solutions of methylnaltrexone are prepared. A pH-adjusting acid is
added to adjust the pH to 4.25 or less, preferably to a range of
between 3.0 and 3.5. The solution is then autoclaved according to
standard procedures. One such procedure involves autoclaving at
122.degree. C. and 15 pounds of pressure for 20 minutes. The
pharmaceutical preparation can contain any one, any combination of
or all of a chelating agent, an isotonicity agent, a buffering
agent, an antioxidant, a cryoprotective agent, and an opioid.
According to another aspect of the invention, a pharmaceutical
preparation containing methylnaltrexone in a aqueous solution is
prepared by combining a chelating agent with the methylnaltrexone
solution and then autoclaving the solution. The aqueous solution of
methylnaltrexone may contain any one of, any combination of or all
of a buffering agent, an antioxidant, an isotonicity agent and an
opioid.
[0068] According to yet another aspect of the invention, a
pharmaceutical preparation containing methylnaltrexone in a
lyophilized formulation is prepared by combining a cryoprotective
agent, such as mannitol, with the methylnaltrexone formulation. The
lyophilized preparation may also contain any one of, any
combination of or all of a buffering agent, an antioxidant, an
isotonicity agent and an opioid.
[0069] The invention also involves methods of inhibiting the
formation of methylnaltrexone degradation products in a solution
containing methylnaltrexone by combining any one of, any
combination of or all of a chelating agent, a buffering agent and
an antioxidant with methylnaltrexone or salt thereof in solution.
In one preferred embodiment, the aqueous solution containing the
chelating agent, buffering agent and/or antioxidant is first
prepared, then a powdered source of methylnaltrexone or salt
thereof is dissolved into the aqueous solution.
[0070] The invention also involves methods of inhibiting the
formation of methylnaltrexone degradation products in a gel
containing methylnaltrexone by combining any one of, any
combination of or all of a chelating agent, a buffering agent and
an antioxidant with methylnaltrexone or salt thereof in a gel
matrix. In one preferred embodiment, the gel containing the
chelating agent, buffering agent and/or antioxidant is first
prepared, then a powdered source of methylnaltrexone or salt
thereof is dissolved into the gel. As used herein, solution
embraces gels.
[0071] The pharmaceutical preparations of the invention may be
provided in particles. Particles as used herein means nano or
microparticles (or in some instances larger) which can consist in
whole or in part of the peripheral opioid antagonists or the other
therapeutic agent(s) as described herein. The particles may contain
the therapeutic agent(s) in a core surrounded by a coating,
including, but not limited to, an enteric coating. The therapeutic
agent(s) also may be dispersed throughout the particles. The
therapeutic agent(s) also may be adsorbed into the particles. The
particles may be of any order release kinetics, including zero
order release, first order release, second order release, delayed
release, sustained release, immediate release, and any combination
thereof, etc. The particle may include, in addition to the
therapeutic agent(s), any of those materials routinely used in the
art of pharmacy and medicine, including, but not limited to,
erodible, nonerodible, biodegradable, or nonbiodegradable material
or combinations thereof. The particles may be microcapsules which
contain the antagonist in a solution or in a semi-solid state. The
particles may be of virtually any shape.
[0072] Both non-biodegradable and biodegradable polymeric materials
can be used in the manufacture of particles for delivering the
therapeutic agent(s). Such polymers may be natural or synthetic
polymers. The polymer is selected based on the period of time over
which release is desired. Bioadhesive polymers of particular
interest include bioerodible hydrogels described by H. S. Sawhney,
C. P. Pathak and J. A. Hubell in Macromolecules, (1993) 26:581-587,
the teachings of which are incorporated herein. These include
polyhyaluronic acids, casein, gelatin, glutin, polyanhydrides,
polyacrylic acid, alginate, chitosan, poly(methyl methacrylates),
poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl
methacrylate), poly(hexylmethacrylate), poly(isodecyl
methacrylate), poly(lauryl methacrylate), poly(phenyl
methacrylate), poly(methyl acrylate), poly(isopropyl acrylate),
poly(isobutyl acrylate), and poly(octadecyl acrylate).
[0073] The invention also provides methods for preparing stable
pharmaceutical preparations containing aqueous solutions of
methylnaltrexone or salts thereof to inhibit formation of
methylnaltrexone degradation products. A solution is provided that
contains methylnaltrexone or salts thereof and at least one
methylnaltrexone inhibiting agent. The solution is processed under
at least one sterilization technique prior to and/or after terminal
filing the solution in the sealable container to form a stable
pharmaceutical preparation, wherein the method is carried out
without the addition of a pH-adjusting base to the solution.
EXAMPLES
Example 1
Manufacturing Process for a Pharmaceutical Formulation of
Methylnaltrexone
[0074] A manufacturing process can be outlined as follows: [0075]
1. Add required amount of water for injection (.about.80% or final
volume) to a stainless steel tank. [0076] 2. Add chelating agent to
the tank and stir till dissolved. [0077] 3. Add buffering agent to
the tank and stir till dissolved. [0078] 4. Add methylnaltrexone to
the tank and stir till dissolved. [0079] 5. Add isotonicity agent
to the tank and stir till dissolved. [0080] 6. Adjust the pH of the
solution to pH 3.25. [0081] 7. Add water for injection to increase
the volume to the required amount. [0082] 8. Transfer material to
supply pressure vessel. [0083] 9. Sterile filter into a sterile
stainless steel pressure vessel. [0084] 10. Fill into
bottles/vials, purge with nitrogen and then stopper the
bottles/vials. [0085] 11. Sterilize the filled vials by
autoclaving. Exact amount of excipients to be used:
TABLE-US-00001 [0085] Disodium edetate = 0.75 mg/ml Added in step 2
Sodium Citrate = 0.199 mg/ml Added in step 3 Citric acid = 0.35
mg/ml Added in step 3 Sodium Chloride = 8.5 mg/ml Added in step
5
[0086] The order of addition of excipients is described above.
Steps 2 to 5 can take place in any order.
[0087] When all excipients and drug have been added, step 6, pH of
the solution is adjusted by addition of acid. If a buffering agent
is used in the solution, pH adjustment may not be required.
[0088] There are no specifics on the temperature or the stirring
speed during the formulation. The temperature during formulation
can be as high as 80.degree. C.
Example 2
Preferred Manufacturing Process for a Pharmaceutical Formulation of
Methylnaltrexone
[0089] A preferred manufacturing process is as follows:
[0090] 100 ml of 20 mg/ml solution of methylnaltrexone
solutions
1. Add 80 ml of water for injection (.about.80% or final volume) to
a stainless steel tank. 2. Add 75 mg of disodium edetate, a
chelating agent, to the tank and stir till dissolved. 3. Add 19.9
mg of sodium citrate and 35 mg of citric acid (as buffering agents)
to the tank and stir till dissolved. 4. Add 2000 mg of
methylnaltrexone to the tank and stir till dissolved. 5. Add 850 mg
of sodium chloride, an isotonicity agent, to the tank and stir till
dissolved. 6. Adjust the pH of the solution if necessary. 7. Add
water for injection to increase the volume to 100 ml. 8. Transfer
the material to supply pressure vessel. 9. Sterile filter using a
0.22 micron filter into a sterile stainless steel pressure vessel.
10. Fill, purge with nitrogen and then stopper the bottles/vials.
11. Sterilize the filled vials by autoclaving.
Example 3
12 Month Stability of Pharmaceutical Preparation
Methylnaltrexone
[0091] Methylnaltrexone (bromide salt) and its degradation products
in an isotonic saline solution were tested upon manufacture of the
solution (no added stabilizers, sterile filtered, not autoclaved)
and upon storage at room temperature for 12 months using a
Hewlett-Packard HP 1100 series, HPLC system equipped with
quaternary gradient pump, programmable variable wavelength UV
detector and a Millennium data acquisition system. Two mobile
phases were prepared as follows:
[0092] The reagents, standards and media included naltrexone
methobromide as a reference standard, trifluoroacetic acid (ACS
grade), acetonitrile (HPLC grade), Milli-Q water (or equivalent),
and methanol (HPLC grade). The solutions were prepared as follows.
Mobile phase A (85:15:0.1) (water:methanol:trifluoroacetic acid):
850 mL of Milli-Q water was added to a suitable container, to which
150 mL of methanol and 1.0 mL of trifluoroacetic acid were added.
The solution was mixed well and allowed to equilibrate to room
temperature. The solution was degassed by helium sparge. Mobile
phase B (methanol): Methanol was added to a suitable container and
degassed by helium sparge.
[0093] Instrumental Conditions
[0094] Analytical Column: Metachem Inertsil ODS3, 5 .mu.m,
150.times.4.6 mm or equivalent
[0095] Mobile phase: A mixture of Mobile phase A and B is used as
shown in Table I:
TABLE-US-00002 TABLE I Time (minutes) % A % B 0 100 0 12 65 35 15
35 65 15.1 100 0 20 100 0
Column temperature: 50.degree. C.
Detection: UV at 280 nm
[0096] Injection volume: 20 .mu.L Run time: 20 minutes Flow rate:
1.5 mL/minute Quantitation: Peak area responses
Results:
[0097] 20 mg/ml saline drug product lot CTM-02085
TABLE-US-00003 Initial 12 months Peak % % No. RRT Degradants RRT
Degradants 1 degradation product 0.72 0.07 0.74 0.25 2 degradation
product 0.89 <0.05 0.89 0.72 3 methylnaltrexone 1.00 99.7 1.00
98.6 4 degradation product 1.48 0.06 1.40 0.16 5 O-Methylnaltrexone
1.57* 0.17 1.54* 0.17 Bromide (process impurity)
[0098] Samples from the methylnaltrexone saline formulation (not
autoclaved) were analyzed for methylnaltrexone degradation products
before and after storage for 12 months at 25.degree. C.
[0099] The starting material was analyzed by HPLC. As shown in FIG.
1, methylnaltrexone is a peak having an RRT of 1.0 (4.364 minutes).
An additional peak was identified as O-methyl naltrexone
methobromide, RRT about 1.57 (6.868 minutes). The
O-methyl-naltrexone is not a degradant of methylnaltrexone but a
result from the methylnaltrexone (drug substance) manufacturing
process.
[0100] The material stored for 12 months was similarly analyzed by
HPLC. The chromatogram is shown in FIG. 2.
[0101] As in the starting material, the HPLC analysis of the sample
stored for 12 months showed methylnaltrexone RRT of 1.00 (3.839
minutes), O-methyl-methylnaltrexone RRT of about 1.53 (5.866
minutes). However, HPLC analysis revealed that the methylnaltrexone
saline formulation which was stored for 12 months had at least
three degradation products formed during the manufacturing or
during storage of the finished drug product. The degradant peak
RRT's were approximately 0.74 (2.828 minutes), 0.89 (3.435 minutes)
and 1.40 (5.326 minutes).
[0102] HPLC analysis was also conducted, prior to storage, on a
methylnaltrexone solution manufactured using an isotonic saline
solution (no added stabilizers), sterile filtered, and autoclaved.
This saline, autoclaved solution contained the degradation products
formed during manufacturing or storage, as described above (data
not shown).
Example 4
Preparation of a Subcutaneous Formulation
[0103] The degradation products seen with very low citrate level
were the same as those seen with normal saline solution. These low
citrate formulas were autoclaved and after three months the amount
of degradation products seen were less than 0.1% for each
degradation product. The formula used for the citrate/EDTA
formulation is listed below:
TABLE-US-00004 mg/mL Methynaltrexone 30 mg Sodium Chloride 4 mg
Citric acid 0.0875 mg Trisodium Citrate 0.0496 mg Disodium edetate
0.75 mg Water for injection q.s. to 1 gram
The pH of this solution is 3.5 and can withstand autoclaving
process.
Example 5
Manufacturing Process for a Lyophilized Pharmaceutical Formulation
of Methylnaltrexone
[0104] The lyophilization cycle listed below is standard procude
well known to one of ordinary skill in the art. This cycle was used
for the preparation of lyophilized preparation of methylnaltrexone
analyzed in Examples 6 and 7.
1. Load chamber at room temperature (20-25 C) 2. Lower shelf temp
to -45 degrees C. at 1.0 degrees C./min 3. Hold shelf temp at -45
for 120 minutes 4. When condenser is below -50 degrees C., evacuate
the chamber to 100-125 mt. 5. Ramp shelf to -20 degrees C. at 0.5
degrees C./min. 6. Hold at -20 degrees C. for 16 hours 7. Ramp
shelf to +27 degrees C. at 0.10 degrees C./min 8. Hold for a
minimum of 8 hours. Maintain chamber pressure at 100-125 mt for the
entire cycle. 9. Restore chamber to 11.0 PSIA+ or -1.0 with sterile
filtered Nitrogen and then seat the
[0105] closures (2'' Hg), then bleed to atmospheric pressure with
Nitrogen to unload.
Example 6
Stability of Lyophilized Formulations of Methylnaltrexone
[0106] The following data reports the stability of lyophilized
formulations of methylnaltrexone using different cryoprotecting
agents.
TABLE-US-00005 total degradation Cryoprotecting Agent pH products
Mannitol 5.0 0.34% Polyvinyl pyrrolidone 4.1 0.37% Polyethylene
glycol 5.7 0.44% Histidine 7.4 0.55%
Example 7
Stability of Lyophilized Formulations of Methylnaltrexone
[0107] The following data reports the stability of lyophilized
formulations of methylnaltrexone in comparison to buffered
formulations.
Amount of total related substances at various stages of
manufacturing
TABLE-US-00006 1 2 3 4 5 6 Key Monothio- Citrate Citrate Acetate
Lyophilized Lyophilized Ingredient glycerol Buffer Buffer Buffer
using using pH 3.5 pH 5 pH 3.6 Mannitol Lactose Unautoclaved 0.13
0.12 0.16 0.20 0.14 0.12 Autoclaved 0.91 0.23 0.61 1.39 n/a n/a
Stability (2 1.10 0.16 0.48 1.26 0.15 0.15 mths at room temp)
[0108] It should be understood that various changes and
modifications to the preferred embodiments described herein will be
apparent to those of ordinary skill in the art. Such changes and
modifications can be made without departing from the spirit and
scope of this invention without diminishing its advantages. It is
therefore intended that such changes and modifications, including
equivalents, be covered by the appended claims. All of the patents,
patent applications and references listed herein are incorporated
by reference in their entirety.
* * * * *