U.S. patent application number 10/528875 was filed with the patent office on 2006-06-22 for water-swellable polymers.
Invention is credited to Lilias Currie, Janet A. Halliday, Frank Koppenhagen, Mark Livingstone, Sarah Stewart, Jukka Tuominen.
Application Number | 20060134161 10/528875 |
Document ID | / |
Family ID | 9944922 |
Filed Date | 2006-06-22 |
United States Patent
Application |
20060134161 |
Kind Code |
A1 |
Halliday; Janet A. ; et
al. |
June 22, 2006 |
Water-swellable polymers
Abstract
A water-swellable linear polyurethane polymer is formed by
reacting a polyethylene oxide (e.g. PEG 4000 to 35,000), a
difunctional compound (e.g. a diamine or diol such as
1,10-decanediol) with a diisocyanate. The ratio of the three
components is generally in the range 0.1-1.5 to 1 to 1.1-2.5. The
polyurethane is water-swellable in the range 300 to 1700% and
soluble in certain organic solvents such as dichloromethane. It can
be loaded with pharmaceutically active agents, particularly of high
molecular weight, to produce controlled release compositions, such
as pessaries etc.
Inventors: |
Halliday; Janet A.; (West
Lothian, GB) ; Tuominen; Jukka; (Glasgow, GB)
; Livingstone; Mark; (Irvine, GB) ; Koppenhagen;
Frank; (Belmont, CA) ; Currie; Lilias;
(Blantyre, GB) ; Stewart; Sarah; (Aberdeen,
GB) |
Correspondence
Address: |
FISH & NEAVE IP GROUP;ROPES & GRAY LLP
ONE INTERNATIONAL PLACE
BOSTON
MA
02110-2624
US
|
Family ID: |
9944922 |
Appl. No.: |
10/528875 |
Filed: |
September 26, 2003 |
PCT Filed: |
September 26, 2003 |
PCT NO: |
PCT/GB03/04208 |
371 Date: |
March 23, 2005 |
Current U.S.
Class: |
424/422 ; 528/68;
528/85 |
Current CPC
Class: |
A61K 9/02 20130101; C08G
18/758 20130101; A61K 31/215 20130101; C08G 18/6674 20130101; A61K
47/34 20130101; C08G 2210/00 20130101 |
Class at
Publication: |
424/422 ;
528/068; 528/085 |
International
Class: |
A61F 2/00 20060101
A61F002/00; C08G 18/32 20060101 C08G018/32 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 27, 2002 |
GB |
0222522.5 |
Claims
1. A water-swellable linear polymer obtainable by reacting together
(a) a polyethylene oxide; (b) a difunctional compound, and (c) a
difunctional isocyanate.
2. A polymer according to claim 1 wherein the polyethylene oxide
has a number average molecular weight of 4000 to 35,000.
3. A polymer according to claim 1 wherein the polyethylene oxide
has a number average molecular weight of 8000 to 12,000.
4. A polymer according to claim 1 wherein the difunctional compound
is a diamine or diol.
5. A polymer according to claim 4 wherein the diol is a C.sub.5 to
C.sub.20 diol.
6. A polymer according to claim 5 wherein the diol is a
1,10-decanediol.
7. A polymer according to claim 5 wherein the diol is
1,6-hexanediol, 1,12-dodecanediol or 1,16-hexadecanediol.
8. A polymer according to claim 1 wherein the ratio of components
(a) to (b) to (c) in terms of equivalent weights is in the range
0.1-1.5 to 1 to 1.1-2.5.
9. A polymer according to claim 8 wherein the ratio is 0.2-0.9 to 1
to 1.2-1.9
10. A polymer according to claim 9 wherein the ratio is 0.5-0.9 to
1 to 1.5-1.9
11. A polymer according to claim 1 which is swellable in water up
to 500%.
12. A polymer according to claim 1 which is swellable in water up
to 1700%.
13. A polymer according to claim 1 which is soluble in
dichloromethane.
14. A method of making a polymer according to claim 1 which
comprises reacting together components (a), (b) and (c).
15. A controlled release composition which comprises a polymer of
claim 1 together with an active agent.
16. A composition according to claim 15 wherein the molecular
weight of the active agent is in the range 200 to 20,000.
17. A composition according to claim 15 wherein the active agent is
a prostaglandin.
18. A composition according to claim 15 wherein the active agent is
terbutaline sulphate, clindamycin sulphate, oxytocin, misoprostol
or progesterone.
19. A composition wherein the active agent is an H.sub.2 receptor
antagonist, antimuscaririe, prostaglandin analogue, proton pump
inhibitor, aminosalycilate, corticosteroid, chelating agent,
cardiac glycoside, phosphodiesterase inhibitor, thiazide, diuretic,
carbonic anhydrase inhibitor, antihypertensive, anti-cancer,
anti-depressant, calcium channel blocker, analgesic, opioid
antagonist, antiplatel, anticoagulant, fibrinolytic, statin,
adrenoceptor agonist, beta blocker, antihistamine, respiratory
stimulant, micolytic, expectorant, benzodiazepine, barbiturate,
anxiolytic, antipsychotic, tricyclic antidepressant, 5HT,
antagonist, opiate, 5HT, agonist, antiemetic, antiepileptic,
dopaminergic, antibiotic, antifungal, anthelmintic, antiviral,
antiprotozoal, antidiabetic, insulin, thyrotoxin, female sex
hormone, male sex hormone, antioestrogen, hypothalamic, pituitary
hormone, posterior pituitary hormone antagonist, antidiuretic
hormone antagonist, bisphosphonate, dopamine receptor stimulant,
androgen, non-steroidal anti-inflammatory, immuno suppressant local
anaesthetic, sedative, antipsioriatic, silver salt, topical
antibacterial, vaccine.
20. A composition according claim 15 in the form of a suppository,
pessary, buccal insert or film.
Description
[0001] The present invention relates to water-swellable linear
polymers, suitable for the production of controlled release
compositions for release of pharmaceutically active agents over a
prolonged period of time.
[0002] Certain cross-linked polyurethane polymers are known from
European Patent Publication EP0016652 and EP0016654. These patent
specifications describe cross-linked polyurethanes formed by
reacting a polyethylene oxide of equivalent weight greater than
1500 with a polyfunctional isocyanate and a trifunctional compound
reactive therewith, such as an alkane triol. The resultant
cross-linked polyurethane polymers are water-swellable to form a
hydrogel but are water-insoluble and may be loaded with
water-soluble pharmaceutically active agents. One particular
polyurethane polymer is the reaction product of polyethylene glycol
8000, Desmodur (DMDI i.e. dicyclohexylmethane-4,4-diisocyanate) and
1,2,6-hexane triol and which has been used commercially for vaginal
delivery of prostaglandins.
[0003] However, such polyurethane polymers possess a number of
practical disadvantages. Whilst the use of a triol cross-linking
agent is effective in providing polymers of relatively reproducible
swelling characteristics, the percent swelling is typically
200-300% (i.e. the increase in weight of the swollen polymer
divided by the weight of the dry polymer). Pharmaceutically active
agents are loaded by contacting the dry polymer with an aqueous
solution of pharmaceutically active agent, such that the solution
becomes absorbed into the polymer, forming a hydrogel. The swollen
polymer is then dried back to a chosen water content before use. A
consequence is that with the conventional cross-linked
polyurethane, the degree of swelling limits the molecular weight of
the pharmaceutically active agent which can be absorbed into the
hydrogel structure to below about 3000. A further disadvantage is
that only water-soluble pharmaceutically active agents may be used.
Finally, since the conventional cross-linked polyurethane polymer
is essentially insoluble in both water and organic solvents,
processing of the formed polymer into other solid forms, such as
films or coatings, is not possible.
[0004] The object of the present invention is to provide a
polyurethane polymer of the aforementioned type which is not
cross-linked but is linear but which still possesses the desirable
properties of reproducible swellability found in the prior
cross-linked polyurethanes.
[0005] Initial work on the production of linear polyurethane
polymers proved unsatisfactory, since the polymers were not stable
but continued to react over extended time periods. Also, the
swellability was not constant or reproducible, and changed with
time.
[0006] The present invention is based on the discovery that linear
polyurethanes having suitable characteristics may be obtained by
reacting a polyoxyethylene glycol with a diol or other difunctional
compound and a difunctional isocyanate.
[0007] In particular, the present invention provides a
water-swellable linear polymer obtainable by reacting together
[0008] (a) a polyethylene oxide;
[0009] (b) a difunctional compound; and
[0010] (c) a difunctional isocyanate.
[0011] Alternatively stated, the invention provides a
water-swellable linear polyurethane formed of moieties derived from
(a), (b) and (c) bonded together.
[0012] The linear polymer produced is swellable in water to an
enhanced degree, depending upon the ratio of the three components
(a), (b) and (c), for example up to 500%, up to 800% or even above
1,000%, thus allowing higher molecular weight pharmaceutically
active water-soluble agents to be loaded into the swollen hydrogel
derived from the linear polymer. Usually, the polymer is swellable
to 200% to 2000%, for example 250 to 1700%. Depending on the
particular active agent, swellabilities in the ranges 300-1000,
400-800, 1000-1500, 1100-1300 etc., may be achieved with the
polyurethanes of the invention. The linear polymer of the invention
is also soluble in certain organic solvents, such as
dichloromethane, which allows the polymer to be dissolved and cast
into films or coatings. It also allows active agents of poor water
solubility but which are soluble in organic solvents, to be loaded
into the polymer.
[0013] In this description the term "equivalent weight" is used as
meaning the number average molecular weight divided by the
functionality of the compound.
[0014] Polyethylene oxides contain the repeat unit
(CH.sub.2CH.sub.2O) and are conveniently prepared by the stepwise
addition of ethylene oxide to a compound containing a reactive
hydrogen atom. Polyethylene glycols are prepared by the addition of
ethylene oxide to ethylene glycol to produce a difunctional
polyethylene glycol structure HO(CH.sub.2CH.sub.2O).sub.nH wherein
n is an integer of varying size depending on the molecular weight
of polyethylene oxide. Polyethylene oxides used in the present
invention are generally linear polyethylene glycols i.e. diols
having an equivalent weight of 1500 to 20,000, particularly 3000 to
10,000 and especially 4000 to 8000. Molecular weights are usually
in the region 4000 to 35,000.
[0015] The difunctional compound is reactive with the difunctional
isocyanate, and is typically a difunctional amine or diol. Diols in
the range C.sub.5 to C.sub.20, preferably C.sub.8 to C.sub.15 are
preferred. Thus, decane diol has been found to produce particularly
good results. The diol may be a saturated or unsaturated diol.
Branched diols may be used but straight chain diols are preferred.
The two hydroxy groups are generally on terminal carbon atoms.
Thus, preferred diols include 1,6-hexanediol, 1,10-decanediol,
1,12-dodecanediol and 1,16-hexadecanediol.
[0016] The difunctional isocyanate is generally one of the
conventional diisocyanates, such as
dicyclohexylmethane-4,4-diisocyanate,
diphenylmethane-4,4-diisocyanate, 1,6-hexamethylene diisocyanate
etc.
[0017] The ratio of the components (a) to (b) to (c) (in terms of
equivalent weights) is generally in the range 0.1-1.5 to 1 to
1.1-2.5, particularly 0.2-0.9 to 1 to 1.2-1.9. A preferred range is
0.5-0.9 to 1 to 1.5-1.9 Of course, the skilled man through
reasonable experimentation would determine the best ratio of
ingredients to give the desired properties. The amount of component
(c) is generally equal to the combined amounts of (a) and (b) to
provide the correct stoichiometry.
[0018] Polymers produced at extreme ends of the ranges may not
necessarily give optimal properties. For example, high amounts of
(a) polyethylene oxide may undesirably lead to the polymer being
water-soluble. Small amounts may reduce the percentage swelling.
Generally, the ratio of (a) polyethylene oxide to (b) difunctional
compound is preferably 0.1-1.5 to one, preferably 0.2-0.9 to
one.
[0019] The polymers are generally produced by melting the
previously dried polyethylene glycol together with the difunctional
compound (e.g. diol) at a temperature of around 85.degree. C. A
catalyst such as ferric chloride is incorporated. The molten
mixture is dried under vacuum to remove excess moisture and the
diisocyanate added thereto. The reaction mixture is then poured
into billet moulds and cured for a specified time. Thus, the
polymer is initially formed as a moulded solid. However, the linear
polymers of the present invention are soluble in certain organic
solvents. This allows the polymer to be dissolved and the resultant
solution cast to form films. The solution may also be employed for
coating granules, tablets etc., in order to modify their release
properties. Alternatively, the solution can be poured into a
non-solvent so as to precipitate polymer/active microparticles.
[0020] Thus, the invention also provides controlled release
compositions comprising the linear polymer together with an active
agent. The active agent may be a pharmaceutically active agent for
human or animal use. It may also be any other agent where sustained
release properties (e.g. algicides, fertilisers etc.) are required.
The pharmaceutical solid dosage forms include suppositories,
pessaries for vaginal use, buccal inserts for oral administration
etc. These dosage forms are generally administered to the patient,
retained in place until delivery of active agent has occurred and
the spent polymer is then removed.
[0021] The linear polymer of the present invention may be swollen
to a higher degree than the conventional cross-linked polymer and
is thus suitable for the uptake of high molecular weight
pharmaceutically active agents (up to and exceeding a molecular
weight of 3000 e.g. up to 10,000, up to 50,000, up to 100,000 or
even up to 200,000 depending on swellability) and is thus
particularly suitable for the uptake and delivery of proteins and
peptides. Generally, the molecular weight of the active agent is in
the range 200 to 20,00. A wide variety of water-soluble
pharmaceutically active substances such as those listed in
EP0016652 may thus be incorporated. Furthermore, the linear
polymers of the present invention may be loaded with
pharmaceutically active agents which are poorly water-soluble,
provided that these can be dissolved in a common solvent with the
polymer. The resultant solution can then be cast into any desired
solid forms. Pharmaceutically active agents of particular interest
include:
[0022] Proteins e.g. interferon alpha, beta and gamma, insulin,
human growth hormone, leuprolide; Benzodiazepines e.g. midazolam;
Anti-migraine agents e.g. triptophans, ergotamine and its
derivatives; Anti-infective agents e.g. azoles, bacterial
vaginosis, candida; and opthalmic agents e.g. latanoprost.
[0023] A detailed list of active agent includes H.sub.2 receptor
antagonist, antimuscaririe, prostaglandin analogue, proton pump
inhibitor, aminosalycilate, corticosteroid, chelating agent,
cardiac glycoside, phosphodiesterase inhibitor, thiazide, diuretic,
carbonic anhydrase inhibitor, antihypertensive, anti-cancer,
anti-depressant, calcium channel blocker, analgesic, opioid
antagonist, antiplatel, anticoagulant, fibrinolytic, statin,
adrenoceptor agonist, beta blocker, antihistamine, respiratory
stimulant, micolytic, expectorant, benzodiazepine, barbiturate,
anxiolytic, antipsychotic, tricyclic antidepressant, 5HT.sub.1
antagonist, opiate, 5HT, agonist, antiemetic, antiepileptic,
dopaminergic, antibiotic, antifungal, anthelmintic, antiviral,
antiprotozoal, antidiabetic, insulin, thyrotoxin, female sex
hormone, male sex hormone, hormone, antioestrogen, hypothalamic,
pituitary hormone, posterior pituitary hormone antagonist,
antidiuretic hormone antagonist, bisphosphonate, dopamine receptor
stimulant, androgen, non-steroidal anti-inflammatory, immuno
suppressant local anaesthetid, sedative, antipsioriatic, silver
salt, topical antibacterial, vaccine.
[0024] The invention also provides a method of manufacturing the
linear polymer by reacting together components (a), (b) and
(c).
[0025] Embodiments of the present invention will now be described
by way of example only in Sections A and B.
Tests Carried Out on New Linear Polymer
[0026] All batches of linear polymer according to the invention
were tested as follows.
[0027] I. Appearance. The polymer should be free of air
bubbles.
[0028] II. Percentage Swelling. Accurately weigh each of ten slices
(to 3 decimal places) and note the dry weight (mark each slice with
an ID number). Swell the slices in 300 ml demineralised water at
25.degree. C..+-.1.degree. C. in a waterbath for 24 hours. Remove
slices and blot dry with a paper towel. Reweigh each slice and
determine the swelling factor as follows: % .times. .times.
Swelling ( pph ) = Swollen .times. .times. weight - dry .times.
.times. weight dry .times. .times. weight .times. 100 1
##EQU1##
[0029] III. Percent Water Soluble Extractables. (% WSE). Wash
thoroughly and dry loss-on-drying vessels in an oven, overnight at
105.degree. C., cool for 2 hours in a desiccator and then weight.
Record weight to 4 decimal places. [0030] Accurately weigh out 10
slices and put into a 250 ml conical flask. Add 150 ml
demineralised water and swirl gently for 30 seconds. Decant the
water and repeat. To the rinsed pessaries add 50 ml demineralised
water. Shake on a flat bottom shaker for 24 hours at room
temperature. [0031] Prepare 2 blanks (water only) and 2 samples
(water+extract) each time the determination is carried out.
Calculate each individual blank determination and the mean of these
two values. This is to be used to obtain the Corrected Total
Weight. Decant the water from the slices and pass ca 10 ml of the
water (using a plastic syringe) through a Millipore filter (1.2 um)
into a previously weighted LOD vessel and weigh again. Place in an
oven at 105.degree. C. and evaporate sample to dryness (18
hours/overnight). Remove from oven, cool for 2 hours in a
dessicator and weigh.
[0032] Calculation--(All Weights in Grams) Total .times. .times. Wt
.times. .times. of .times. .times. Blank = Wt .times. .times. of
.times. .times. Residue In .times. .times. LOD .times. .times.
Vessel .times. 50 Wt .times. .times. of .times. .times. water
.times. .times. added To .times. .times. LOD .times. .times. Vessel
##EQU2## Total .times. .times. Wt .times. .times. of .times.
.times. Extract = Wt .times. .times. of .times. .times. Extract In
.times. .times. LOD .times. .times. Vessel .times. 50 Wt .times.
.times. of .times. .times. sample .times. .times. added To .times.
.times. LOD .times. .times. Vessel ##EQU2.2## Corrected .times.
.times. Total .times. .times. Wt = Wt .times. .times. of .times.
.times. Extract - Wt .times. .times. of .times. .times. blank
##EQU2.3## % .times. .times. ( w / w ) .times. .times. Water
Soluble .times. .times. Extractables = Corrected .times. .times. Wt
.times. .times. of .times. .times. Extract Wt .times. .times. of
.times. .times. Pessaries .times. .times. Used .times. 100
##EQU2.4##
[0033] IV. Crystallinity. Cut a small portion from the slice and
seal in a 50 ul aluminium pan. Prepare a sealed empty pan of the
same dimensions as a reference. Place the pans in the sample and
reference holders respectively and run the temperature programme.
Calculate the onset temperature and enthalpy using the Data
Station. Crystallinity is equal to the ratio of the melt enthalpy
of sample to melt enthalpy of 100% crystalline polyethylene oxide,
enthalpies expressed in joules/g. % .times. .times. crystallinity =
Enthalpy .times. .times. of .times. .times. sample 220.12 .times.
100 ##EQU3##
[0034] V. Percentage Swelling 72 hours
[0035] VI. Percentage Swelling 144 hours
[0036] These percentage-swelling tests were carried out as the
standard percentage-swelling test but the total incubation time was
increased from 24 hours to either 72 or 144 hours.
[0037] Further selective tests included:
[0038] VII. Percentage Swelling Over Time
[0039] Where three slices of each polymer batch tested were
immersed in water and weighed at time intervals over a 24-hour
period.sup.(10). The percentage swelling was then calculated from
these weights.
[0040] VIII. Stability Testing
[0041] Samples were tested for stability at 40.degree. C. over a
four-week period. At the specified time point intervals of one, two
and four weeks the percentage swelling (24 hours) was calculated
and used as an indication of polymer stability.
[0042] IX. Solubility in Different Solvents
[0043] Three polymer slices of each batch tested were placed into
separate vials for each solvent used. For each batch, the different
slices were tested twice using either whole or cut slices and to
each vial around 10 mL of solvent was added. The solvents used were
acetone, dichloromethane, ethanol and methanol.
[0044] X. Water Solubility Testing
[0045] Ten slices of each batch tested were placed in a conical
flask and around 300 mL of demineralised water was added. The
flasks were placed on a flat bottom shaker for seven days.
Section A
A1. Polymer Manufacture
[0046] Various stoichiometric ingredient ratios of PEG:DD:DMDI were
used to produce new polymers. Altering the ingredient ratio
resulted in a change in the properties of the polymer. PEG is
polyethylene glycol; DD is decane-1,10-diol; and DMDI is
dicyclohexyl methane-4,4-diisocyanate. TABLE-US-00001 TABLE 1 New
Polymers Manufactured PEG:DD:DMDI Batch Numbers 1:1:2 (comparison)
FX02140, FX02143 0.7:1:1.7 FX02158 0.5:1:1.5 FX02148 0.25:1:1.25
FX02141, FX02144, FX02149, FX02161
[0047] (The ratio of the known cross-linked polymer FX02139 used
for comparison is PEG8000:hexanetriol:DMDI of 0.8:1.0:2.3)
[0048] PEG and DD were weighed into a round-bottomed flask balance
and melted overnight at a temperature of 85.degree. C.
[0049] The required amount of ferric chloride (FeCl.sub.3) plus an
excess was weighed into a tared 200 mL beaker with spatula. This
was made up to 100 g with molten PEG/DD from the previous step.
This mixture of PEG/DD/FeCl.sub.3 was stirred vigorously and kept
in the oven at 85.degree. C., with frequent stirring, until
required.
[0050] The remaining molten PEG/DD was dried under vacuum at
95.degree. C. for one and a half hours to remove excess moisture.
The moisture content of the PEG/DD was tested using the volumetric
Karl Fischer titration method with the specification for moisture
being set at no more than 0.05%.
[0051] Next, 80 g of the PEG/DD/FeCl.sub.3 mixture was weighed into
a 2 L jug and this ensured the correct weight of FeCl.sub.3. The
amount of PEG/DD required, taking into account the 80 g already
present from the PEG/DD/FeCl.sub.3 mixture, was then added to the 2
L jug which was returned to the oven whilst setting up the
equipment in the fume cupboard.
[0052] A mixer set at 427 rpm was used to agitate the contents of
the 2 L jug for 150 seconds, and the DMDI was added during the
first 30 seconds.
[0053] This final mixture was then poured from the 2 L jug into
billet moulds, placed in an oven at 95.degree. C. and cured for a
specified time, which ranged from 10 to 30 hours. After this time,
the oven was turned off and the billets left to cool to
ambient.
[0054] The polymer was then demoulded, and the resultant polymer
slabs sliced.
A2. Polymer Properties
[0055] (a) Characteristics of New Polymer
[0056] The characteristics of the new polymer batches manufactured
are summarised in Tables 2-5. TABLE-US-00002 TABLE 2 New polymer
with a PEG:DD:DMDI ratio of 1:1:2 (Comparison) FX00206 FX01153
FX01167 FX02140 FX02143 (FK) (VJ) (VJ) (SS) (SS) Cure Time 20 hours
20 hours 20 hours 10 hours 20 hours 10 minutes Appearance Normal
Normal Normal looking looking but looking but darker in darker in
colour than colour than original original polymer polymer
Percentage 646%* 1334.14% 1918% 1110% 1320% Swelling RSD 1.82 RSD
RSD 0.8 RSD 4.37 2.58 % WSE 0.35% 2.03%** 7.54%** 1.11%** 1.24%**
*Polymer not sliced but cut into relatively thick slices **Filtrate
too thick for filter paper
[0057] It was found that the new polymer with a PEG:DD:DMDI ratio
of 1:1:2 lost its integrity during the water soluble extractable
testing and one further test of water solubility was carried out on
this ingredient ratio to confirm this. These polymers were
apparently water soluble to an extent and therefore unsuitable.
TABLE-US-00003 TABLE 3 New polymer with a PEG:DD:DMDI ratio of
0.25:1:1.25 FX01156 FX02141 FX02144 FX02149 FX02161 (VJ) (SS) (SS)
(SS) (SS) Cure Time 20 hours 10 hours 10 hours 20 hours 30 hours
Appearance Golden Golden Normal Darker Darker yellow; yellow;
looking colour than colour than undissolved undissolved but
original original FeCl FeCl darker in polymer; polymer; present;
present; colour undissolved some waxy waxy than FeCl undissolved
original polymer present FeCl Percentage 427.41% 284% 287% 304%
304% Swelling RSD 0.58 RSD 1.09 RSD RSD 0.62 RSD 0.35 0.77 % WSE
1.23% 0.16% 0.44% 0.24% 0.02% Crystallinity 43.63% 43.33% 44.50%
44.02% RSD 2.24 RSD RSD 0.50 RSD 0.96 1.46
[0058] TABLE-US-00004 TABLE 4 New polymer with a PEG:DD:DMDI ratio
of 0.5:1:1.5 FX01197 (VJ) FX02070 (LC) FX02148 (SS) Cure Time 20
hours 20 hours 10 hours Appearance Darker colour than original
polymer; air bubbles present; some undissolved FeCl present
Percentage 422.4% 347% 492% Swelling RSD 0.69 RSD 2.6 RSD 1.35 %
WSE 0.1214% 0.1% Crystallinity 49.69% RSD 0.47
[0059] TABLE-US-00005 TABLE 5 New polymer with a PEG:DD:DMDI ratio
of 0.7:1:1.7 FX02158 (SS) Cure Time 10 hours Appearance Darker in
colour than original polymer Percentage Swelling 730% RSD 0.94 %
WSE 0.73% Crystallinity 49.6% RSD 2.06
[0060] (b) Extended Percentage Swelling TABLE-US-00006 TABLE 6
Results of Swelling at 24, 72 and 114 Hours Percentage Percentage
Percentage Percentage Increase Batch Swelling 24 Swelling 72
Swelling 144 from 24 to Number Hours Hours Hours 144 Hours FX02141
284% 291% 293% 3% RSD 1.09 RSD 0.51 RSD 0.77 FX02144 287% 299% 300%
5% RSD 0.77 RSD 0.33 RSD 0.51 FX02149 304% 311% 318% 5% RSD 0.62
RSD 0.99 RSD 1.00 FX02161 304% 308% 313% 3% RSD 0.35 RSD 0 . . . 43
RSD 0.66 FX02148 492% 504% 529% 8% RSD 1.35 RSD 1.04 RSD 2.20
FX02158 730% 786% 827% 13% RSD 206 RSD 3.36 RSD 3.36 FX02139 308%
298% -3% (cross- RSD 0.59 RSD 0.76 linked)
[0061] (c) Percentage Swelling Over Time is given in FIGS. 1 and 2:
[0062] FIG. 1 shows Percentage Swelling Over Time of Two New
Polymers (FX02141 and FX02144) Compared With Original Polymer
(FX02139); and [0063] FIG. 2 shows Percentage Swelling Over Time of
Three New Polymers
[0064] (d) Stability of Linear Polymer TABLE-US-00007 TABLE 7
Stability Testing of FX02150 (Purified FX02144) Time Percentage
Swelling 0 (FX02144) 287% RSD 0.77 1 week 370% RSD 4.57 2 week 374%
RSD 5.10 4 week 379% RSD 2.81
[0065] (g) Solubility Testing of Linear Polymer TABLE-US-00008
TABLE 8 Solubility Testing of New Polymer in Four Different
Solvents Batch Number Acetone Dichloromethane Ethanol Methanol
FX02144 Polymer not Polymer dissolved Polymer Polymer swollen
swollen; slices resulting in a clear swollen, slices & broken
up, white and in solution opaque and opaque & still small
pieces; intact; slices visible - settles forms appear smooth to
bottom suspension on shaking but rapidly sediments FX02148 Polymer
not Polymer dissolved Polymer Polymer swollen; slices resulting in
a clear swollen, slices dissolved white & solution opaque and
resulting in a clear breaking up intact; slices solution appear
smooth FX02158 Polymer not Polymer dissolved Polymer Polymer
swollen; slices resulting in a clear swollen; slices dissolved
white; break solution slightly resulting in a up on vigorous
opaque; clear solution shaking appear textured FX02140 Polymer not
Polymer dissolved Polymer Polymer swollen; slices resulting in a
clear swollen; slices dissolved white; break solution clear and
resulting in a up on vigorous textured clear solution shaking
looking
[0066] TABLE-US-00009 TABLE 9 Solubility Testing of New Polymer in
Water Batch Number Results FX02144 Slices swollen and opaque. No
signs of dissolving. Water clear FX02148 Slices swollen and opaque.
No signs of dissolving. Water clear FX02158 Slices swollen and
opaque. No signs of dissolving. Water clear FX02140 Slices lose
their integrity and ultimately dissolve. Water frothy
A3. Controlled Release Compositions Dissolution Testing
[0067] A dosage form when placed into a vessel containing liquid
media will release drug in a defined manner dictated by the
formulation. This process known as dissolution can be used as an in
vitro marker of the mechanism of release in the body. Sampling is
carried out at regular intervals over a period of several hours and
the amount of drug in the samples is analysed by spectrophotometer
or HPLC. The data are normally represented as the release of
labelled content against time.
(i) Pilocarpine
Potency
[0068] Ten units are swollen, macerated and quantitatively
extracted into 500 ml of mobile phase. Pilocarpine is then assayed
by HPLC relative to a reference standard. Detection is by UV
spectrophotometer. The method is capable of detecting pilocarpine
and its main degradation products, pilocarpic acid, iso-pilocarpine
and iso-pilocarpic acid. The method is based upon the European
Pharmacopeia method for pilocarpine.
Dissolution
[0069] Pilocarpine in vitro release from the units is performed by
a USP paddle method at 50 rpm, 37.degree. C. The pilocarpine
released is assayed by HPLC as in the potency method.
Loading
[0070] The blank polymer slices are placed in purified water and
agitated at about 4.degree. C. for approximately 16-20 hours; the
water is then decanted. Water swollen polymer slices are placed in
an ethanol:water solution and agitated at about 4.degree. C. for
approximately 6-8 hours. The slices are then dried. Pilocarpine is
dissolved in water which is then added to the dry polymer slices.
The slices and drug loading solution are agitated at approximately
4.degree. C. for approximately 16-20 hours to allow the uptake of
drug. At the end of the dosing period the remaining drug solution
is decanted and the swollen polymer slices are dried for 18-28
hours.
[0071] Polymer batch FX02144 was purified (FX02150) and then loaded
with pilocarpine (FX02151).
[0072] FIG. 3 shows normalised graph of percentage Pilocarpine
released against time for linear polymer FX02151 compared with
original polymer FX01234 and FX01194
(ii) Loading with PGE.sub.2 (Dinoprostone)
Potency
[0073] Ten units are swollen, macerated and quantitatively
extracted into 500 ml of mobile phase. Dinoprostone is then assayed
by HPLC relative to a reference standard. Detection is by UV
spectrophotometer. The method is capable of detecting Dinoprostone
and its main degradation products, PGA2,8-iso PGE2 and 15
keto-PGE2. The method is based upon the EP method for
dinoprostone.
Dissolution
[0074] Dinoprostone in vitro released from the units is performed
by a USP paddle method at 50 rpm, 37.degree. C. The dinoprostone
released is assayed by HPLC as in the potency method.
Purification and Loading
[0075] The blank polymer slices are placed in purified water and
agitated at about 4.degree. C. for approximately 6-8 hours, then
the water is decanted. The swollen slices are again placed in
purified water and agitated at about 4.degree. C. for approximately
16-20 hours; the water is then decanted. Water swollen polymer
slices are placed in an ethanol:water solution and agitated at
about 4.degree. C. for approximately 6-8 hours. A solution of
Dinoprostone is made by dissolving the appropriate amount of
Dinoprostone in ethanol. The resulting solution is added to water
and ethanol. This makes up the drug loading solution which is then
added to the swollen polymer slices to give a 25% w/w ethanol:water
mix. The slices and drug loading solution are agitated at,
approximately 4.degree. C. for approximately 16-20 hours to allow
the uptake of drug. At the end of the dosing period the remaining
drug solution is decanted and the swollen polymer slices are dried
for 18-28 hours.
[0076] Prostaglandin E.sub.2 was loaded by an analogous process
into a batch of cross-linked polymer (FX02139, loaded FX02159) and
a batch of linear polymer (FX02144, loaded FX02157), both with 0.6
mm thick slices. The measured potencies were 9.4 mg (FX02159,
control) and 9.7 mg (FX02157) respectively.
[0077] FIG. 4 shows PGE.sub.2 release profiles of cross-linked
polymer and new linear polymer.
A4. Manufacture of Films
[0078] In initial experimentation into film manufacture, six vials
were set up containing one, two, three, four, five and eight slices
of polymer respectively. The polymer batch used was FX02141. To
each vial around 10 mL of dichloromethane was added. All vials were
sonicated until the polymer dissolved. The resultant solutions were
poured onto a watchglass (20 cm diameter) and allowed to dry in a
fume cupboard uncovered.
[0079] In further film development work, the amounts of polymer and
solvent were weighed into a suitable glass container, which was
then sealed and sonicated until the polymer dissolved. Some films
were poured on a watchglass as before, whilst others were poured in
a petri dish (8 cm diameter). To control the drying of the films,
some solutions poured were covered with a 1 L glass beaker.
[0080] Films were also manufactured using a doctor blade, with the
solution being poured onto a glass plate in a fume cupboard and
spread along the length of the plate. TABLE-US-00010 TABLE 10
Initial Film Manufacture Results Number of Slices of FX02141 in 10
mL Dichloromethane (DCM) Notes on Resultant Film 1 Lots of small
air bubbles. 0.023 mm thick 2 Removed from glass too quickly and
film was self adhesive and formed a clump of sticky polymer 3 Air
bubbles present from shaking which leads to holes in film. Film
opaque in colour. 0.083 mm thick 4 Smooth, opaque film; some air
bubbles. Around 8 cm in diameter. 0.112 mm thick 5 Good film that
looks uniform on one side but half was partially stuck together due
to being removed from watchglass before it was fully dry. 0.133 mm
thick 8 Very strong film; air bubbles a problem. Oval in shape - 7
cm by 5 cm. 0.354 mm thick
[0081] The film made with five slices of polymer in solvent was
swollen in demineralised water in a plastic petri dish. The swollen
form of the film was found to be strong. The film was placed on a
watchglass to dry. Once dried, the film regained its shape and
strength. TABLE-US-00011 TABLE 11 Films Manufactured Using Polymer
Batch FX02141 Dissolved in Dichloromethane Weight % w/w Weight DCM
Polymer in Vial FX02141 (g) added (g) DCM Details 1 0.8911 12.763
6.98 Loaded with cresol red. 2 0.9478 13.806 6.87 Loaded with
bromophenol blue 3 0.7897 14.797 5.34 Poured onto watchglass with
another watchglass placed on top; film not uniform 4 0.9238 10.661
8.67 Poured onto watchglass; film used for swelling over time test
5 0.9572 15.936 6.01 Poured onto watchglass, covered with a 1 litre
beaker; film uniform 6 0.8679 13.899 6.24 Poured into a glass
petrie dish, covered with beaker; uniform film; film used for
crystallinity testing; film brittle 7 0.9751 15.286 6.38 Poured in
a glass petrie dish, covered with beaker; film brittle 8 1.0680
11.193 9.54 Made into a 53.20% w/w solution of ethanol in
DCM/polymer mixture; didn't go into a film 9 1.0618 13.335 7.96
Loaded with bromophenol blue; film swollen 10 0.8490 11.557 7.35
Made into a 34.73% w/w solution of acetonitrile in DCM/polymer
mixture; film brittle - opaque looking 11 0.6528 10.029 6.51 Made
into a 45.00% w/w solution of methanol in DCM/polymer mixture 12
0.9013 6.541 13.78 Made into a 108% w/w solution of acetone in
DCM/polymer mixture, poured onto watchglass and covered with
beaker; film not uniform
[0082] Portions of films made from Vials 1 and 2 were cut and
placed into vials of demineralised water to determine whether the
film could release the loaded dye. TABLE-US-00012 TABLE 12 Films
Manufactured Using Polymer Batch FX02158 in Different Solvents %
w/w Weight Polymer FX02158 Weight Solvent in Vial (g) Added (g)
Solvent Details A 0.7677 10.0211 g 7.66 Non-uniform: one large
methanol clearer patch visible; feels smooth; opaque film; slightly
textured looking C 0.7755 15.9041 g 4.88 Uniform in appearance;
dichloromethane opaque film covered in small clear spots all over;
feels rough; not brittle E 0.7631 9.6095 g 5.23 Uniform film;
smooth to dichloromethane touch; very brittle and and 4.9686 g
breaks on touching; methanol opaque film covered in clear spots
which are smaller and more spread out than vial c
[0083] The polymer in vials C and E began dissolving immediately,
whereas vial A was slower. The solutions from these vials were
poured into separate glass petri dishes in a fume cupboard and each
covered with a one-litre beaker. They were left until dry. It was
noticed that the solution from vial c dried quicker than that of
vials a and e. TABLE-US-00013 TABLE 13 Films Manufactured to
Compare Drying Techniques Weight Polymer Weight DCM % w/w polymer
in Duran (g) (g) DCM 1 1.9542 37.2 5.25 FX02158 2 1.9806 35.6 5.56
FX02158 3 1.8595 40.0 4.65 FX02144 4 1.8508 37.0 5.00 FX02144
[0084] The solutions from all four durans were poured separately
into glass petri dishes in a fume cupboard.
[0085] Durans 1 and 3 were covered with a one-litre glass beaker,
and durans 2 and 4 were left uncovered.
[0086] Films from durans 1 and 3 feel rough to touch, whereas films
from durans 2 and 4 are smooth. Film from duran 2 has a rougher
patch at one side.
[0087] All films manufactured from durans 1-4 were of comparable
strength and none were brittle.
[0088] Two films were manufactured using the doctor blade. Both
polymers used were dissolved in DCM (about 5% w/w) to make the
solution, and both solutions were poured onto the same glass dish
under the same conditions.
[0089] The film manufactured with polymer FX02144 was brittle and
fell apart on storage whereas the film made with FX02158 (which was
loaded with bromophenol blue for a demonstration) remained
intact.
[0090] To access the release of a drug from a polymer film, the
percentage swelling over time was calculated. This was graphically
represented, using the percentage swelling over time of the polymer
slice of same batch used in film manufacture as a reference. The
results are shown in FIG. 5.
[0091] The average weight of a film portion used was 0.0272 g; and
the average weight of a polymer slice (FX02141) was 0.1381 g.
A5. Discussion
a. Appearance
[0092] During appearance testing, it was observed that new linear
polymer billets were slightly darker in colour when compared to
known cross-linked polymer billets. This was accounted for by
comparing the FeCl.sub.3 content in both. It was calculated that
known cross-linked polymer contained 0.01% w/w FeCl.sub.3 in PEG
whereas linear polymer had 0.0266% w/w FeCl.sub.3 in PEG.
b. Cure Time
[0093] Previous linear polymers were manufactured with a 20 hour
cure time, however batches FX02140 and FX02141 were manufactured
with a 10 hour cure time.
[0094] By comparison of two batches with the same ingredient ratio
but different cure times [FX02140 (10 hour cure time) and FX02143
(20 hour cure time)], it was seen that a cure time of 10 hours
produced more promising results with a lower RSD for percentage
swelling test and a lower percent water soluble extractables. As a
result, a 10 hour cure time was then used for batches FX02144,
FX02148 and FX02158.
[0095] However, the effect of cure time was further investigated
using batches FX02141, FX02149 and FX02161 with cure time of 10, 20
and 30 hours respectively. By comparison of results from these
three batches, it was found that there was no correlation in
crystallinity; % WSE decreased as the cure time increased and the
percentage swelling for FX02144 is about 20% less than the
swellings of FX02149 and FX02161 which are identical. The RSD for
percentage swelling decreased are cure time increased.
c. Ingredient Ratio
[0096] Polymer manufactured with a PEG:DD:DMDI ratio of 0.25:1:1.25
was shown to have the same characteristics as the cross-linked
polymer, with all results within the known cross-linked polymer
specifications.
[0097] The linear polymer according to the invention meets these
specifications and the results are reproducible. Furthermore, the
linear polymer is soluble in certain solvents whereas the known
cross-linked polymer is insoluble.
[0098] The known cross-linked polymer, with a percentage swelling
of around 300%, cannot be loaded with drugs of high molecular
weight, such as peptides and proteins.
[0099] In comparison, a linear polymer of the present invention,
FX02158 (PEG:DD:DMDI 0.7:1:1.7), was shown to have a percentage
swelling of 730% and insoluble in water.
d. Swelling Profile
[0100] As the ratio of PEG:DD increased, the percentage swelling at
24 hours also increases. The accepted percentage swelling test for
the known cross-linked polymers in 24 hours. This was extended to
72 and 144 hours for the polymer according to the invention to
ascertain the time required for the polymer slice to reach maximum
swelling.
[0101] With higher rations of PEG:DD, it was found that the
percentage swelling increased by a larger difference between 24 and
144 hours when compared to polymers with a low PEG:DD ratio. There
was a 3% increase in percentage swelling of FX02141 (PEG:DD 0.25:1)
from 24 to 144 hours compared to a 13% increase in FX02158
(PEG:DD:0.7:1).
[0102] Polymers with higher PEG:DD ratios have not reach their
maximum percentage swelling by 24 hours. This is confirmed by
percentage swellings over time curves (FIG. 2). Polymer slices with
a PEG:DD ratio of 0.25:1 reach their maximum swelling by around 5
hours when the curve plateaus, however, polymer slices with a
higher PEG:DD ratio of 0.7:1 it was seen that the percentage
swelling was increasing at 144 hours with the gradient of the curve
at this point being positive.
e. Stability
[0103] Stability testing at 40.degree. C. was carried out on
FX02150 (purified FX02144) over a period of 4 weeks. The results
have shown that the percentage swellings increased with time and
this is comparable to results of cross-linked polymers at 4.degree.
C.
f. Drug Release
[0104] Polymer batch FX02144 (PEG:DD:DMDI 0.25:1:1.25) was loaded
with pilocarpine and PGE.sub.2. This polymer has similar
characteristics to cross-linked polymer and therefore, release
profiles of both drugs from the two different polymers could be
compared.
[0105] The release characteristics of pilocarpine were shown to be
comparable between linear and cross-linked polymer. This was
confirmed by comparison of percentage swelling over time of the
linear batch with cross-linked polymer (FIG. 1) where the rate of
swelling was the same for both.
[0106] However, PGE.sub.2 release was found to be different. The
linear polymer released the drug slower than the cross-linked
polymer.
g. Solubility Testing
[0107] Four different polymers, with different ingredient ratios,
were manufactured and none of these polymers were soluble in
ethanol or acetone.
[0108] FX02144 was insoluble in methanol, whereas other batches
tested were soluble in this solvent.
[0109] All batches tested were soluble in dichloromethane.
h. Film Preparation
[0110] From initial experimentation a promising combination of
polymer and solvent was found to be 4-5 slices (approx equivalent
to 0.7 g polymer) in 10 mL DCM. This was scaled up to 13 slices in
30 mL DCM and the film manufacture was shown to be reproducible
with similar films achieved using this combination.
[0111] A manufactured film was swollen in demineralised water and
the swollen form was found to be strong and stretchy. This swollen
film was then removed from the water and allowed to dry. Once dried
the film regained its shape and strength.
[0112] On further film development, the film was tested to
determine whether it could release a loaded dye. Portions of films
loaded with dye were submerged in water, and the water colour
changed over time showing that the film had the ability to release
a loaded substance.
[0113] It was discovered that a film manufactured by dissolving the
polymer in different solvents had an effect on the total drying
time of the film, the uniformity, texture and strength of the final
film. In addition, the technique used to dry the films had an
effect on its final appearance in terms of uniformity and
texture.
[0114] The percentage swelling over time of a polymer film produced
was calculated, and compared to the percentage swelling over time
of the polymer slices used to make the film. As expected, the
portions of film reached their maximum percentage swelling much
quicker than the polymer slice because the thickness and average
weight of the film portions were much less than the polymer slices.
This can be used as an indication of release rate of a drug from a
polymer film.
Section B
B1 Polymer Manufacture
[0115] Various type of polyethylene glycols, diols and
diisocyanates, and various stoichiometric ratios of these compounds
were used to further demonstrate their effects on the properties of
the new polymer. PEG4000, PEG8000, PEG12000 and PEG35000 are
polyethylene glycols having molecular weight of 4000, 8000, 12000
and 35000, respectively; HD is 1,6-hexanediol, DD is
1,10-decanediol, DDD is 1,12-dodecanediol and HDD is
1,16-hexadecanediol; DMDI is dicyclohexylmethane-4,4-diisocyanate
and HMDI is 1,6-hexamethylene diisocyanate.
[0116] Polymers, except batch numbers BP03007, BP03014 and BP03015,
were produced with the same polymerisation method as in Section A.
The only difference was that the melted PEG and diol mixture was
mixed for 30 mins. in a rotavapor, before 100 g was taken out to
make a catalyst mixture to produce a more homogenous mixture.
[0117] For polymerisation of PEG35000 (batch numbers BP03007 and
BP03014) the polymerisation reactor was changed to a stirring tank
reactor (700 ml) and the polymerisation temperature was increased
to 140.degree. C. to reduce the melt viscosity of the PEG. PEG was
dried overnight in a rotavapor using vacuum and 50.degree. C.
temperature. PEG, diol and ferric chloride were fed to a stirring
tank glass reactor. The mixture was melted for 2 hours under
nitrogen using a 140.degree. C. oil bath. Mixing was turned on for
30 min before diisocyanate was fed to the reactor and then mixed
for 5 min. Polymer was poured to the preheated mould (130.degree.
C.) and kept for 10 hours in an oven at 95.degree. C. After this
time, the oven was turned off and the polymer billets were left to
cool to room temperature. The polymer billets were then demoulded
and sliced.
[0118] A two-step polymerisation method was also used to produce
more controlled polymer structure (batch number BP03015). PEG was
dried overnight using vacuum and 50.degree. C. in a rotavapor.
Diisocyanate was first fed to the stirring tank reactor. Then about
40 g PEG with ferric chloride on the top of it was fed to the
reactor. The reactor was heated to 95.degree. C. and PEG was fed to
the reactor during 3 hours by using about 20 g portions at the each
time. Mixing (30 rpm) was turned on when the reactor temperature
reached 95.degree. C. Then the diol was fed to the reactor and
mixing increased to 60 rpm and mixed for 5 min. Polymer was poured
into the preheated mould (95.degree. C.) and kept for 10 hours in
an oven at 95.degree. C. After this time, the oven was turned off
and the polymer billets were left to cool to room temperature. The
polymer billets were then demoulded and sliced.
B2. Polymer Properties
[0119] The effects of type and ratios of polyethylene glycols,
diols and diisocyanates on the properties of polymers can be seen
in Tables 14-18. TABLE-US-00014 TABLE 14 Molar ratios between PEG
8000 and 1,10-decanediol was changed. Batch Number 03032 03030
03031 03033 PEG 8 000 0.9 0.7 0.7 0.1 (Molar Ratio) DD 1 1 1 1
(Molar Ratio) DMDI 1.9 1.7 1.7 1.1 (Molar Ratio) Cure Time 10 10 10
10 Percentage 1048 612 750 178 Swelling (%) WSE (%) 2.3 1.0 1.4 2.3
Tm (.degree. C.) 62.4 61.4 62.4 54.9 Crystallinity 48.6 52.7 49.3
33.1 (%) Soluble in yes yes yes yes DCM Soluble in no no no yes THF
DD is 1,10-decanediol DMDI is dicyclohexylmethane-4,4-diisocyanate
WSE is water soluble extractable
[0120] TABLE-US-00015 TABLE 15 The length of PEG was changed. Batch
Number Bp03001 03031 BP03005 BP03007 BP03014 PEG (MW) 4 000 8 000
12 000 35 000 35 000 PEG 0.7 0.7 0.7 0.7 0.1 (Molar Ratio) DD 1 1 1
1 1 (Molar Ratio) DMDI 1.7 1.7 1.7 1.7 1.1 (Molar Ratio) Cure time
10 10 10 10 10 Percentage 395 750 993 Lost 742 Swelling (%)
Intergrity WSE (%) 1.3 1.4 N.D. WS CH Tm (.degree. C.) 53.8 62 64.0
65.7 65.3 Crystallinity 36.3 49.3 46.5 64.7 46.4 (%) Soluble in yes
yes yes yes yes DCM Soluble in yes no no no no THF MW is molecular
weight DD is 1,10-decanediol DMDI is
dicyclohexylmethane-4,4-diisocyanate WS water soluble CH changes in
shapes
[0121] TABLE-US-00016 TABLE 16 The length of diol and the amount of
diol was changed. Batch Number 03035 03031 Bp03002/1 03036 03034
BP03006 Diol HD DD DDD DDD DDD HDD PEG 8 000 0.7 0.7 1.5 0.9 0.7
0.7 (molar ratio) Diol 1 1 1 1 1 1 (molar ratio) DMDI 1.7 1.7 2.5
1.9 1.7 1.7 (molar ratio) Cure Time 10 10 10 10 10 10 Percentage
Swelling (%) 899 751 1679 602 640 470 WSE (%) 0.92 1.4 5.7 0.7 0.89
N.D. Tm (.degree. C.) 61.8 62 61.1 60 60.6 60.1 Crystallinity 52.8
49.3 48.7 43.1 38.2 45.8 (%) Soluble in yes yes yes yes yes yes DCM
Soluble in no no no no no no THF HD is 1,6-hexanediol DD is
1,10-decanediol DDD is 1,12-dodecanediol HDD is 1,16-hexadecanediol
DMDI is dicyclohexylmethane-4,4-diisocyanate
[0122] TABLE-US-00017 TABLE 17 The effect of diisocyanate. Batch
Number 03031 BP03003 Diisocyanate DMDI HMDI PEG 8 000 0.7 0.7
(molar ratio) DD 1 1 (molar ratio) DMDI 1.7 1.7 (molar ratio) Cure
Time 10 10 Percentage 751 1070 Swelling (%) WSE (%) 1.4 N.D. Tm
(.degree. C.) 62 63.4 Crystallinity 49.3 52.2 (%) Soluble in yes
yes DCM Soluble in no no THF DMDI is
dicyclohexylmethane-4,4-diisocyanate HMDI is 1,6-hexamethylene
diisocyanate
[0123] TABLE-US-00018 TABLE 18 Two-step Polymerisation method Batch
number BP03016 PEG 8 000 0.7 (molar ratio) DD 1 (molar ratio) DMDI
1.7 (molar ratio) Cure Time 10 Percentage 1750 Swelling (%) WSE (%)
N.D. Tm (.degree. C.) 61.2 Crystallinity 52.4 (%) Soluble in yes
DCM Soluble in no THF DD is 1,10-decanediol DMDI is
dicyclohexylmethane-4,4-diisocyanate
B3 Controlled Release Compositions Linear Polymer Characterisation
& Drug Loading Examples
[0124] Batches of linear polymer (03030, 03032 and 03033), together
with cross-linked polymer batch 03003 (polymer ratio PEG
8000:hexanetriol:DMDI of 1.0:1.2:2.8) for comparison were sliced to
produce polymer slices of dimension 10 mm.times.30 mm.times.11.0
mm. The polymer slices were purified at 25.degree. C. using three
washes in purified water and/or purified water/ethanol. Next, all
slices were dried under vacuum.
[0125] Five drugs namely clindamycin phosphate, oxytocin,
terbutaline sulphate, misoprostol and progesterone were loaded into
the various polymers. These drugs were chosen as they covered
various aspects such as highly water soluble, poorly water soluble,
peptides, steroids and lower molecular weight molecules.
[0126] The drugs were loaded into the polymer by dissolving each
drug candidate into a suitable solution, immersing the polymer
slices for an appropriate time then removing from the solution and
drying. Table 19 details the loading parameter and conditions.
TABLE-US-00019 TABLE 19 Loading parameters for various drug
candidates Drug CLI OXY TBS MIS PRO General Batch no. A03003 (CLP)
CL 03009 OX 03001 FX 02248 MS 03025 PG 03002 A03030 (LP) CL 03017
OX 03002 TB 03001 MS 03030 -- A03032 (LP) CL 03020 OX 03003 TB
03002 -- -- A03033 (LP) -- -- -- MS 03033 PG 03003 Drug
content/unit 70 mg 1 mg 10 mg 200 .mu.g 10 mg Drug solubility Very
soluble Very soluble Soluble Insoluble Insoluble (in water) (500
mg/ml) (250 mg/ml) (3 mg/ml) (<0.4 mg/ml) No. of pessary (n)
18-23 18-23 18-23 18-23 18-23 Loading Loading solution 4.76% w/w
PBS solution Purified water 25% w/w 75% w/w NaCl solution (pH 7.4)
EtOH EtOH solution solution Loading temperature 25.degree. C.
25.degree. C. 25.degree. C. 4.degree. C. 25.degree. C. Incubation
Incubation temperature 25.degree. C. 25.degree. C. 25.degree. C.
4.degree. C. 25.degree. C. Incubation duration 16-24 hours 16-24
hours 16-24 hours 16-24 hours 16-24 hours Drying Drying method
Vacuum oven Vacuum oven Vacuum oven Vacuum oven Rotavapor Drying
temperature Room Room Room Room Room temperature temperature
temperature temperature temperature Drying duration .gtoreq.72
hours .gtoreq.24 hours .gtoreq.24 hours .gtoreq.24 hours .gtoreq.24
hours (as required) (as required) (as required) (as required) (as
required) Abbreviations: CLI--Clindamycin phosphate; OXY--Oxytocin;
TBS--Terbutaline sulphate; MIS--Misoporstol; PRO--Progesterone;
NaCl--Sodium chloride; PBS--Phosphate buffered saline;
EtOH--Ethanol
[0127] The drug loaded polymer were analysed for in vitro drug
release following USP Method XXIII, Apparatus 2 at 37.degree. C.,
with 50 rpm paddle speed. Drug release was analysed by ultraviolet
spectroscopy or high pressure liquid chromatography (HPLC) as
appropriate. Various dissolution parameters or settings are
summarised in Table 20. TABLE-US-00020 TABLE 20 Dissolution
parameters and settings Drug CLI OXY TBS MIS PRO Dose per 70 1 10
0.2 10 unit (mg) Dissolution 900 100 250 250 ml 900 volume, V (ml)
Dissolution Water Phosphate Water Water Water media buffer solution
(pH 7.4) Wavelength, 210 562 276 280 (after 249 .lamda. (nm)
derivitisation) Abbreviations: CLI--Clindamycin phosphate;
OXY--Oxytocin; TBS--Terbutaline sulphate; MIS--Misoporstol;
PRO--Progesterone; NA--Not available
[0128] FIG. 6 to 10 show the mean dissolution profiles of each drug
candidate from the various polymers.
[0129] The effect of drug type on mean dissolution profile of
linear polymer batch A03030 is shown in FIG. 11.
[0130] Rate of drug release k values of each dissolution profile
was determined by calculating the slope of graph % drug release
versus square root time. All the linear relationship between % drug
release and square root time has R.sup.2 correlation value
>0.95%. Rate of drug release k from the dissolution profiles of
each drug candidate from various pessaries are shown in Table 21.
TABLE-US-00021 TABLE 21 Rate of drug release (k minutes.sup.-1/2)
of drug candidates from cross- linked and linear polymer pessaries
Rate of drug release, k (minute.sup.-0.5) Polymer type Water A03003
(CLP) A03033 (LP) A03030 (LP) A03032 (LP) solubility Molecular %
Swelling (in water) (mg/ml) weight Drug 295.4 230.0 678.9 1202.8
500 505 CLI 10.701 -ND- 12.765 12.380 Very 1007 OXY 6.749 -ND-
7.875 7.85 soluble 250 274 TBS 13.628 -ND- 13.262 11.954 3 383 MIS
4.507 2.213 4.378 -ND- <0.4 315 PRO 2.414 1.256 -ND- -ND-
Abbreviations: CLI--Clindamycin phosphate; OXY--Oxytocin;
TBS--Terbutaline sulphate; MIS--Misoporstol; PRO--Progesterone;
CLP--Cross-linked polymer; LP--Linear polymer; ND--No data
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