U.S. patent application number 10/550699 was filed with the patent office on 2007-01-25 for medicament delivery device and a method of medicament delivery.
This patent application is currently assigned to MPATHY MEDICAL DEVICES LIMITED. Invention is credited to James Browning.
Application Number | 20070020311 10/550699 |
Document ID | / |
Family ID | 9955655 |
Filed Date | 2007-01-25 |
United States Patent
Application |
20070020311 |
Kind Code |
A1 |
Browning; James |
January 25, 2007 |
Medicament delivery device and a method of medicament delivery
Abstract
A medicament delivery device and method of delivery a medicament
is provided wherein the device is insertable into the uterine
myometrium for the delivery of medicaments to the pelvic area and
organs thereof, for example, the bladder, peritoneum, the vulva,
vagina, fallopian tubes, ovaries and uterus and then to the
bloodstream.
Inventors: |
Browning; James; (GLASGOW,
GB) |
Correspondence
Address: |
DRINKER BIDDLE & REATH;ATTN: INTELLECTUAL PROPERTY GROUP
ONE LOGAN SQUARE
18TH AND CHERRY STREETS
PHILADELPHIA
PA
19103-6996
US
|
Assignee: |
MPATHY MEDICAL DEVICES
LIMITED
|
Family ID: |
9955655 |
Appl. No.: |
10/550699 |
Filed: |
March 26, 2004 |
PCT Filed: |
March 26, 2004 |
PCT NO: |
PCT/GB04/01390 |
371 Date: |
July 27, 2006 |
Current U.S.
Class: |
424/426 |
Current CPC
Class: |
A61K 9/0039 20130101;
A61L 31/028 20130101; A61K 9/0036 20130101; A61L 2300/602 20130101;
A61F 6/142 20130101; A61L 31/16 20130101; A61P 31/00 20180101; A61M
2205/04 20130101; A61L 31/043 20130101; A61L 31/042 20130101; A61L
31/06 20130101; A61L 31/04 20130101; A61M 31/007 20130101; A61L
31/145 20130101; A61F 2210/0004 20130101; A61P 15/00 20180101; A61L
31/148 20130101; A61F 6/06 20130101; A61F 6/02 20130101 |
Class at
Publication: |
424/426 |
International
Class: |
A61F 2/02 20070101
A61F002/02 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 27, 2003 |
GB |
0307082.8 |
Claims
1-24. (canceled)
25. An implantable medicament delivery device insertable into the
female uterine myometrium to provide controlled delivery of a
medicament over a period of time said device comprising means for
providing controlled delivery of a medicament, an elongate body
having an outer surface, a first end and a second end wherein the
second end includes a head portion wherein the head portion is a
lateral extension from the longitudinal axis of the elongate body
and the head portion allows manipulation and surveillance of the
implant.
26. The device as claimed in claim 25, wherein the means to provide
controlled delivery of the medicament is provided in or on the body
of the implant.
27. The device as claimed in claim 26, wherein, in use, when
inserted in the myometrium, the body of the medicament delivery
device is surrounded by smooth muscle and soft tissue of the
myometrium and the medicament passes through the smooth muscle and
soft tissue and targets the pelvic region and organs thereof.
28. The device as claimed in claim 25, wherein the means to provide
controlled delivery of a medicament is provided in or on the head
portion of the implant.
29. The device as claimed in claim 28, wherein, in use, when the
device is inserted into myometrial tissue, the head portion
protrudes from the myometrial tissue into the vagina and targets
the medicament to the tissues of the vagina.
30. The device as claimed in claim 25, wherein the first end of the
body has a semi-sharp point.
31. The device as claimed in claim 25, wherein the device is
absorbable.
32. The device as claimed in claim 25, wherein the head portion is
a substantially flat plate which extends in all radial directions
from the second end of the body of the device.
33. The device as claimed in claim 25, wherein the second end
comprises retrieval means.
34. The device as claimed in claim 33, wherein the retrieval means
is an elongate flexible member.
35. The device as claimed in claim 25 which has an axial length
from 5 mm to 45 mm.
36. The device as claimed in claim 25 which has a diameter of from
0.5 mm to 4 mm.
37. The device as claimed in claim 25 comprising at least one
medicament.
38. The device as claimed in claim 37, wherein the least one
medicament is selected from anti-infectives, antimicrobials,
prebiotics, probiotics, acidifiers, antivirals, antibiotics,
anti-allergenics, anti-inflammatories, anti-fungals,
anti-cholinesterases, nutritional agents, cardiovascular agents,
anti-hypertensive agents and chemotherapeutic agents.
39. The device as claimed in claim 37, wherein the device comprises
a medicament for oestrogen dependent proliferative disorders of the
pelvis for example endometriosis or fibroids.
40. The device as claimed in claim 37, wherein said the medicament
is at least one member chosen from the group including progestins,
GnRH agonists/antagonists, NSAIDs, COX-II inhibitors, combined oral
contraceptives, Danazol, smooth muscle relaxants or aromatase
inhibitors.
41. The device as claimed in claim 25, wherein, in use, the
cumulative release of medicament is in an amount selected from 5%,
10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99%
relative to the total amount of medicament in the device after
implantation for a period of 1 day, 1 week, 2 weeks, 1 month, 2
months, 3 months, 4 months, 6 months, 1 year, 2 years, 3 years, 4
years or 5 years.
42. A kit for implanting a device as claimed in claim 25
comprising: a device as claimed in claim 25; and an insertion tool
comprising an elongate shaft, said shaft having a handle means at a
first end thereof and device mounting means at a second opposite
end wherein the medicament delivery device is mountable on the
device mounting means of the insertion tool.
43. A method for introducing a medicament into the body of a female
mammal, comprising the step of: inserting an implantable medicament
delivery device, said device comprising means capable of providing
controlled delivery of a medicament over a period of time, into the
myometrium.
44. The method as claimed in claim 43 comprising the steps of:
providing an implantable medicament delivery device; introducing
the medicament delivery device into a myometrium of a uterine body
through serosa surrounding the myometrium during open or
laproscopic surgery.
45. The method as claimed in claim 43, wherein the myometrium is
the smooth muscle myometrial tissue of the cervix.
46. The method as claimed in claim 45 comprising the steps of:
providing an implantable medicament delivery device; introducing
the medicament delivery device into the body via the vagina;
penetrating the myometrium via the uterine cervix; and inserting
the medicament delivery device into the myometrium.
47. The method as claimed in claim 46, wherein the medicament
implantable device is introduced into the body using an insertion
tool.
48. The method as claimed in claim 43 comprising inserting the
device as claimed in claim 4 into the myometrium to provide long
term local delivery of medicaments to the vaginal cavity and
epithelium and thereby into the pelvic region and organs thereof
including to the bladder, peritoneum, vulva, vagina, ovaries,
fallopian tubes and/or the uterus and/or then into the
bloodstream.
49. The method as claimed in claim 43 comprising inserting the
device as claimed in claim 2 into the myometrium to provide long
term local delivery of medicaments to the myometrium and thereby
into the pelvic region and organs thereof including to the bladder,
peritoneum, vulva, vagina, ovaries, fallopian tubes and/or the
uterus and/or then into the bloodstream.
Description
[0001] This invention relates to a medicament delivery device and a
method of delivering a medicament. In particular, but not
exclusively the present invention relates to a device and a method
for providing an implant in the uterine myometrium (in females) or
prostate gland (in males) and the delivery of medicament to the
pelvic area and organs thereof, for example the bladder,
peritoneum, and in females the vulva, vagina, fallopian tubes,
ovaries and uterus and then into the bloodstream.
[0002] There are many drugs which may be administered to the human
and animal body for the prevention or treatment of disease.
Different types of drugs call for different ways of administering
the drug to the human or animal body.
[0003] Currently, most benign gynaecological conditions, for
example endometriosis or fibroids, are treated using traditional
methods of medicament or drug delivery, primarily oral and
intravenous administration. Where possible, drugs are provided in
pill, capsule, powder or liquid form for oral administration to a
human or animal. The drug is then absorbed by the digestive system
and will usually enter the blood stream via the liver to take
effect. However, far from all drugs are suitable for such
administration. For example, many drugs are broken down by the
digestion process and destroyed before they can enter the blood
stream. This problem is caused by what is commonly referred to as
the "first pass liver metabolism" of the human or animal body, i.e.
the process by which all substances absorbed by the digestive
system must pass through the liver into the blood stream.
Therefore, to provide sufficient drug to the female reproductive
organs, relatively large doses of a drug are required. These large
doses can cause side effects.
[0004] To avoid or minimise the problem of the first pass liver
metabolism, drugs can be provided by injection, for example drugs
desired to take an instant effect in the blood stream of a human or
animal body may be injected into a vein, i.e. intravenously.
Alternatively, drugs may be injected into muscle tissue from which
the drug is absorbed more slowly into the blood stream. Drugs for
injection into muscle tissue may, for example, be provided in an
oily base which helps to regulate the rate of absorption. However,
injections can be painful and difficult, particularly injections
into muscle tissue, and can lead to tissue damage where frequent
injections are required on a long term basis, e.g. of insulin for
diabetics.
[0005] Other types of drug delivery include nasal sprays for
administration of drugs to the nasal tissues and lungs; patches,
such as the Nicorette.RTM. patch, for the application of Nicotine,
or Ortho Evra, a contraceptive patch which releases
oestrogen/progesterone through the skin; and lotions or ointments
for topical application, i.e. directly to an affected part of the
body.
[0006] However, these alternative types of drug delivery means can
suffer from disadvantages. For example, skin patches can cause skin
irritation, suffer from disattachment and cause cosmetic
issues.
[0007] Although the above drug delivery methods are useful for
particular types of drugs and medicines, with the exception of
intramuscular depot injections, they are unable to provide
therapeutic levels of drugs over a long term, e.g. weeks, months
and years rather than days, without repeated application by the
patient, a carer, physician or general practitioner.
[0008] For application of drugs on a long term basis, various
implants have been developed. One such type of implant may be
inserted under the skin and have a mechanism for slowly releasing a
drug into the blood stream of the human or animal in which it is
implanted. For example, Norplant.RTM. or Implanon.RTM. comprise an
implant having small capsules or rods which slowly release
levonorgestrel or etonorgestrel into the blood stream to provide a
contraceptive effect for women. Norplant.RTM. can be effective for
up to five years.
[0009] However, these implants inserted under the skin suffer from
a number of disadvantages. In particular the insertion of such an
implant is painful, can cause significant bruising and discomfort
at the implant site and requires local anaesthesia on both
insertion and removal. In addition, as such implants are placed
under the skin in for example the arm, they can be visible and
cause discolouration of the skin. Furthermore, as the arm contains
many different types of tissue and planes of tissue, movement of
the implant along or through these tissue planes can occur. This
can mean the implant moves to locations other than where it was
placed during insertion which can lead to complications for the
patient, in particular during removal of the implant. Difficulties
with the Norplant.RTM. implant has led to it being withdrawn from
clinical use.
[0010] For gynaecological conditions, long term local drug delivery
through the vagina or endometrium is useful to deliver drugs to the
pelvic region and organs thereof for example to the bladder,
peritoneum, vulva, vagina, ovaries and uterus.
[0011] Current delivery means include vaginal creams, gels,
intrauterine devices (contraceptive coils, IUD or IUCD) and vaginal
rings or tampons.
[0012] Intrauterine devices (IUDs) are placed in the endometrial
cavity typically to provide a contraceptive effect. For example,
Leiras (Schering AG) market an intrauterine device called Mirena
which releases 20 mcg of levonorgestrel, to reduce the thickening
of the endometrium of the uterus, each day for up to 5 years.
[0013] Vaginal rings, comprising soft plastic rings of around 4 cm
to 5 cm in diameter impregnated with a desired drug, are placed in
the vagina around the cervix where they slowly release a drug into
the bloodstream through the soft tissue of the cervix. Organon's
Nuvaring releases oestrogen/progesterone.
[0014] Although the above provide long term local drug delivery to
the pelvic region, for various reasons, they tend to suffer from
low levels of patient compliance.
[0015] Typically creams and gels are considered by patients to be
messy and unhygienic while vaginal rings can be uncomfortable,
particularly during sexual intercourse, and may cause discharge.
Intrauterine devices require inconvenient regular visits to the
clinic for physician fitting and can cause severe discomfort such
as stomach cramps due to the direct application of levonorgestrel
to the endometrium of the uterus. In addition, such intrauterine
devices may cause discharge, menstrual disturbance and fertility
effects.
[0016] It is an aim of the present invention to provide means to
deliver medicaments to the pelvic region which minimises the above
difficulties.
[0017] According to the present invention there is provided an
implantable medicament delivery device which is insertable into the
myometrium or prostate comprising means capable of providing
controlled delivery of a medicament over a period of time.
[0018] A medicament may be any pharmaceutical, neutraceutical,
prophylactic or therapeutic agent wherein a therapeutic agent
includes, but is not limited to, means for radiotherapy such as
radioactive sources for example caesium, iridium, radioactive
iodine, radioactive strontium or radioactive phosphorus.
[0019] The term "medicament" herein also includes energy sources
which may be delivered to the myometrium by targeting the delivery
device. Such energy sources include electromagnetic radiation,
heating and cooling energies such as to selectively destroy
tissues.
[0020] Preferably the medicament delivery device is an implant
which can be insertable into the myometrium, or prostate and
retainable therein for a defined period of time.
[0021] The retention of the implantable delivery device in the
myometrium (in females) or prostate (in males) provides for direct
and local delivery of a medicament to the pelvic region and organs
thereof for example the bladder, peritoneum, bloodstream and in
females the vulva, vagina, ovaries, fallopian tubes and uterus over
a determined period of time.
[0022] Preferably the implantable delivery device is capable of
being insertable in and retainable in the smooth muscle myometrial
tissue of the cervix.
[0023] Insertion and retention of the implantable medicament
delivery device in the myometrium of the cervix enables the implant
to be checked and monitored by speculum examination or other
visualisation or palpation following implantation.
[0024] Alternatively the implantable delivery device may be
inserted in any suitable location in the myometrium, usually of the
body of the uterus. The implant may be placed in the myometrium of
the body of the uterus, or other positions not accessible by access
via the vagina.
[0025] Preferably the implantable medicament delivery device
comprises a body having an outer surface and opposing first and
second ends said body comprising a medicament wherein the first end
of the body is a semi-sharp point.
[0026] A semi-sharp point enables the tissue to be sufficiently
disrupted to allow insertion of the implantable device, but causes
minimal tissue damage.
[0027] In one preferred arrangement the body of the device is
elongate and the second end of the body includes a head portion
wherein the head portion is a lateral extension from the
longitudinal axis of the elongate body.
[0028] Preferably the head portion is a substantially flat plate
which extends in all radial directions from the second end of the
body of the device.
[0029] The provision of a semi-sharp point at a first end of the
delivery device is advantageous as it allows the device to be
easily inserted into the smooth muscle of the myometrium or the
tissue of the prostate.
[0030] Preferably the means capable of providing the controlled
delivery of a medicament over a period of time is a
pharmaceutically acceptable carrier such as at least one of a
hydrogel, a silicone based material, elastomer, proteinaceous
material, polyethylene glycol (PEG) material, polysaccharide or
other carbohydrate material, microspheres, polymeric material or
plastics material which may comprise, be contained by, or coated
onto the device, or other means known to those skilled in the
art.
[0031] Preferably the means capable of providing the controlled
delivery of a medicament are present in the body of the device.
[0032] Alternatively, in those embodiments wherein there is a head,
the means capable of providing the controlled delivery of a
medicament may be present in the head of the device.
[0033] In particular embodiments the means are present in both the
body and the head of the device.
[0034] In embodiments where the means capable of providing the
controlled delivery of a medicament are provided in the body of the
device, medicament delivery is substantially through the myometrium
to the tissues and organs of the pelvic region.
[0035] In embodiments where the means capable of providing the
controlled delivery of a medicament are provided in the head of the
device, medicament delivery is substantially to the vaginal cavity
and tissues and organs of the pelvic region.
[0036] Preferably the second end of the device includes retrieval
means.
[0037] Retrieval means are advantageous as they allow the implant
to be removed from the myometrium or prostate tissue after a
determined period of time. Thus the delivery device can be easily
removed from the body and does not require to be retained in the
body forever. Removal of the implantable device provides a means of
control over the length of time an active agent of a medicament is
delivered.
[0038] The retrieval means can be any means which allow the removal
of the implantable device from the myometrium or the prostate
following a determined period of time.
[0039] In arrangements of the device which are insertable and
retainable in the myometrium, preferably the retrieval means
comprises an elongate flexible member, for example a thin length of
cord, twine or fibre or string.
[0040] Preferably the elongate flexible member can be left outside
the myometrium and soft tissue surrounding the uterus and/or
vaginal cavity without causing irritation to a patient, nor
affecting sexual intercourse. When it is desired to remove the
implantable delivery device from the tissues in which the implant
is inserted, for example the myometrium, the flexible member can be
manipulated to pull the implant out of the tissue.
[0041] Preferably the second end of the device for example the head
and/or retrieval means remain visible or palpable during
examination by a physician when, in use, the delivery device is
inserted into the myometrium or prostate.
[0042] This is advantageous as the location of the implantable
delivery device can be easily monitored and checked by visual or
physical inspection.
[0043] Preferably, the overall implantable device of the present
invention is significantly smaller than the overall size of coils,
IUD or vaginal rings. This is advantageous as there will be less
discomfort to the person in which the drug delivery device is
implanted and less likelihood of rejection of the implant by the
body or responses such as inflammation.
[0044] Preferably the device has an axial length in the range 5 mm
to 45 mm.
[0045] More preferably the device has an axial length in the range
10 mm to 45 mm.
[0046] Preferably the device has a diameter of from 0.5 mm to 4
mm.
[0047] Preferably the body has a large surface area to volume
ratio. This has the advantage of providing maximal absorption of
the drug into the surrounding tissues and/or smooth muscle.
[0048] The device of the present invention may be used to deliver a
wide range of active agents for example, but not limited to,
steroids, hormones such as a progestin, agents which promote a
contraceptive effect, for example levonorgestrel or etonorgestrel,
agents for treating disorders of the pelvis, for example, GnRH
analogues, NSAIDs, COX-II inhibitors and aromatase inhibitors,
vagina and organs and tissues thereof, cytotoxic agents for killing
cancer cells or treating cancer, particularly cancer cells of the
bladder, prostate or cervix or other pelvic malignancies and agents
for the treatment of benign prostatic hypertrophy, impotence,
erectile dysfunction and the like. Further, the device may be used
to deliver agents for the treatment of an over active bladder, such
drugs including anti-cholinergic drugs or calcium antagonists, or
agents for radiotherapy.
[0049] Preferably the medicament of the device is chosen from the
group consisting of, but not limited to, anti-infectives,
antimicrobials, antivirals, antibiotics, anti-allergenics,
anti-inflammatories, anti-fungals, anti-cholinesterases,
nutritional agents such as essential amino-acids, fats and
vitamins, prebiotics, probiotics and acidifiers, cardiovascular
agents, anti-hypertensive agents and chemotherapeutic agents.
[0050] Preferably the medicament is a therapy for oestrogen
dependent proliferative disorders of the pelvis, for example
endometriosis and/or fibroids and other pelvic disorders as would
be known to those skilled in the art for example functional cysts
and polycystic ovary syndrome.
[0051] Preferably said therapy for endometriosis includes
progestins, GnRH agonists and antagonists, NSAIDs, COX-II
inhibitors, combined oral contraceptives, Danazol, smooth muscle
relaxants or aromatase inhibitors. The skilled person would also
appreciate other similar therapies which could be used in relation
to such disorders and the suitable dosage that would be
required.
[0052] A drug delivered by the present invention may additionally
or alternatively include a microbicide. A microbicide is any agent
detrimental to, or destructive of, the life of microbes, viruses or
bacterial organisms. Such a microbicide could be used to destroy
organisms responsible for sexually transmitted diseases such as
gonorrhoea, chlamydia, genital herpes, Human Immunodeficiency
Virus, Human Papilloma Virus or bacterial vaginosis.
[0053] The concentration and the time period over which the above
active agents and those described below should be provided will be
as determined by those skilled in the art. Those skilled in the art
can determine these parameters, which depend on for example the
potency (the amount required to effect the desired change),
toxicity and in vivo diffusion of the active agent using standard
procedures.
[0054] Preferably, in use, the cumulative release of therapeutic
agent is in an amount selected from 5%, 10%, 15%, 20%, 25%, 30%,
40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% and 100% relative to the
total amount of medicament in the device after implantation for a
period of 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 6
months, 1 year, 2 years, 3 years, 4 years or 5 years.
[0055] According to a second aspect of the present invention there
is provided a kit for implanting a device of the first aspect of
the invention comprising [0056] a device according to the first
aspect of the invention and an insertion tool, said tool comprising
an elongate shaft, said shaft having handle means at a first end
thereof and device mounting means at a second opposite end wherein
the medicament delivery device of the first aspect of the invention
is mountable on the insertion tool.
[0057] According to a third aspect of the present invention there
is provided a method of providing a medicament to a female mammal
comprising the step of inserting a device according to a first
aspect of the invention into the myometrium.
[0058] The implantable delivery device is capable of being inserted
into the smooth muscle myometrial tissue of the cervix via the
vagina, into the myometrium of the uterine body through serosa
surrounding the myometrium during open or laparoscopic surgery or
into the myometrium through the endometrial cavity.
[0059] Preferably the method of the third aspect of the invention
comprises the steps of [0060] a) providing the implantable
medicament delivery device of the first aspect of the invention,
[0061] b) introducing the medicament delivery device into the body
via the vagina, [0062] c) penetrating the myometrium with the
medicament delivery device, and [0063] d) inserting the medicament
delivery device into the myometrium.
[0064] Preferably the method further comprises the step of mounting
the implantable medicament delivery device on an insertion tool
articular embodiments of the medicament delivery device are
implantable in the prostate. The prostate is a gland in males which
surrounds the urethra below the bladder.
[0065] Preferably the implant is insertable into the prostate by a
transrectal route. Alternatively the implant can be inserted into
the prostate by a trans-perineal route.
[0066] Preferably the medicament delivery device is insertable into
the prostate using ultrasound.
[0067] Provision of an implantable medicament delivery device in
the prostate has the advantage that drugs can be delivered to the
tissue of the prostate, tissue surrounding the prostate, and the
bloodstream. Further, delivery of drugs directly to the prostate
means the drugs are not subjected to liver metabolism as would be
the case for drugs provided orally.
[0068] Preferably the prostate implantable medicament delivery
device provides for the cumulative release of a therapeutic agent
in an amount selected from 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%,
60%, 70%, 80%, 90%, 95%, 99% and 100% relative to the total amount
of medicament in the device after implantation for a period of 1
week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 1
year, 2 years, 3 years, 4 years or 5 years.
[0069] According to a fourth aspect of the present invention there
is provided the use of a delivery device according to the first
aspect of the invention to provide long term local delivery, for
example 3 months to 5 years, of medicaments to the pelvic region
and organs thereof, for example to the bladder, peritoneum, vulva,
vagina, ovaries and uterus.
[0070] In one preferred embodiment of the fourth aspect of the
invention a device according to the first aspect of the present
invention is used to deliver medicament(s) to treat gynaecological
conditions, for example endometriosis, fibroids, cervical cancer or
overactive bladder.
[0071] In a second preferred embodiment of the fourth aspect of the
invention a device according to the first aspect of the present
invention is used to treat male conditions for example benign
prostatic hypertrophy, impotence, erectile dysfunction and the
like.
[0072] The medicament delivery device and method of the present
invention promote smooth, controlled release of drugs to the pelvic
region, which allows absorption of drugs without subjecting drugs
to liver metabolism.
[0073] Embodiments of the present invention will now be described
by way of example only with reference to the accompanying drawings,
in which:
[0074] FIG. 1 is an illustration of an implantable medicament
delivery device according to the invention for delivery of
medicament to the tissues of the myometrium and pelvic region;
[0075] FIG. 2 is an illustration of an implantable medicament
delivery device according to the invention for delivery of
medicament to the tissues of the vaginal cavity and pelvic
region;
[0076] FIGS. 3, 4, 5 and 6 are illustrations of embodiments of the
medicament delivery device according to the invention;
[0077] FIG. 7 is a saggital illustration of the female pelvic
region of a medicament delivery device of FIG. 1 in use;
[0078] FIG. 8 is an end view of the illustration in FIG. 4 along
the line A-A illustrating the placement of the device;
[0079] FIG. 9 is a coronal view of the illustration in FIG. 4 along
line B-B;
[0080] FIG. 10 shows an illustration of the embodiment of a
medicament delivery device as shown in FIG. 1 mounted on an
insertion tool;
[0081] FIG. 11 shows an illustration of the embodiment of a
medicament delivery device as shown in FIG. 2 mounted on an
insertion tool;
[0082] FIG. 12 shows an illustration of an embodiment of device
mounting means wherein the mounting means are formed by a stepped
protrusion on the insertion tool capable of cooperating with a
depression provided on the delivery device;
[0083] FIG. 13 shows an embodiment of a handle means of an
insertion tool; and
[0084] FIG. 14 is an illustration of an embodiment of an implant of
the present invention inserted in the prostate.
[0085] Referring to FIG. 1, in one embodiment, the implantable
medicament delivery device comprises an elongate cylindrical body 2
with a first end 4 and a second end 6. In this embodiment head
portion 8 extends laterally from the second end 6 of the body 2
such that a flange is provided around the circumference of the body
2 at the second end. A semi-sharp point 10 is provided at the first
end 4 of the body 2. In the embodiment shown the head portion 8 is
a substantially flat plate which includes a depression 12. When, in
use, the body of the device is implanted in the tissues of the
myometrium, the head portion 8 minimises the likelihood of the
tissue of the implant being pushed too far into the tissue during
insertion of the implant or the myometrium tissue growing over the
implant. It also provides means by which the position of the
implant can be checked by visual or physical means.
[0086] In the embodiment described which is insertable into the
myometrium, retrieval means 14 are provided by a cord. The cord
extends substantially from the centre point of the depression 12 in
the head portion 8. In use, the cord extends from the second end of
the implant and allows the device to be removed from the tissue
after suitable delivery of the medicament or if the patient
requests removal. The device is typically retained in the body for
at least a day, a few weeks, months or up to 5 years. It may be
removed at any point during this period. In embodiments wherein the
device is comprised of biodegradable material the device may not
need to be removed at a later time point and thus will not require
a head portion or retrieval means.
[0087] In this embodiment the means capable of providing controlled
delivery of the medicament is located in or on the elongate body 2
of the device. Delivery of the medicament is substantially through
the myometrium and into pelvic organs and tissues. This embodiment
of the device is particularly advantageous for the delivery of
medicament for the treatment of endometriosis and or fibroids.
[0088] FIG. 2 shows an embodiment of the present in invention
wherein the elongate body 2 may be shorter in length, approximately
5 mm to 20 mm in length and in which the head portion 8 is larger
typically around 12 mm in width. In such an embodiment the means
capable of providing controlled delivery of a medicament over a
period of time is located in or on the head portion.
[0089] In use, the body 2 is inserted in the tissues of the
myometrium and the head portion remains in the vaginal cavity. This
embodiment of the device substantially delivers medicament to the
vaginal cavity, mucosa thereof and pelvic tissues, such an
embodiment is particularly advantageous for delivery of medicaments
suitable for treating bacterial vaginosis.
[0090] Alternative embodiments of the implantable device are
illustrated by FIGS. 3 to 6. In these embodiments the body of the
implant may be spiral or corkscrew shaped (FIG. 3), generally J or
U shaped such that the second end of the implant forms a loop or
hook (FIGS. 4 and 6) or an elongate mesh cylinder (FIG. 5). As
shown in FIG. 4 a semi-sharp point may not be required at the first
end of the body 4 to allow insertion into the tissues.
[0091] The body may be any suitable shape which allows the implant
to be inserted into the myometrium or prostate. Indeed the cross
section of the body can be of any preferred shape, which allows
insertion of the implant into the myometrium or prostate, or that
influences the drug delivery characteristics of the implantable
delivery device. For example the body of the device may be
cross-shaped to increase the surface area of the delivery device
exposed to the surrounding tissue. Further, the body may be formed
by a mesh or other method to increase the surface area of the
implant in contact with the myometrial or prostate tissue. The
amount of surface area of the implant in contact with surrounding
tissue or muscle can influence the drug delivery characteristics of
the implant.
[0092] As shown in FIGS. 4 and 6 the retrieval means may comprise a
hook at the second end of the implantable device wherein the second
end of the body 2 is bent toward the first end to provide a hook.
In this embodiment the retrieval means restricts the body 2 from
becoming buried in the soft tissue enabling retrieval of the
implant from soft tissue and the smooth muscle of the myometrium or
the prostate. In addition, the hook provides means by which the
location of the implant can be checked by a physician by visual or
physical means.
[0093] Alternatively, as shown in FIG. 3, the retrieval means can
be a slot capable of accepting a screwdriver or other means for
rotating the implantable delivery device in the tissue to insert or
remove the device from the tissue.
[0094] In the embodiment illustrated by FIG. 1 the body 2 comprises
the medicament delivery means. In particular embodiments, not shown
in FIG. 1, a length of the body 2 between the point 4 and retrieval
means 14 may have a reduced diameter relative to the diameter of
the body 2 at the first 4 and second ends 6. In such embodiments
the drug delivery means may comprise a cylinder of material formed
around the reduced diameter portion of the body 2. The medicament
delivery means can be any suitable pharmaceutically acceptable
carrier for example, a hydrogel carrying the active agent to be
delivered by the medicament delivery device. In another example,
the delivery means is a silicone based material, elastomer,
proteinaceous material, polyethylene glycol (PEG) material,
polysaccharide or carbohydrate material, microspheres, polymeric
material or plastics material which may comprise, be contained by,
or coated onto the device. The above drug delivery devices may also
comprise, be contained by, or coat the head 8 of the device. This
allows, as discussed in relation to the embodiment illustrated in
FIG. 2, for delivery of medicament to the vaginal cavity.
[0095] In a preferred embodiment, the body of the implant which may
be porous, non-porous or microporous, can be dipped into a solution
of the selected drug delivery medium containing a solution or
slurry of drug, such that a thin layer of drug and drug delivery
medium is coated onto the body of the implant and bonds securely in
the dry state to the body of the implant via a mechanical or
adhesive hold.
[0096] Alternatively, the medicament can be impregnated, or
absorbed by or into the device and allow the medicament to be
released over time. As a further alternative the medicament may be
applied to the device using any suitable means that allow the
medicament to be attached or bonded to the device and which allow
the medicament to be available for absorption/release into the
surrounding tissues, for example the myometrium or vaginal
cavity.
[0097] The drug delivery medium may be capable of slowly releasing
the active agent of the medicament into the myometrium, vaginal
cavity or the prostate, and thus providing drugs to the pelvic
region and organs thereof the surrounding soft tissues and blood
vessels.
[0098] Hydrogel releases drug by diffusion or via microcracks in
the hydrogel. An alternative biodegradable hydrogel system releases
drug via an erosion or degradation mechanism. Varying release rates
of drugs can be achieved, as can continuous dosing with small
levels of drugs, and flexibility of drug release may depend on
different drugs being utilised
[0099] Depending of the release characteristics of the hydrogel and
the chemical composition of the active agent; release of the active
agent will typically occur up to 5 years from implantation of the
delivery device.
[0100] The medicament delivery device may be formed by any
biocompatible material, for example the medicament delivery device
can be formed from plastics or biocompatible metals. Suitable
materials include, but are not limited to, high density
polyethylene (HDPE), ultra high molecular weight polyethylene
(UHMWPE), polypropylene (PP), polyvinyl chloride (PVC),
polymethylmethacrylate (PMMA), polyethyleneterephthalate (PET),
polytetrafluoroethylene (PTFE), polycarbonate (PC),
styrene-butadine-styrene (SBS), stainless steel (361/316L/317),
nickel free stainless steel, cobalt chrome alloy (CoCrMo), titanium
(specifically Ti6Al4V) and Liquid Metal.
[0101] In one particular embodiment of the delivery device, the
delivery device is formed from the medium carrying the drug. In
this example, if the medium carrying the drug is absorbable, the
complete delivery device may be absorbed by the body over the
period of time that the drug is administered.
[0102] Wherein the implant itself is the medium by which the drug
to be administered is carried it can be envisaged that an insertion
device for example a trocar containing the implant may be used to
deliver the implant. In this embodiment the delivery device may be
pushed out of or injected from the trocar into the myometrium 44.
The use of an implant comprising the medium in which the drug to be
administrated is included, would allow insertion of the implant
into the myometrium 44 and delivery of the drug to be limited to a
shorter time scale for example 1 day, 3 months to 12 months. The
implant would not require to be removed at a later date as it may
degrade over time and be absorbed by the body.
[0103] The drug may be delivered to the myometrium 44 and be
absorbed within a few minutes, hours, days or weeks depending on
the medium. It can be appreciated that where the implant comprises
the drug delivery medium, removal of the implant is not required.
An absorbable implant therefore does not require retrieval
means.
[0104] The uterine myometrium has few or no somatic pain fibres and
thus insertion, provision and withdrawal of the implant in the
myometrium will cause minimal pain and discomfort to the
patient.
[0105] A device of the present invention capable of being implanted
into the myometrium tissue is advantageous over subcutaneous
delivery devices previously known in the art, such as Norplant.RTM.
which are inserted under the skin which has somatic sensory (pain)
nerves.
[0106] As there is little tissue or muscle movement in the
myometrium compared with for example the tissues of the arm or the
leg and the myometrium does not comprise as many layers or planes
of tissue as in the arm or leg, there is little likelihood of the
implant moving to a different location following insertion.
[0107] As shown in FIG. 7, the female human genital area comprises
a bladder 30, urethra 32, vaginal cavity 34, cervix 36, uterus 38
and anus 40. In particular, the cervix 36, at a position between
the vaginal cavity 34 and uterus 38, comprises the cervical canal
42 leading from the vaginal cavity 34 into the uterus 38 and
surrounding smooth muscle known as the myometrium 44. The
myometrium is defined by the serosa 46 (an epithelial layer of
cells) and the endometrium 48. An end view of the cervix along line
A-A is shown in FIG. 8.
[0108] In use, an embodiment of the implant can be inserted into
the myometrium via the vagina and then through the cervix or
alternatively may be inserted into the myometrium during open or
laproscopic surgery.
[0109] The myometrium of the cervix is in a convenient location, at
the top of the vaginal cavity, for insertion and removal of the
implant via vaginal access. Further insertion of the device by this
route has the advantage that the implant can be suitably located
using a speculum in an outpatient setting. The insertion of the
implant in the myometrium would be similar in both the time taken
and the discomfort to the patient as the taking of a smear.
[0110] Insertion of the implantable medicament delivery device
during open or laproscopic surgery has the advantage of allowing
the implant to be placed at any suitable location in the
myometrium, usually in the body of the uterus. The implant may thus
be placed in the myometrium of the body of the uterus, or other
positions which would not be accessible by access via the
vagina.
[0111] Location of the implant within the smooth muscle myometrial
tissue of the cervix and uterus provides a novel means of drug
delivery to the pelvic region and organs thereof for example to the
bladder, peritoneum, vulva, vagina, ovaries and uterus. Local
delivery of active agents of a medicament via insertion of the
implant in the uterine myometrium promotes rapid, efficient
absorption of the active agent directly into these organs the
surrounding tissue and then the bloodstream. Further, delivery of
medicaments in this way avoids the first pass liver effect.
[0112] The active insertion of the implantable delivery device into
the smooth muscle of the cervix of the uterine body means that the
present invention differs from an IUD or a vaginal ring as an IUD
is located in the cavity of the uterus (endometrium) and vaginal
rings are placed at the top of the vagina around the cervix.
[0113] While inserted in the myometrium the device will not be felt
by the patient. As previously discussed, this provides a further
advantage of the present invention over intrauterine devices and
vaginal rings. Furthermore, the device of the present invention
will not cause menstrual or fertility disturbances and will be
acceptable to women of a range of religious faiths.
[0114] Moreover, drug delivery by means placed around tissues or in
cavities such as vaginal rings and intrauterine devices can suffer
from decreased absorption as the active agents have to pass through
epethelial layers overlying the surrounding tissues before they
enter the tissue. For example, drugs released from a vaginal ring
must pass through the vaginal epithelium before being absorbed into
the vaginal wall and passing into the blood stream.
[0115] Locating medicament delivery means and delivery of the
medicament in the myometrium minimises the risk of poor absorption
as the active agents are not required to pass through epithelium.
Medicament absorption is facilitated by high local blood flow.
[0116] In particular embodiments locating medicament delivery means
in the myometrium and delivery of the medicament into the vaginal
cavity enables delivery to the epithelium lining the vagina and the
local tissues thereof.
[0117] Therefore drug delivery directly into the myometrium or
vagina will likely require smaller amounts of a drug to achieve
significant clinical affect, substantially reducing the risk of
side effects.
[0118] In specific embodiments of the medicament delivery devices,
suitable for delivery of drugs to the tissues of the myometrium,
for example FIG. 1, the body 2 of the medicament delivery device
typically has a diameter of 2 mm and a length of 20 mm. These
diameters and lengths are, of course, for guidance only and other
suitable dimensions will be apparent to those skilled in the art.
For example depending of the amount of drug to be delivered the
length of the body may be 20 mm or 30 mm.
[0119] FIG. 2 shows an embodiment of the device for delivery of
drugs to the vaginal cavity. In this embodiment, the body is
preferably around 5 to 10 mm in length and the head is around 8 to
15 mm in width.
[0120] The implant may have any structure suitable for insertion
and retention in the smooth muscle of the myometrium or the tissue
of the prostate. For example the implant may comprise barbed
portions or surface patterns to promote retention of the implant in
the myometrium or prostate. This may be advantageous if movement of
the tissue in which the implant is inserted is likely to cause the
implant to work loose and move from its intended position.
[0121] To aid insertion of the medicament delivery device into the
myometrium by a vaginal route an insertion tool may be used.
[0122] An embodiment of an insertion tool is shown in FIGS. 10 and
11 with the implantable devices illustrated by FIG. 1 and 2
respectively mounted thereon. In the embodiment shown, the
insertion tool comprises a curved stainless steel shaft 60 of
approximately 20 to 25 cm in length and around 2 mm in diameter. A
handle element 62 of around 2 to 4 cm may be provided on the shaft.
A particular embodiment of a handle element is illustrated in FIG.
13.
[0123] A first end of the shaft is provided with device mounting
means 74 and a second end is provided with handle means 62. In the
example shown the device mounting means, illustrated more clearly
in FIG. 12, comprises a stepped protrusion 66 which provides a
surface 68 against which the second end of the implantable device
can abut. In particular, as shown in FIG. 12 a protruding portion
70 of the device mounting means is received by the depression 12
provided on the head portion 8 of the implantable device. The cord
14 of the implantable device is pulled along the length of the
shaft 60 and is releasably fixable in a notch 72 provided in the
handle means 62 of the insertion tool. The fixing of the cord 14 in
the notch 72 aids the mounting of the device on the shaft of the
insertion tool.
[0124] The device is mounted on the first end of the insertion tool
and then the device is introduced into the body via the vagina.
Using the insertion tool the device is advanced into the vagina 34
towards the cervix 36 and inserted into the myometrium 44. The
point 4 of the implant facilitates the easy insertion into the
smooth muscle of the myometrium 44.
[0125] The device is inserted into the myometrium until only the
head portion of the device or retrieval means remain outside.
[0126] After a determined period of time, the implant can be
removed from the myometrium. Removal may be due to the implant
reaching the end of its useful life, i.e. the drug has been
administered for the intended length of time or the patient
requesting removal of the implant. The implantable delivery device
can be removed by pulling on the retrieval means 14, for example a
cord or hook to withdraw the implant from the myometrium 44. Again,
this is a straightforward procedure without routine need for local
anaesthetic.
[0127] The delivery device is typically removed from the tissue
after it has released a therapeutic agent in an amount selected
from 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,
95%, 99% and 100% relative to the total amount of medicament in the
device after implantation for a period of 1 week, 2 weeks, 1 month,
2 months, 3 months, 4 months, 6 months, 1 year, 2 years, 3 years, 4
years or 5 years.
[0128] Alternative insertion tools may be used to insert the
device.
[0129] For example if the implant has a blunt first end 4, as
illustrated in FIG. 4, an insertion tool with a semi-sharp point
may be used to penetrate the myometrium or prostate tissue and
enable insertion of the implant.
[0130] This may be advantageous, as the implant which is retained
in the tissue does not then require to have a semi-sharp
portion.
[0131] In further embodiments of the insertion tool, instead of or
in addition to device mounting means, the insertion tool may
comprise means for releasably containing the implant within the
tool. This embodiment of the insertion tool is driven into the
myometrium, the implantable device is released into the myometrium
and the tool is then withdrawn leaving the implant in place. For
example, the insertion tool may comprise a collar for releasably
retaining the medicament delivery device.
[0132] During insertion, use and removal the implantable device may
be manipulated using any suitable surgical tool, such as forceps or
the like.
[0133] As discussed above, the implantable medicament delivery
device can be provided with medicament for release into the
surrounding tissues in a number of ways.
[0134] Where the medium carrying the active agent of the medicament
is provided by the body of the delivery device, the agent is
released from the medium and passes through drug delivery means
present in the delivery device to enter the surrounding tissue, for
example the myometrial tissues. Drug delivery means may be provided
along the entire length, at least part of the body, the head, or
the body and head of the implantable device.
[0135] When inserted in the myometrium the body of the medicament
delivery device is surrounded by smooth muscle and soft tissue. As
smooth muscle of the cervix is highly vascularised, drug delivery
to these tissues show good pharmacokinetics.
[0136] These drugs are able to pass through the highly vascularised
tissues of the myometrium and target the pelvic region and organs
thereof, for example, the bladder, peritoneum, and in females the
vulva, vagina, ovaries and uterus. The drugs may further enter the
bloodstream without being subjected to first pass liver
metabolism.
[0137] Alternatively, drug delivery means may be provided at the
head portion at the second end of the delivery device. When, in
use, the implant is inserted into myometrial tissue, the head
portion protrudes from the myometrial tissue into the vagina. In
this particular embodiment, the implant provides a means of
targeting drug delivery to the tissues of the vagina.
[0138] The implantable delivery device may be retained in the
myometrium or the prostate and drug delivered over a period of at
least, 1 day, 1 to 3 months, 1 to 6 months, 1 to 12 months, 1 to 2
years, 1 to 3 years or 1 to 5 years.
[0139] The implant of the present invention may be used to deliver
a wide range of drugs. In particular, the implant can be used to
deliver drugs which cannot be delivered orally.
[0140] Examples of conditions which can be treated using the drug
delivery device will now be provided.
Endometriosis
[0141] Endometriosis is a painful condition caused by the
endometrium (cells lining the uterus) migrating to other parts of
the body. This can cause functional and hormonally responsive
endometrial lesions. Typically lesions are found on the uterine
muscles, ovary, peritoneum and intestine. Symptoms of endometriosis
include excessive bleeding, dysmenorrhoea, pelvic pain and
infertility (up to 60% of women suffering from endometriosis become
infertile).
Fibroids
[0142] Fibroids or myoma are benign encapsulated tumours of the
smooth muscle and/or fibrous tissue elements of the uterine
myometrium. They are usually asymptomatic, but may give rise to
menstrual and/or fertility problems.
[0143] At present, an oral treatment (Danazol) is one of the most
effective drugs to treat endometriosis, but the androgenic side
effects of this drug limits treatment to 6 months. Endometriosis
can also be treated using subcutaneous depot injections or nasal
sprays of GnRH analogues. However, these treatments also have
unpleasant side effects such as bone density loss, hot flushes and
nausea.
[0144] The present implantable medicament delivery device provides
pharmacokinetic advantages over the above for the treatment of
endometriosis and fibroids. In particular the present delivery
system provides long term delivery of a drug locally to the pelvic
region, without the disadvantage of current local delivery systems
such as vaginal rings or intrauterine devices.
[0145] A number of active agents may be provided using the device
of the present invention for treatment of endometriosis.
Progestin
[0146] Progestins have advantages over Gonadotrophin Releasing
Hormone (GnRH) Agonists in that they are cheaper with an improved
side effect profile. In addition, Progestin therapy is most
effective in controlling the symptoms associated with
endometriosis, more specifically dysmenorrhea.
[0147] Progestin refers to synthetic progestogens wherein
Progestogen is a generic term for all substances with progesterone
like activity. Progesterone refers to the natural progesterone
molecule.
[0148] There are two main groups of progestogen, progesterone and
its analogues (dydrogesterone, gestrinone and medroxyprogesterone)
and testosterone analogues (norethisterone and norgestrel). The
newer progestogens (desogestrel, megestrol, norelgestromin,
norgestimate, etonogestrol, etynodiol or ethynodiol and gestodene)
are all derivatives of norgestrel; levonorgestrel is the active
isomer of norgestrel and has twice its potency. Progesterone and
its analogues are less androgenic than the testosterone
derivatives. Testosterone analogues are the norethindrone family
(estranes)--including norethindrone, norethindrone acetate,
ethynodiol diacetate, lynestrenol, and norethisterone acetate; and
the levonorgestrel family (gonanes)--including levonorgestrel,
norgestrel, desogestrel, norgestimate, gestodene, megestrol,
norelgestromin, and etonogestrol.
[0149] Common progestins include medroxyprogesterone and
levonorgestrel.
Non Steroidal Anti Inflammatory Drugs (NSAIDS)
[0150] Non Steroidal Anti Inflammatory Drug (NSAIDs) have good
efficacy, low cost and comparatively mild side effect profile, and
offer immediate pain management. They are most effective in
controlling the symptoms associated with endometriosis. Common
NSAID's include mefenamic acid, diclofenac or piroxicam.
GnRH Analogues
[0151] The main therapy shown to improve the severity of
endometriosis is the gonadotrophin releasing hormone (GnRH)
agonists.
[0152] However, this class suffers two main drawbacks, these being
cost and severe side effects profile primarily bone density loss
associated with inducing a temporary chemical menopause. Common
GnRH agonists include leuprolide, goserelin and nafarelin.
[0153] In addition to the above sole therapies the device of the
present invention can also be used to deliver a number of
combination therapies. For example, [0154] Progestin/NSAID,. [0155]
Progestin/GnRH analogues, [0156] GnRH/NSAID or, [0157] GnRH add
back therapy (tibolone) GnRH with Add Back Therapy
[0158] Add-back therapy in conjunction with a GnRH agonist does not
eradicate bone loss, however it does reduce the rate of bone
demineralization and hence, enable longer use of GnRH agonists. The
progestin tibolone is of particular interest for use as add back
therapy, particularly for osteoporosis prophylaxis.
[0159] Owing to the poor solubility of all proposed drugs in water,
a hydrogel (flooded with water, thus low driving force only
required to release drugs) is ideally used as the drug carrier on
the implant. The porous but permeable active drug/carrier can be
coated onto the body of the implant via mechanical/adhesive hold.
In such an embodiment a microporous implant may be necessary. This
exterior coating of hydrogel/active drug may be biodegradable and
should be a highly concentrated but thin layer (high drug
reservoir/ low distance to travel) to obtain maximum rate of drug
release via an erosion mechanism.
[0160] The amount of drug required to elicit effect can be
determined by those skilled in the art, using conventional means.
However, estimates of the amount of a drug which may be provided
based on preliminary results which should not be considered
limiting in any way on the device of the present invention are
given below by way of example only.
Levonorgestrel
[0161] Currently, oral daily doses for levonorgestrel are 60 mcg.
Using vaginal delivery analogy of 10% drug required compared to
oral doses, daily myometrial doses would be 6 mcg for
levonorgestrel
[0162] A more feasible daily dose to enable drug delivery via a
hydrogel would likely be 20 mcg for levonorgestrel (33% of oral
dose) Assuming 50% w/w of drug to hydrogel, the total weight of the
drug/carrier layer could be in the range of 3 to 15 mg.
[0163] The body of the implant could accommodate 3, 6 or 12 month
or longer doses.
Leuprolide
[0164] Currently, the daily dose for leuprolide is 125 mcg
(intramuscular). Typical daily myometrial doses could be around 62
mcg for leuprolide (50% of intramuscular dose)
[0165] However in the absence of clinical data, it is impossible to
estimate the clinical effectiveness of such doses of
leuprolide.
[0166] Assuming 50% w/w of drug to hydrogel, the total weight of
the drug/carrier layer would be in the range of 10 m to 45 mg.
[0167] The body of the implant could accommodate 3, 6 or 12 month
or longer doses.
Piroxicam
[0168] Currently, oral daily doses for piroxicam are 10 to 40 mg.
Using vaginal delivery analogy of 10% drug required compared to
oral doses, a daily myometrial doses could be 3 mg for piroxicam. A
more feasible daily dose to enable drug delivery via a hydrogel
could be 300 mcg for piroxicam (1% of oral dose). However in the
absence of clinical data, it is impossible to estimate the clinical
effectiveness of such low doses of piroxicam.
[0169] Assuming 50% w/w of drug to hydrogel, the total weight of
the drug/carrier layer would be around 50 to 220 mg.
[0170] The body of the implant could accommodate 3, 6, or 12 month
or longer doses.
Levonorgestrel/Piroxicam
[0171] Currently, oral daily doses for levonorgestrel are 60 mcg,
and piroxicam 10-40 mg. Using vaginal delivery analogy of 10% drug
required compared to oral doses, daily myometrial doses could be 3
mg for piroxicam 6 mcg for levonorgestrel. A more feasible daily
dose to enable drug delivery via a hydrogel (levonorgestrel dose as
per Mirena coil dose) would be 300 mcg for piroxicam (1% of oral
dose), 20 mcg for levonorgestrel (33% of oral dose). However in the
absence of clinical data, it is impossible to estimate the clinical
effectiveness of such low doses of piroxicam.
[0172] Assuming 50% w/w of drug to hydrogel, the total weight of
the drug/carrier layer would be in the range of around 55 mg to 230
mg.
[0173] The body of the implant could accommodate 3, 6, 12 month or
longer doses.
Levonorgestrel/Leuprolide
[0174] Currently, daily doses for levonorgestrel are 60 mcg (oral),
and leuprolide 125 mcg (intramuscular). Using vaginal delivery
analogy of 10% drug required compared to oral doses, daily
myometrial doses could be 62.5 mcg for leuprolide and 6 mcg for
levonorgestrel. A more feasible daily dose to enable drug delivery
via a hydrogel would be 62.5 mcg for leuprolide (50% of
intramuscular dose) and 20 mcg for levonorgestrel (33% of oral
dose). However in the absence of clinical data, it is impossible to
estimate the clinical effectiveness of such low doses of
leuprolide.
[0175] Assuming 50% w/w of drug to hydrogel, the total weight of
the drug/carrier layer could be in the range of around 14 mg to 60
mg.
[0176] The body of the implant could accommodate 3, 6, 12 month or
longer doses.
Leuprolide/Tibolone
[0177] Currently, daily doses for leuprolide are 125 mcg
(intramuscular), and tibolone 2.5 mg (oral). Using vaginal delivery
analogy of 10% drug required compared to oral doses daily
myometrial doses could be 62.5 mcg for leuprolide (50% of
intramuscular dose) and 250 mcg for tibolone. However in the
absence of clinical data, it is impossible to estimate the clinical
effectiveness of such doses of leuprolide.
[0178] Assuming 50% w/w of drug to hydrogel, the total weight of
the drug/carrier layer would be in the range of around 55 mg to 225
mg.
[0179] The body of the implant could accommodate 3, 6 or 12 month
or longer doses.
Leuprolide/Piroxicam
[0180] Currently, daily doses for leuprolide are 125 mcg
(intramuscular), and piroxicam 10-40 mg (oral). Using vaginal
delivery analogy of 10% drug required compared to oral doses daily
myometrial doses could be 62.5 mcg for leuprolide and 3 mg for
piroxicam.
[0181] A more feasible daily dose to enable drug delivery via a
hydrogel could be 62.5 mcg for leuprolide (50% of intramuscular
dose) and 300 mcg for piroxicam (1% of oral dose). However in the
absence of clinical data, it is impossible to estimate the clinical
effectiveness of such doses of piroxicam and leuprolide.
[0182] Assuming 50% w/w of drug to hydrogel, the total weight of
the drug/carrier layer would be in the range of around 65 mg to 261
mg respectively.
[0183] The body of the implant could accommodate 3, 6 or 12 month
or longer doses.
Bacterial Vaginosis
[0184] Bacterial vaginosis, an abnormal colonisation of the vagina
which may lead to vaginitis, is an inflammation which occurs in the
vagina. It includes several strains of organism that cause
bacterial vaginosis, yeast infections and trichomoniasis. Bacterial
vaginosis occurs mostly during the reproductive years although
women of all ages are susceptible. Typically infection affects the
vagina, urethra, bladder and skin in the genital area.
[0185] Primary causes of bacterial vaginosis include an overgrowth
of anaerobic bacteria and the Gardnerella organism. Although the
healthy vagina includes a small amount of these bacteria and
organisms, when the vaginal balance is disrupted by the overgrowth
of these bacteria, another protective aerobic bacterium
(lactobacilli) is unable to adequately perform its normal function.
Lactobacilli normally provides a natural disinfectant (similar to
hydrogen peroxide) which helps maintain the healthy and normal
balance of microorganisms in the vagina. The vaginal anerobic to
aerobic bacteria ratio is 1000 to 1, normal vaginal flora is 5 to 1
ratio. During vaginosis a change in pH of vaginal fluid also
occurs.
[0186] Bacterial Vaginosis can cause a range of symptoms such as
discharge. In addition, the change in pH of the vaginal fluid to
more than 4.5 can also cause odour and some itching.
[0187] The medicament delivery device of the present invention may
be used to deliver medicaments to restore normal vaginal bacteria
by inhibiting anaerobic bacteria, but not the normal vaginal
lactobacilli, in order to eliminate symptoms of discharge and
odour.
[0188] In particular embodiments, one of which is illustrated in
FIG. 2 and discussed above, the medicament delivery device has a
body portion for insertion into the myometrium and a head portion
which extends into the vaginal cavity. The body portion is
preferably around 5 mm to 20 mm in length and the head portion is
around 10 to 12 mm in width.
[0189] In this embodiment the medicament is contained or absorbed
by or coated onto the head portion of the device such that it can
be released over time into the vaginal cavity. Any suitable
pharmaceutical means may be used to carry the drug and enable its
release over time to the vaginal cavity.
[0190] Drugs which may be used to treat bacterial vaginosis include
Flagyl (also known as Metronidazole), acidifiers to decrease pH to
less than 5, less than 4.5, prebiotics, and probiotics. Other
treatments include cleocin, ampicillin, ceftriaxone and
tetracycline. Other drugs suitable for treating bacterial vaginosis
such as pH regulators, suitable antibiotics and other drugs will be
known to those skilled in the art.
[0191] The location of the implant in the smooth muscle myometrium
of the cervix and/or part of the body of the smooth muscle
myometrium of the uterus allows the implant to be easily inserted.
During retention of the implant in the myometrium of the cervix,
straightforward examination of the vaginal cavity 34 by a medical
practitioner can verify that the implant is in its intended
position in the myometrium. Whilst there is little chance of the
implant becoming displaced, as the retrieval means, for example the
cord or hook and in particular embodiments the head portion remains
outside the myometrium, any such displacement can be easily
observed.
[0192] Various improvements and modifications may be made without
departing from the scope of the present invention. For example, as
detailed above the body of the implant may be formed from
absorbable polymers. This would avoid the need to remove the
implant at a later date. Any suitable retrieval means can be
provided on the implant to allow the implant to be moved into and
out of the tissue of the myometrium or prostate.
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