U.S. patent application number 10/432848 was filed with the patent office on 2004-06-10 for dermatological formulations.
Invention is credited to Kanis, Rebecca Louise, McDonagh, Emma Louise.
Application Number | 20040109902 10/432848 |
Document ID | / |
Family ID | 9904040 |
Filed Date | 2004-06-10 |
United States Patent
Application |
20040109902 |
Kind Code |
A1 |
McDonagh, Emma Louise ; et
al. |
June 10, 2004 |
Dermatological formulations
Abstract
Aqueous preparations of substantially equimolor amounts of a
zinc salt and clindamycin phosphate form a polymer useful in the
topical treatment of acne and rosacea, with very low systemic
levels of clindamycin.
Inventors: |
McDonagh, Emma Louise;
(Kelso, GB) ; Kanis, Rebecca Louise; (Edinburgh,
GB) |
Correspondence
Address: |
FISH & RICHARDSON PC
225 FRANKLIN ST
BOSTON
MA
02110
US
|
Family ID: |
9904040 |
Appl. No.: |
10/432848 |
Filed: |
January 28, 2004 |
PCT Filed: |
November 28, 2001 |
PCT NO: |
PCT/GB01/05257 |
Current U.S.
Class: |
424/642 ; 514/32;
514/494 |
Current CPC
Class: |
A61K 9/0014 20130101;
A61P 17/10 20180101; A61K 9/06 20130101; A61K 31/7056 20130101;
A61P 17/00 20180101; A61K 47/38 20130101; A61P 43/00 20180101; A61K
33/30 20130101; A61K 31/7056 20130101; A61K 2300/00 20130101; A61K
33/30 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/642 ;
514/494; 514/032 |
International
Class: |
A61K 031/315; A61K
033/32; A61K 031/7052 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 28, 2000 |
GB |
0029018.9 |
Claims
1. An aqueous preparation for topical application comprising
substantially equimolar amounts of clindamycin phosphate and a
water-soluble zinc salt for use in the treatment of dermatoses.
2. A preparation according to claim 1, having a substantially
neutral pH.
3. A preparation according to claim 2, having a pH between 5.5 and
8.0.
4. A preparation according to any preceding claim, having a pH
above 5.5.
5. A preparation according to claim 4, having a pH of 6.0 or
above.
6. A preparation according to any preceding claim, wherein the
concentration of clindamycin is from 0.1% to 10% by weight.
7. A preparation according to claim 6, wherein the concentration of
clindamycin is from 0.5% to 5% w/w.
8. A preparation according to claim 7, wherein the concentration of
clindamycin is 1% to 2% w/w.
9. A preparation according to any preceding claim, wherein the zinc
salt is zinc acetate.
10. A preparation according to any preceding claim, wherein the
zinc salt is zinc acetate dihydrate.
11. A preparation according to any preceding claim, comprising a
non-aqueous vehicle or diluent in an amount of between 40% and 80%
by weight.
12. A preparation according to claim 11, wherein the ratio of
non-aqueous:aqueous components is between 4:1 and 2:3 by
weight.
13. A preparation according to claim 12, wherein the ratio is
between 2.5:1 and 1.5:1.
14. A preparation according to any preceding claim, comprising a
pharmacologically acceptable, hydrophilic co-solvent.
15. A preparation according to claim 14, wherein the co-solvent
comprises one or more of propylene glycol, glycerine, a
polyethylene glycol, a macrogol and ethanol.
16. A preparation according to claim 15, comprising between 10% and
50% ethanol by weight of the preparation.
17. A preparation according to claim 16, comprising between 20% and
30% ethanol.
18. A preparation according to any preceding claim, comprising a
thickener.
19. A preparation according to claim 18, wherein the thickener is
selected from carbomers and cellulosic compounds.
20. A preparation according to claim 19, wherein the thickener is
selected from hydroxymethylcellulose, hydroxypropylcellulose and
hydroxyethylcellulose.
21. A preparation according to claim 19, wherein the thickener is
hydroxyethylcellulose.
22. A preparation according to any of claims 18 to 21, wherein the
thickener is present in an amount of between 0.5 and 3% by weight
of the preparation.
23. A delayed release preparation according to any preceding
claim.
24. A preparation according to any preceding claim, wherein the
amount of clindamycin phosphate to zinc salt is between 1.2:1 and
1:2 molar.
25. A preparation according to claim 24, wherein the amount of
clindamycin phosphate to zinc is between 1:1 and 1:1.5 molar.
26. A preparation according to claim 25, wherein the amount of
clindamycin phosphate to zinc is about 1:1 molar.
27. A process for the preparation of a formulation as defined in
any preceding claim, comprising mixing said clindamycin phosphate
with water and a co-solvent, adjusting the pH of the mixture to
between 6.5 and 8.0, and then adding said zinc salt.
28. A process according to claim 27, comprising adjusting the pH to
between 7.0 and 7.5.
29. A process according to claim 27 or 28, wherein the co-solvent
is ethanol in an amount of up to 70% by weight of the solvent
mixture.
30. A process according to any of claims 27 to 29, wherein
substantially equal amounts of water and alcohol are used.
31. A process according to any of claims 27 to 30, comprising
substantially completely dissolving the clindamycin phosphate in
the solvent mixture prior to adding the zinc salt.
32. A process according to any of claims 27 to 31, wherein the pH
is adjusted by use of concentrated sodium hydroxide solution.
33. A process according to any of claims 27 to 32, wherein the
water forms at least 30% of the solvent mix by weight.
34. A process according to any of claims 27 to 33, comprising a
pharmacologically acceptable, hydrophilic co-solvent in an amount
of between 1% and 80% by weight.
35. A process according to any of claims 27 to 34, wherein the
co-solvent comprises a volatile, non-aqueous component and a
non-volatile, non-aqueous component, and wherein the volatile,
non-aqueous component forms between 10 and 50% of the total
co-solvent, by weight.
36. A process according to claim 35, wherein the volatile,
non-aqueous component is ethanol and the non-volatile, non-aqueous
component is propylene glycol.
37. A method for the treatment of a dermatological condition
comprising application of a pharmacologically effective amount of a
formulation as defined in any of claims 1 to 26, to the skin of a
patient in need thereof.
38. A preparation according to any of claims 1 to 26 for use in the
treatment of a condition treatable by clindamycin or clindamycin
phosphate.
39. A preparation according to any of claims 1 to 26 for use in the
treatment of acne vulgaris.
40. A preparation according to any of claims 1 to 26 for use in the
treatment of rosacea.
Description
[0001] The present invention relates to dermatological formulations
comprising clindamycin and zinc, especially for the treatment of
acne or rosacea, to methods of treatment of dermatoses with such
formulations, and to methods for preparing such formulations.
[0002] Acne vulgaris is a common skin condition that has been
reported to affect up to 85% of adolescents. The pathology of the
condition is not completely understood, but appears to be
associated with the local metabolism of sex hormones during
adolescence. This stimulates an increase in the size of the
sebaceous glands which, in turn, results in the production of
excess sebum. This lipid rich medium provides an excellent growth
medium for Propionibacterium acnes (P. acnes).
[0003] Comeocytes retained in the follicular canal, and in the
presence of P. acnes, block the follicles, with the formation of a
hyperkeratotic plug (microcomedo) which frequently, and
progressively, enlarges to give rise to the clinically visible
comedones, the non-inflammatory lesions characteristic of acne
(whiteheads and blackheads).
[0004] The anaerobic, lipid rich conditions produced within the
follicle after microcomedone formation provide the perfect
environment for rapid proliferation of P. acnes. Metabolites from
this bacterium can then diffuse into the dermis, provoking a T
cell/helper cell mediated inflammatory response. This can be
further exacerbated by the rupture of the duct and the involvement
of certain species of Micrococcaceae.
[0005] In itself acne is not a serious condition. However, given
its general, social unacceptability, it can often give rise to
severe psycho-social problems, so there is, accordingly, great
pressure to find an effective treatment.
[0006] Various treatments for acne exist, but are generally
hampered by the fact that they are generally unreliable.
[0007] A limited number of antibiotics is used to treat acne. In
moderate to severe cases, oral treatment may be appropriate, in
which case tetracycline, minocycline, doxycycline and erythromycin
are commonly prescribed.
[0008] For mild to moderate acne, topical preparations are the
preferred treatment. Traditionally, benzoyl peroxide has been used
but formulations containing erythromycin or clindamycin have become
more common. When used alone, either of these compounds has been
shown to produce a 50% to 60% reduction in inflammatory
lesions.
[0009] Zineryt.RTM. comprises 4% erythromycin and 1.2% zinc
acetate. Studies show that this formulation has a 10% greater
efficacy than 2% erythromycin alone, and has become a popular
product. However, Zineryt.RTM. must be reconstituted by a
pharmacist, and only has a shelf-life of five weeks, at room
temperature. In addition, it is a runny preparation and uses an
alcoholic vehicle. Thus, not only are there problems in application
of the lotion to the skin, but alcohol is also a skin drying agent
when used as the primary vehicle.
[0010] EP-A-506207, to Access Pharmaceuticals, describes the
preparation of topical pharmaceutical compositions containing
water-soluble, zinc-containing compounds and pharmacologically
active agents including, amongst others, the lincomycins as
antibacterials. Separately, acne treatment compounds are also
disclosed. This document does not disclose derivatives of the
pharmacologically active compounds, nor does it address any
particular aspect of interaction with zinc, which is there to
create a reservoir effect in the skin. The result is to reduce the
overall transdermal flux of the active agent, but to enhance the
initial uptake of the agent into the dermis where, in association
with the zinc, it is retained in the form of a reservoir.
[0011] Clindamycin phosphate is a known antibiotic effective in the
treatment of acne. Unlike erythromycin, it is not suitable for
systemic administration for this indication, but is useful in
providing a substance other than erythromycin to treat acne,
thereby helping to avoid proliferation of erythromycin resistant
strains of bacteria.
[0012] Topical clindamycin (Cleocin T Topical Lotion) has been
demonstrated to be a safe and effective alternative to oral
tetracycline therapy, when applied twice daily for 12 weeks to 43
patients with rosacea [Wilken et al., Treatment of rosacea: topical
clindamycin versus oral tetracycline Int. J. Dermatol. (1993);
32:65-67]. Despite this study, there has been limited development
in the use of topical clindamycin to treat rosacea.
[0013] U.S. Pat. No. 4,621,075, to Fawzi, discloses combinations of
clindamycin phosphate and zinc acetate in a non-aqueous,
pharmaceutically acceptable, topical vehicle. The formulations may
contain up to 5% water without significant adverse effects on the
formation of the desired gels, although no water-containing
formulations are exemplified. Diisopropyl sebacate is a required
component of this vehicle, the other component preferably being
ethanol. The disclosed formulations must be capable of gelling, and
it is specifically shown than a 1:1 molar ratio does not gel. In
this formulation, diisopropyl sebacate acts as a skin permeation
enhancer.
[0014] The formulations of U.S. Pat. No. 4,621,075 are very oily to
the touch, and do not form clear solutions, with large undissolved
particles being left suspended in the final formulation. They are
not ideal for the treatment of acne, both because of the oleaginous
nature of the skin condition to be treated, and because of the
presence of excess ethanol in the formulation. Not only is the
greasiness of the formulation not likely to promote good patient
compliance, but a greasy formulation is also inappropriate to treat
acne. The large amounts of ethanol in the brittle formulation
rapidly evaporate to leave a thick oleaginous, or dry, deposit,
causing the clindamycin phosphate to come out of solution, and
drying out the skin in the process, thereby further enhancing the
greasy effect and hindering transdermal adsorption.
[0015] WO 97/15282 discloses treatments for dermatological
disorders comprising three known types of acne treatment agents: an
antimicrobial agent, an alpha or beta hydroxyacid, and a zinc
compound.
[0016] Surprisingly, we have now found that a stabilised, aqueous
preparation of zinc salt and clindamycin phosphate forms a high
molecular weight polymer which does not appear to be taken into the
skin, thereby reducing flux still further, and which only needs to
be applied once a day, by comparison with the twice-daily regimen
for other clindamycin products on the market.
[0017] Thus, in a first aspect, the present invention provides an
aqueous preparation, or formulation, for topical application
comprising substantially equimolar amounts of clindamycin phosphate
and a water-soluble zinc salt for use in the treatment of
dermatoses.
[0018] In U.S. Pat. No. 4,621,075, for example, it is noted that
the presence of water prevents the formation of the desired gels,
with the constituents simply going into solution without
gelling.
[0019] What we have found is that it is possible to form gels of
clindamycin phosphate with zinc salts in the presence of water,
provided that a substantially neutral, aqueous preparation of
clindamycin phosphate is used. Aqueous solutions of clindamycin
phosphate do not form easily. If an alkaline solution is added to
the mix of clindamycin phosphate and solvent in an amount suitable
to bring the preparation to neutrality, or even slight alkalinity,
then a gel will tend to form quickly, on addition of the zinc salt.
These gels have superior qualities to the gels disclosed in U.S.
Pat. No. 4,621,075.
[0020] Thus, in a preferred embodiment, the preparations of the
present invention have a substantially neutral pH.
[0021] The conditions for gel formation are preferably
substantially neutral, preferably between 5.5 and 8.0, and
particularly between 7 and 7.5, where gel formation is generally
optimal. Once the gel has been formed, then pH may be allowed to
vary over a range of substantially neutral pH's, especially between
a pH of 5.5 and 8.0, without decomposition. For example, the
initial gel may be further, optionally substantially, diluted with
other components, such as are discussed below, which may lead to a
variation in the pH. In addition, formation of the gel may lead to
a drop in pH, as described below. However, provided that such
variation does not fall outside of the above range, then the
compositions will generally be stable.
[0022] The formulations of U.S. Pat. No. 4,621,075 have no pH, as
they are non-aqueous, so are unable to provide the stability or
gel-forming environment of the present invention.
[0023] As noted above, the optimal pH for the formation of the
zinc/clindamycin phosphate polymer is around pH 7. Clindamycin
phosphate is a zwitterionic compound and, at pH 7, the phosphate
group is largely deprotonated, while the tertiary amine is
essentially protonated. The phosphate group is, thus, able to
complex with the zinc ions of the zinc salt. Increasing or
decreasing the pH outside of the above ranges generally leads to
the formation of other species and, further, reduces the
pharmacological effectiveness of the formulation.
[0024] Without being restricted by theory, what we have found is
that, essentially, a large, electrostatically bound polymer forms
in substantially neutral, aqueous preparations of clindamycin
phosphate and zinc salt. These polymers preferably form when the
molar amount of zinc salt is approximately equivalent to, or
greater than, the amount of clindamycin phosphate. Polymer forms
when the amounts of zinc salt and clindamycin phosphate are not
equimolar, but the properties of the formulation may be affected by
the excess of that constituent present in the greater amount. This
is less so with excess zinc salt, but especially where the amount
of zinc is much less than equimolar, then any gel formed tends to
be thin.
[0025] The polymer formed between zinc and clindamycin phosphate
does not tend to pass into the skin, and it is likely that the
polymer becomes lodged in the stratum corneum. This may well be due
to the nature of the polymer itself, but we have also noted that,
using in vitro cellulosic membranes, increased levels of zinc
further reduce the ability of clindamycin phosphate to penetrate
the skin.
[0026] When applied to the skin, it appears that clindamycin
phosphate, or a complex of clindamycin phosphate and zinc, rapidly
becomes adsorbed in the stratum corneum, rather than being absorbed
in the dermis, as previously observed in the art for formulations
comprising zinc.
[0027] More specifically, when such prior art formulations as
Dalacin.RTM. T are applied to the skin under controlled conditions,
while some clindamycin phosphate penetrates the dermis and enters
the plasma, most of the clindamycin phosphate remains on the
surface of the skin, and is recoverable by swabbing. By contrast,
levels of clindamycin phosphate recoverable from the skin, 48 hours
after application of a formulation of the invention, drop by as
much as 50%. However, whereas with Dalacin.RTM. T, clindamycin
phosphate is readily detectable in both the dermis and the plasma,
formulations of the present invention show little or no clindamycin
phosphate present in the dermis, and substantially reduced levels
of clindamycin in the plasma.
[0028] Accordingly, the formulations of the present invention are
advantageous over the art in a number of respects. The aqueous
nature of the formulation prevents the skin from drying out, a
common problem observed with formulations containing an excess of
ethanol. While the zinc is likely to have the reservoir effect of
the art, it also serves to bind the clindamycin phosphate as a
polymer, so that use of the formulations of the invention results
in negligible systemic concentrations of clindamycin phosphate.
Further, rather than leave clindamycin exposed on the skin surface,
it is rapidly absorbed or adsorbed into the surface layers of the
skin, thereby protecting it from being washed off. This is
particularly useful, as it mimics the effect of providing much
greater levels of clindamycin without the concomitant risk of
raising systemic levels. In addition, the formulations of the
invention are pleasant to use, and are suitably formulated to be
dispensed from a squeezable tube or bottle, for example, as
compared to the formulations of U.S. Pat. No. 4,621,075, which tend
to be brittle.
[0029] The formulations of the present invention comprise a
polymeric combination of zinc and clindamycin phosphate which is in
a dynamic equilibrium with its constituent parts. Thus, at any
given time, zinc and clindamycin phosphate are individually
identifiable within the preparation. The amount of complex, or
polymer, will vary according to the conditions both in the
formulation and on the skin. Application of the formulation to the
skin serves to dispense clindamycin phosphate straightaway but,
more particularly, the polymer acts as a slow release formulation,
dispensing clindamycin phosphate to the skin. Thus, there is both
immediate and long term action, which allows the formulations of
the present invention to be applied only once daily but, yet, to
have the same therapeutic effect as established clindamycin
preparations.
[0030] The co-ordination complex of clindamycin phosphate and zinc
is not dependent on the nature of the anion associated with the
zinc in the original zinc salt. As such, the zinc salt used in the
present invention is not critical to the invention. However, it
will be appreciated that the selected anion should be
pharmaceutically acceptable in topical formulations. The salt will
be selected from salts of suitable organic or inorganic acids, and
is preferably readily soluble in water, or in the solvent mixture
used for the dissolution of clindamycin phosphate.
[0031] Suitable zinc salts may be selected from those obtainable
from both organic and inorganic acids. When the zinc salt is
obtained from an organic acid, then it is generally preferred that
the acid have a small, readily dissociable anion, such as acetate,
propionate or pyruvate, the saturated, lower alkanoic acids and
their hydrated forms being preferred, especially zinc acetate and
particularly zinc acetate dihydrate. It will be appreciated that
the anion is of little or no importance to the polymer, so that the
primary consideration is that the zinc salt be able to readily
provide the zinc cation, and that the anion not hinder formation of
the polymer. It will also be appreciated that the anion should be
pharmaceutically acceptable. Similar considerations apply to any
inorganic anion selected. Small anions are generally preferable,
but larger anions may be selected for their therapeutic activity,
for example, as with the organic anions. In general, however,
simple anions, such as the chloride, are preferred, with simple
organic anions being preferred over the inorganic, as these are
more readily soluble in water/cosolvent mixtures.
[0032] While the primary means for stabilising the formulations of
the present invention is by pH control other means include the use
of anti-crystallising agents such propylene glycol, and thickeners,
as discussed further below, as well as diluents and other
substances which do not adversely affect the final formulation, or
which provide advantages in formulation, such as ethanol. It will
be appreciated that all such additional substances, insofar as they
form a part of the final formulation, should preferably be
pharmaceutically acceptable.
[0033] Ethanol, or other hydroxy-substituted hydrocarbon, is
suitable to assist in the dissolution of clindamycin phosphate in
the original formation of the complex, and is also useful in the
preparation of the final formulation. As noted above, clindamycin
phosphate is poorly soluble in water and, even in the presence of a
suitable base, such as sodium or potassium hydroxide, the compound
is not readily soluble. Accordingly, it is preferred to use a
co-solvent, such as ethanol, in order to achieve solution.
[0034] It will be appreciated that the amount of co-solvent
required will be readily determined by those skilled in the art. In
general, any amount of co-solvent that enhances dissolution will be
useful, and it is preferred to use no more than 70% w/w co-solvent.
Suitable alcohols are liquids at room temperature, and are
preferably lower alkanols, such as ethanol or isopropanol. The
preferred co-solvent is ethanol, as this is pharmaceutically
acceptable and readily miscible with water. However, any
pharmaceutically acceptable, non-aqueous co-solvent may be
employed, provided that it is readily miscible with water.
[0035] As it is generally preferred to minimise the amount of
co-solvent, in order to minimise any disadvantages, perceived or
otherwise, of such co-solvent, then it is preferred to use no more
than 50% ethanol overall, and preferably no more than 25%.
Formation of the initial complex may involve up to about 60%
ethanol, although substantially equal amounts of water and alcohol
are preferred.
[0036] It will also be appreciated that the amount of co-solvent
may be maximised in order to achieve solution, with subsequent
removal of all or part of the co-solvent before preparation of the
final formulation. The final formulation may simply be the
complexed, neutralised clindamycin phosphate and zinc salt in water
and co-solvent, or with the co-solvent removed. More preferably,
the final formulation comprises further ingredients, such as
diluents and/or stabilisers, as discussed below.
[0037] Although the polymer formed as the co-ordination complex of
zinc and clindamycin phosphate forms a gel under aqueous
conditions, it is preferred to use low concentrations of
clindamycin phosphate in the topical formulation. Preferred
concentrations range from 0.1% to 10%, with more preferred
concentrations being from 0.5% to 5%, especially around 1% to 2% by
weight. At these concentrations, the gel formed by the interaction
of clindamycin phosphate in zinc is not especially strong so that,
accordingly, it may be desirable to incorporate a thickener.
Suitable thickeners include silicon dioxide, silicates, carbomers
and cellulosic compounds, such as hydroxymethylcellulose,
hydroxypropylcellulose and hydroxyethylcellulose, with
hydroxyethylcellulose being currently preferred. Any other
appropriate thickeners may also be used, provided that they do not
substantially impede the formation of the zinc/clindamycin
phosphate co-ordination complex, and are pharmaceutically
acceptable.
[0038] Where such thickeners are employed, it is only necessary
that they be employed in sufficient quantities to prevent the gel
from running. Quantities greater than this may be employed, as
desired, in order to achieve the desired consistency.
[0039] It is particularly preferred to employ the cellulosic
compounds as thickeners or texture modifiers, as these also tend to
be able to retain water in the formulation. In addition, the effect
on the final formulation is generally to modify the flow
characteristics such as to convey pseudoplastic flow character on
the formulation, which ensures a pleasing texture on the
formulation, and assists in dispensing the formulation, for
example.
[0040] Amounts of thickeners or congeners may suitably be in the
range of about 0.2 to about 8% w/w, although more effective such
gellants may be used in lower levels, such as about 0.5 to about
3%, preferably about 0.7 to about 2%, with levels of about 0.8 to
about 1.5% being useful, especially in the case of the cellulose
derivatives, for example.
[0041] As noted above, the preferred pH for forming the polymer is
around 7. In the present invention, it is generally preferred to
first prepare a solution or suspension of clindamycin phosphate and
then to adjust the pH of this preparation to about a pH of 7. More
particularly, under the conditions in the accompanying Examples, we
have found that pH 7.5 provides good results. Once at this pH, the
clindamycin phosphate is completely soluble, especially in the
presence of ethanol, for example.
[0042] After adjustment to an essentially neutral pH, the zinc
salt, such as zinc acetate, is added. This is preferably done after
the pH-adjusted solution has been stirred until all of the
clindamycin phosphate has dissolved, but this is not necessary.
Stirring of this resulting mix leads, generally immediately or
within a few minutes, to a thickening of the solution. There is no
particular limit as to the type of agitation involved. Stirring is
one convenient means, and stirring with high shear, especially in
the preparation of large batches, ensures that the resulting gel is
homogeneous.
[0043] Such formulations can then be used directly, or are
preferably diluted to the preferred concentrations, as noted above,
together with the incorporation of any preferred excipients,
surfactants, colourings, stabilisers, gellants and any other
materials which it is desired to incorporate in the final
composition.
[0044] Thus, the present invention further provides a method for
the manufacture of a preparation as described above, comprising
first dissolving or suspending clindamycin phosphate in an aqueous
vehicle and then adjusting the resulting solution or suspension to
a substantially neutral pH, preferably wherein the pH is from pH
7.0 to pH 7.5, inclusive.
[0045] There is no particularly preferred alkali, but we find
aqueous sodium or potassium hydroxide to be convenient, especially
sodium hydroxide. The amount is that which is necessary to bring
the aqueous preparation containing the clindamycin phosphate to a
pH between 7 and 7.5 or, more generally, a pH from 5.5 to 8.0. The
aqueous preparation containing the clindamycin phosphate may be in
the form of a solution, suspension, simple mixture, or any
combination of these forms. After the alkali has been added,
especially to over a final pH of about 6.5, the remaining
undissolved clindamycin phosphate rapidly enters solution at
ambient temperature in the presence of co-solvent, preferably at
least 25% by weight, especially when the co-solvent is ethanol.
[0046] When the zinc salt is added to the clindamycin phosphate,
complexing of the zinc with the deprotonated phosphate groups
results in a neutral polymer but releases protons and the zinc salt
anion, so that an acidic solution will tend to form. Where the
anion is acetate, for example, then this is not only readily
soluble in any water/co-solvent mixture, but also forms less
caustic acid solutions in association with protons than inorganic
anions, such as chloride, for example.
[0047] Thus, the amount of alkali is preferably selected not only
to deprotonate the phosphate groups of clindamycin, which
preferentially appears to occur at a pH of 7 or above but which,
especially depending on conditions, may occur at lower pH's, but
also to yield a final formulation having a pH above 5.5, preferably
6.0 or above, after the addition and incorporation of zinc
salt.
[0048] The term "aqueous vehicle", as used herein, relates to any
suitable liquid vehicle comprising a substantial amount of water,
preferably at least 30%.
[0049] It is generally preferred that this initial preparation of
clindamycin phosphate and zinc salt in an aqueous vehicle is used
in the preparation of a final formulation. It is also generally
preferred that the initial preparation forms less than 50% of the
final formulation by weight, with the remainder of the constituents
being added after the zinc salt has been added. This allows the
polymer to form under optimal conditions, prior to making up to the
final formulation.
[0050] Indeed, the zinc salt may be added prior to addition of the
alkali, or contemporaneously therewith, but this might interfere
with the effect on the clindamycin phosphate, and is not generally
preferred.
[0051] The final formulation should generally be selected so as to
not to encourage the decomposition of the polymer. Any dilution of
the vehicle containing the initial complex is likely to lead to a
certain amount of decomposition, especially if the dilution is with
a major proportion of water. Accordingly, it is preferred to use a
suitable topical vehicle comprising a significant amount of a
non-aqueous vehicle or diluent. In this respect, a significant
amount is generally at least 40%, and may be up to about 80% by
weight.
[0052] Generally, it is preferred to loosely maintain a similar
ratio of aqueous:non-aqueous throughout the preparation of both the
initial complex and the final formulation. There is no particular
ratio that should be observed, but it is preferred to take the
solubility of clindamycin phosphate and the zinc salt into account.
Clindamycin phosphate is not an especially readily soluble
substance even in neat ethanol, while zinc salts, such as the
acetate, are readily soluble in water and, to a lesser extent, in
ethanol, so that a ratio of about 2:1 non-aqueous:aqueous is
generally useful in the final formulatin, although a range of about
1:1 to 2.5:1 is also convenient. In particular, the initial
preparation of the gel may employ higher quantities of non-aqueous
co-solvent. Other ranges will be immediately apparent to the
skilled person. The above combinations allow sufficient dissolution
of clindamycin phosphate, while maintaining a sufficient quantity
of water to encourage zinc ion solvation and interaction with the
zwitterionic clindamycin phosphate.
[0053] It will also be appreciated that the co-solvents for the
final formulation need not necessarily be involved in maintaining
clindamycin phosphate in solution, provided that they do not
actively drive it out. Instead, they may be involved in other
aspects of the formulation, such as described in more detail below.
However, it is generally desirable to incorporate a certain level
of co-solvent for the purposes of enhancing, encouraging, or
maintaining the clindamycin phosphate in solution, and this can
suitably form a part of the non-aqueous component of the final
formulation.
[0054] Thus, it is preferred to employ levels of
non-aqueous:aqueous of between 4:1 and 2:3, more preferably 3:1 and
1:1, particularly 2.5:1 and 1.5:1, and especially around 2:1 in
both the initial vehicle and the final formulation, the ratio being
the same or different, preferably the same for both.
[0055] The formulations of the present invention may be in any
suitable form, and may be in the form of creams, ointments,
lotions, gels or any other suitable form, but are preferably
sufficiently viscous not to run off the area of skin to which they
are applied and such that an appropriate quantity of the
formulation can be applied to the area in question. The aqueous and
non-aqueous components may be selected appropriately in order to
achieve the desired formulation type. The preferred formulation is
a gel.
[0056] It is also an advantage of the present invention that it is
not generally necessary to use a skin permeation enhancer, such as
diisopropyl sebacate. In particular, the presence of such an
enhancer leads to greater build up of clindamycin phosphate in the
dermis and, inevitably, to greater levels of clindamycin in the
plasma. By contrast, this is generally avoided in the formulations
of the present invention, especially in the absence of skin
permeation enhancers.
[0057] We have found that it is advantageous to employ a physical
stabilising compound in the present invention. Aqueous formulations
of zinc and clindamycin phosphate, after storage, may form
crystals, and this is not desirable. Thus, it has been found that
it is possible to avoid such crystal formation by the incorporation
of agents, such as propylene glycol. Although propylene glycol has
been found to be useful in the present invention, any other
suitable, hydrophilic solvent which is also pharmacologically
acceptable may be used, such as glycerine, or different grades of
polyethylene glycols, or macrogols. Such stabilising compounds may
be used in any appropriate amount, varying from about 1% by weight
to about 80%.
[0058] Such hydrophilic solvents, or co-solvents may be employed as
substantially the whole of the additional non-aqueous phase of the
final formulation, if desired. More preferably, the additional
non-aqueous material added to achieve the final formulation
contains an amount of any initial co-solvent employed in the
preparation of the initial preparation of clindamycin
phosphate/zinc complex. This amount may be up to 100%, but is
preferably between 10 and 50% of the additional non-aqueous
component, and more preferably between 15 and 30%, such as about
20%. Greater amounts may tend to evaporate and concentrate the
solution, and this may be undesirable.
[0059] Any non-aqueous substance added to achieve the final
formulation is preferably non-volatile, or is not so volatile as to
substantially completely evaporate within a short period after
application to the skin. In this respect, ethanol may be considered
to be volatile, while propylene glycol may be considered to be
non-volatile, for example.
[0060] Formulations of the present invention have also been found
to be thixotropic, and generally increase in viscosity with
storage. There is no particular problem with storage, and preferred
formulations of the present invention can be stored for at least
two years without adverse effects.
[0061] Further provided are methods for the treatment of dermatoses
comprising application of a pharmacologically effective amount of a
formulation as described above. Suitable amounts of formulation to
be applied to the skin may comprise about 0.01 to about 0.3 ml
cm.sup.-2, for example, more preferably about 0.05 to about 0.1 ml
cm.sup.-2, but there is no particularly preferred regimen, and it
is simply sufficient to apply formulation to the affected area, or
the area desired to be treated.
[0062] Dermatoses suitable for treatment by the present invention
particularly include acne vulgaris, but also include any other
conditions treatable by clindamycin or clindamycin phosphate,
especially rosacea.
[0063] The present invention will now be further illustrated with
respect to the following, non-limiting Examples. The materials used
in the Examples were sourced as follows: Clindamycin phosphate (USP
BN B21946), Genzyme; sodium hydroxide pellets (BN B552682), zinc
acetate dihydrate (BN D0325), hydroxyethylcellulose (BN 9906B038),
and propylene glycol (BN 08101-1), August Wolff; ethanol (99-100%
v/v) and ethanol (96% v/v), BDH; polyethylene glycol 400, Sigma
Pharmaceuticals; zinc acetate (anhydrous), Aldrich Chemical Co.;
diisopropyl sebacate, A&E Connock Ltd.; and Spectra/Por.RTM.
Biotech CE membrane (MWCO 5000), NBS Biologicals, Cambs, UK.
Deionised water was obtained using an Option 3 Water Purifier
(Elga).
[0064] The Examples will be illustrated with respect to the
accompanying drawings, in which:
[0065] FIG. 1 shows the flow curves representing the behaviour of
the formulations having a CP:ZnA molar ratio of 1:1.5;
[0066] FIG. 2 shows the flow curves representing the behaviour of
formulations from U.S. Pat. No. 4,621,075 examples II and IV,
compared with formulations of the present invention;
[0067] FIG. 3 shows the flow curves representing the behaviour of
the formulations of U.S. Pat. No. 4,621,075, but containing water
in amounts between 0 and 40%;
[0068] FIG. 4 shows the effect of CP release from P&G II,
P&G IV, complex of the invention and formulation of the
invention (CP:ZnA, 1:1 molar ratio) over time; and
[0069] FIG. 5 demonstrates the effect of the addition of water at
5, 15 and 40% to P&G formulations on the release rate of
clindamycin phosphate.
EXAMPLE 1
Clindamycin Gel 1% w/w
[0070] Method of Preparation
[0071] 1.Formula
[0072] A formula was made up, as shown below:
1 Ingredient Unit Formula (% w/w) Complex Clindamycin phosphate
1.188.sup.1,2 Purified water 12.0 Ethanol 96% 10.0 Sodium hydroxide
q.s. to pH 7.5 30% w/w Zinc acetate dihydrate 0.516 Formulation
Hydroxyethylcellulose 1.0 Propylene glycol 40.0 Ethanol 96% 10.0
Purified water q.s. to 100% .sup.1Equivalent to 1.0% Clindamycin
.sup.2For convenience this is referred to as Clindamycin 1%
.sup.3Batch weight corrected for clindamycin phosphate potency
[0073] 2. Manufacture
[0074] Complex
[0075] a) Mix ethanol and purified water using a homogeniser.
[0076] b) With continuous homogenisation, add the clindamycin
phosphate (weight corrected for assay and water content) to form a
suspension.
[0077] c) While mixing continues, slowly add sodium hydroxide 30%
w/w to a pH of 7.5 (allowing clindamycin phosphate to dissolve).
Record pH and calculate total amount of water added.
[0078] d) Dissolve zinc acetate dihydrate in purified water and mix
until a clear solution is formed.
[0079] e) With continuous homogenisation add the zinc acetate
solution to the pH 7.5, clindamycin phosphate solution. Continue
mixing, until a homogeneous, translucent, white gel forms.
[0080] This process may take place as a number of smaller
sub-batches.
[0081] Cellulose Gel Base
[0082] f) Mix propylene glycol and ethanol 96% until
homogeneous.
[0083] g) While homogenising, add hydroxyethylcellulose until a
clear, homogeneous, gel is formed.
[0084] Final Gel Manufacture
[0085] h) Add the clindamycin phosphate zinc complex to the base
gel and mix until a uniform, white opaque gel is produced.
[0086] i) Add water to 100% and mix to homogeneity.
[0087] j) Fill into tubes.
EXAMPLE 2
[0088] U.S. Pat. No. 4,621,075 discloses combinations of
clindamycin phosphate and zinc acetate in a non-aqueous, topical
vehicle at a molar ratio greater than 1:1.2. The patent states that
ratios below this result in poor or no gel formation. This Example
establishes the differences between the formulations of the present
invention and U.S. Pat. No. 4,621,075 (referred to herein as the
"P&G patent", or just "P&G"). As used herein, CP is
clindamycin phosphate and ZnA is zinc acetate dihydrate.
[0089] In contradiction to the patent, it was found that gel
formation occurred at CP:ZnA, 1:1 molar ratio. All P&G
formulations were very oily to the touch.
[0090] The rheology of formulations of the present invention and
P&G formulations is studied in this Example. Simple fluids
where the rate of flow is directly related to the applied stress
can be regarded as Newtonian fluids. However, most pharmaceutical
fluids do not follow this law because the viscosity of the fluid
varies with the rate of shear and thus are regarded as
non-Newtonian fluids. One deviation is plastic flow, which occurs
when the flow curve does not pass through the origin, but
intersects with the shear stress axis at a point referred to as the
yield value. This is because the plastic material does not flow
until such a value of shear stress has been exceeded. At lower
stresses, the substance behaves as a solid (elastic) material.
[0091] Pseudoplastic flow arises at the origin, since no yield
value exists and the material will flow as soon as shear stress is
applied. However, the slope of the curve gradually increases with
increasing rate of shear. The viscosity of pseudoplastic materials
is derived from the reciprocal of the linear portion of the flow
curve or any tangent drawn to it (as with other substances).
Accordingly, viscosity decreases as the shear rate is increased for
pseudoplastic materials.
[0092] This Example is divided into three parts. In the first, the
P&G complex was prepared as described in U.S. Pat. No.
4,621,075, example V, with clindamycin phosphate:zinc acetate molar
ratios of approximately 1:0.5, 1:1, 1:1.5 and 1:2, and their
rheology compared to those of a preferred formulation of the
present invention prepared with similar CP:ZnA ratios. As with the
other parts of this Example, the preferred formulation of the
present invention was prepared as both the complex and the final
formulation.
[0093] In the second part of this Example, the P&G formulation
was prepared as described in U.S. Pat. No. 4,621,075, examples II
and IV, and its rheology compared to that of a preferred
formulation of the present invention.
[0094] In the third part, the P&G formulation was prepared as
described in U.S. Pat. No. 4,621,075, example V, with clindamycin
phosphate:zinc acetate molar ratios of 1:1.5, and the effect of 5,
15 and 40% (w/w) water on the rheology of the formulation compared
to those of a preferred formulation of the present invention.
[0095] Part 1
[0096] P&G Formulations
[0097] 28.0 g diisopropyl sebacate will be weighed into a beaker.
70.5 g ethanol will then be weighed out and added to the beaker.
These two components will then be mixed together with moderate
agitation using a magnetic stirrer. The beaker will be kept covered
during mixing in order to minimise ethanol evaporation. 1.0 g
clindamycin phosphate will be added to the beaker and stirring will
continue for about two minutes. 0.5 g zinc acetate (anhydrous) will
then be added and the stirring will continue until the mixture
thickens. The stirring bar will be removed and the mixture will be
set aside. After several hours, a clear gel will form.
[0098] Molar ratios of clindamycin phosphate:zinc acetate
(anhydrous) will be altered by altering the zinc acetate molarity
(adjusted with anhydrous ethanol) with the molarity of clindamycin
phosphate being kept constant. The clindamycin phosphate:zinc
acetate (Molar) ratios examined were:1:0.5; 1:1.0; 1:1.5; and
1:2.0.
[0099] Formulations of the Invention
[0100] The complex was prepared as follows. 40 g ethanol and 40 g
purified water will be mixed using a homogeniser. With continuous
homogenisation, clindamycin phosphate (weight corrected for assay
and water content) will be added to form a suspension. While mixing
continues, sodium hydroxide 30% w/w will be added to a pH of 7.5
(pH and total amount of water will be recorded). 2.064 g of zinc
acetate dihydrate will be dissolved in 8 g of purified water and
mixed until a clear solution is formed. With continuous
homogenisation, zinc acetate solution will be added to the pH 7.5
clindamycin phosphate solution. Mixing is continued until a
homogeneous translucent gel is formed.
[0101] The formulation was prepared as follows. 160 g propylene
glycol will be mixed with 40 g of ethanol 96% v/v until
homogeneous. While homogenising, 4 g of hydroxyethylcellulose will
be added until a clear homogeneous gel is formed. The climdamycin
phosphate:zinc complex will then be added to the thus formed gel
and mixed until a uniform, white opaque gel is produced. Water will
be added, until a final weight of 400 g is achieved, and mixed. The
molar ratio of clindamycin phosphate:zinc acetate dihydrate will be
altered by altering the zinc acetate dihydrate molarity (adjusted
with water) with the molarity of clindamycin kept constant.
[0102] At completion of the preparation, formulations will be
stored at room temperature for 30 minutes prior to the rheology and
diffusion studies, which will be performed simultaneously. Such a
protocol ensures that all the formulations will be tested at the
same age.
2 Ingredient % w/w Complex Clindamycin phosphate 1.188 Purified
water 12.0 Ethanol 96% 10.0 *Sodium hydroxide 30% w/w qs to pH 7.5
Zinc acetate dihydrate 0.516 Gel base Hydroxyethylcellulose 1.0
Propylene glycol 40.0 Ethanol 96% 10 Purified water qs to 100%
*Preparation of 30% (w/v) aqueous sodium hydroxide: 3 g sodium
hydroxide will be dissolved in 10 ml water.
[0103] Part 2
[0104] Formulations of the Invention
[0105] These were prepared as in Part 1, above.
[0106] P&G Formulations
[0107] U.S. Pat. No. 4,621,075 example II--25.0 g polyethylene
glycol will be weighed into a beaker. 73.4 g ethanol will then be
weighed out and added to the beaker. These two components will then
be mixed together with moderate agitation using a magnetic stirrer.
The beaker will be kept covered during mixing in order to minimise
ethanol evaporation. 1.0 g clindamycin phosphate will be added to
the beaker and stirring continued for about two minutes. 0.54 g
zinc acetate (anhydrous) will then be added and the stirring will
continue until the mixture thickens. The stirring bar will be
removed and the mixture will be set aside. After several hours, a
clear gel will form.
3 Ingredients % (w/w) Clindamycin phosphate 1.0 Zinc acid
(anhydrous) 0.54 Polyethylene glycol 400 25.0 Ethanol (anhydrous)
73.46 CP:Zn (1:1.5 molar)
[0108] U.S. Pat. No. 4,621,075 example IV--99.23 g of ethanol will
be weighed out and added to a beaker. 0.50 g clindamycin phosphate
will be added to the beaker and stirred for about two minutes. The
beaker will be kept covered during mixing in order to minimise
ethanol evaporation. 0.27 g zinc acetate (anhydrous) will then be
added and the stirring will continue until the mixture thickens.
The stirring bar will be removed and the mixture will be set aside.
After several hours, a clear gel will form.
4 Ingredients % (w/w) Clindamycin phosphate 0.50 Zinc acetate
(anhydrous) 0.27 Ethanol (anhydrous) 99.23 CP:Zn (1:1.5 molar)
[0109] Part 3
[0110] Formulations of the Invention
[0111] These were prepared as in Part 1, above.
[0112] P&G Formulations
[0113] U.S. Pat. No. 4,621,075 example V--28.0 g diisopropyl
sebacate will be weighed into a beaker. 70.46 g, or other amount in
accordance with the water content (see Table below) ethanol will
then be weighed out and added to the beaker. These two components
will then be mixed together with moderate agitation using a
magnetic stirrer. The beaker will be kept covered during mixing in
order to minimise ethanol evaporation. 1.0 g clindamycin phosphate
will be added to the beaker and stirring will continue for about
two minutes. 0.54 g zinc acetate (anhydrous) will then be added and
the stirring will continue until the mixture thickens. Water (as
applicable) will then be added to the mixture and stirring
continued until a homogenous mixture is formed. The stirring bar
will be removed and the mixture will be set aside. After several
hours, a clear gel will form. The molar ratio of clindamycin
phosphate:zinc acetate (anhydrous) remains constant whist the
addition of water will be replaced by the ethanol content.
5 CP:Zn CPZn CPZn CPZn (1:1.5) (1:1.5) (1:1.5) (1:1.5) Ingredient %
(w/w) % (w/w) % (w/w) % (w/w) Clindamycin phosphate 1.00 1.00 1.00
1.00 Zinc acetate 0.54 0.54 0.54 0.54 Water 0 5.0 15.0 40.0 Ethanol
(anhydrous) 70.46 65.46 55.46 30.46 Diisopropyl sebacate 28.0 28.0
28.0 28.0 CP:Zn (1:1.5 molar)
[0114] Rheology
[0115] Rheological measurements were carried out using a Carri-Med
CSL100 rheometer with the settings shown in the Table below.
[0116] a) 2 mL of formulation to be studied was expelled from a
syringe (5 ml) at an approximate rate of 1 ml/s.
[0117] b) The sample was then gently placed on the centre of the
platform using a spatula.
[0118] c) The instrument was used in a shear stress mode to produce
flow curves.
[0119] d) The number of replicates measured for each formulation
were dependent upon the time required to complete each flow
curve.
6 1. Preshear stress 0 Pa 2. Preshear time 00:00:00 HH:MM:SS 3.
Equilibration time 00:01:00 HH:MM:SS 4. Experimental mode shear
stress sweep 5. Temperature 15.0 .degree. C. 6. Start Stress 0 Pa
7. *End Stress 10.00 Pa 8. Stress mode linear 9. *Ascent time
00:05:00 HH:MM:SS 10. Measurement system type parallel plate 11.
Plate diameter 4.0 cm 12. Measurement system gap 250 .mu.m 13.
Measurement system inertia 1.440 .mu.Nms.sup.2 *The end stress and
ascent time were altered depending on the nature of # the
formulation however, a stress application rate of 2 Pa/min was #
maintained throughout the experiment for all formulations.
[0120] Results
[0121] No gel prepared in accordance with example V of U.S. Pat.
No. 4,621,075 was clear, all gels containing undissolved CP.
[0122] Rheology Studies
[0123] At a CP:ZnA molar ratio of 1:0.5, the flow curves of both
the complex of the invention and P&G formulation were
indicative of plastic flow, whilst the flow curve of the
formulation of the invention was typical of pseudoplastic flow.
These observations were found to be similar for all other CP:ZnA
molar ratios investigated, and are illustrated in FIG. 1, for a
CP:ZnA molar ratio of 1:1.5. As the CP:ZnA molar ratio was
increased from 1:0.5 to 1:1.5, the yield value of the complex of
the invention and the P&G formulation were observed to
increase. However, no significant difference (p>0.05) in yield
value was observed between molar ratios of 1:1.5 and 1:2 for both
the systems.
[0124] In the accompanying FIG. 1, the flow curves representing the
behaviour of the formulations having a CP:ZnA, 1:1.5 molar ratio
are shown. As in other Figures, "Complex" and "Formulation"
indicate the complex and the formulation of the invention,
respectively.
[0125] From the results in Table 1, it was clearly demonstrated
that the formulation with the highest .eta..sub.app was obtained
with all the molar ratios of CP:ZnA in the formulation of the
invention The .eta..sub.app (apparent viscosity--derived from the
reciprocal of the slope of the curve) was also observed to increase
as the molarity of ZnA was increased from 0.5 to 2.0 for all
formulations investigated (with the exception of the P&G
formulation at CP:ZnA 1:2 molar ratio). No obvious trend was
observed when the P&G formulation was compared to the complex
of the invention. At a CP:ZnA molar ratio of 1:0.5, the
.eta..sub.app of the complex of the invention was found to be
significantly (p<0.05) greater than the P&G formulation.
However, although the .eta..sub.app of the P&G formulation was
found to be greater than the complex of the invention at all other
molar CP:ZnA ratios, no significant (p>0.05) difference was
observed.
7TABLE 1 The mean apparent viscosity (.eta..sub.app) determined
from the reciprocal of the gradient obtained from the linear region
of the flow curves. P value compared to .eta..sub.app (Pas)
Formulation of the Formulation Mean .+-. s.d. (n = 2 to 6)
invention CP:ZnA (1:0.5) P&G formulation 0.0017 .+-. 0.0001 P
< 0.05 Complex of the invention 0.0021 .+-. 0.00003 P < 0.05
Formulation 0.0338 .+-. 0.0031 CP:ZnA (1:1) P&G formulation
0.0029 .+-. 0.0005 P < 0.05 Complex of the invention 0.0024 .+-.
0.0001 P < 0.05 Formulation 0.0581 .+-. 0.00154 CP:ZnA (1:1.5)
P&G formulation 0.0056 .+-. 0.0036 P < 0.05 Complex of the
invention 0.0025 .+-. 0.0002 P < 0.05 Formulation 0.0699 .+-.
0.0052 CP:ZnA (1:2) P&G formulation 0.0042 .+-. 0.0017 P <
0.05 Complex of the invention 0.0035 .+-. 0.0002 P < 0.05
Formulation 0.1147 .+-. 0.0214
[0126] Part 2
[0127] In this part, the flow curves of the complex and formulation
of the invention (CP:ZnA, 1:1) and P&G examples II and IV were
compared. As previously mentioned, the complex and formulation of
the invention exhibited plastic and pseudoplastic flow properties,
respectively. A flow curve for the P&G example II formulation
could not be constructed due to its excessively high yield value
(>350 Pa). The flow curve of the P&G example IV formulation
suggests significantly (p<0.05) greater plastic flow properties
compared to the complex of the invention formulation.
[0128] The results are shown in FIG. 2, which shows the flow curves
representing the behaviour of the formulations investigated.
[0129] Table 2 compares the .eta..sub.app of the formulations
investigated. The .eta..sub.app of the P&G example IV
formulation was not found to be significantly different (p>0.05)
to the complex of the invention. However, the formulation of the
invention was found to be significantly (p<0.05) greater than
both the complex of the invention and the P&G example IV
formulation.
8TABLE 2 The mean apparent viscosity (.eta..sub.app) determined
from the reciprocal of the gradient obtained from the linear region
of the flow curves. .eta..sub.app (Pas) Mean .+-. s.d. P value
compared to Formulation (n = 3 to 5) Formulation P&G example IV
0.0018 .+-. 0.0014 P < 0.05 Complex, CP:ZnA (1:1) 0.0024 .+-.
0.0001 P < 0.05 Formulation, CP:ZnA (1:1) 0.0581 .+-. 0.0015
[0130] Part 3
[0131] In this part, the flow curves of the P&G formulation
(CP:ZnA, 1:1.5) at 5, 15 and 40% (w/w) water, the complex of the
invention and formulation of the invention were compared. As
previously observed, the complex of the invention and the final
formulation exhibited plastic and pseudoplastic flow properties,
respectively. Once again, the flow curves of the P&G
formulations were found to be indicative of plastic flow. However,
no obvious trend in the flow curves was observed on the addition of
water to the P&G formulations. The results are shown in FIG. 3,
which shows the flow curves representing the behaviour of the
formulations investigated. The plastic flow properties of the
P&G formulations with 5. and 15% (w/w) water were found to be
similar, while the P&G formulations with 0 and 40% (w/w) water
also exhibited similar plastic flow properties but having a
significantly greater yield value. The flow curves of the P&G
formulations investigated were characteristically more plastic
compared to the complex of the invention.
[0132] Table 3 demonstrates the .eta..sub.app of the formulations
investigated. Again, the results did not show any obvious trend
when the percentage of water was increased to 40% (w/w) in the
P&G formulation. No significant difference in the .eta..sub.app
was observed between P&G formulations with 5% and 15% (w/w)
water, and this was found to be similar for 0 and 40% (w/w) water.
Importantly, all P&G formulations investigated in this study
was found to be significantly (p<0.05) greater in .eta..sub.app
compared to the complex of the invention (CP:ZnA, 1:1) whilst the
.eta..sub.app of the formulation of the invention was found to be
significantly (p<0.05) greater than all other systems
investigated.
9TABLE 3 The mean apparent viscosity (.eta..sub.app) determined
from the reciprocal of the linear region of the gradient of the
flow curves. .eta..sub.app (Pas) Mean .+-. s.d. P value compared to
Formulation (n = 3 to 5) Formulation P&G (CP:ZnA, 1:1.5) 0.0056
.+-. 0.0036 P < 0.05 0% water P&G (CP:ZnA, 1:1.5) 0.0037
.+-. 0.0003 P < 0.05 5% water P&G (CP:ZnA, 1:1.5) 0.0038
.+-. 0.0007 P < 0.05 15% water P&G (CP:ZnA, 1:1.5) 0.0048
.+-. 0.00007 P < 0.05 40% water Complex of the invention, 0.0024
.+-. 0.0001 P < 0.05 CP:ZnA (1:1) Formulation of the 0.0581 .+-.
0.0015 invention, CP:ZnA (1:1)
[0133] The plastic flow exhibited by the complex of the invention
and the P&G formulations in parts 1, 2 and 3 was found to be
dependent upon the complexation between CP and ZnA. This was
clearly demonstrated in part 1, when the .eta..sub.app of the
formulations generally increased as the CP:ZnA molar ratio
increased from 1:0.5 to 1:2.
[0134] The pseudoplastic flow demonstrated for all formulations of
the invention at all CP:ZnA molar ratios investigated may be due to
the hydroxyethylcellulose present therein. A flow curve for the
P&G example II formulation was not constructed, the high yield
value of the formulation suggesting a brittle gel structure.
[0135] All the P&G formulations investigated exhibited more
plastic flow than the complexes of the invention, although no
direct comparisons could be made between the formulations of the
invention and the P&G formulations as both sets of formulations
exhibited different flow properties. This was true even for the
P&G formulations which were made with water (contrary to the
teachings of U.S. Pat. No. 4,621,075), the presence of water making
surprisingly little notable difference to the properties of the
P&G formulations.
[0136] The results show that zinc substantially affects the
rheological properties of complexes of the invention and the
P&G formulation, the plastic flow properties being found to
increase as the CP:ZnA ratio was increased from 1:0.5 to 1:1.5,
although no significant difference was observed between CP:ZnA
ratios of 1:1.5 and 1:2 for either formulation. However, all
P&G formulations (with the exception of CP:ZnA, 1:0.5) were
found to have a significantly higher .eta..sub.app when compared to
the corresponding complexes of the invention, indicating the
presence of different mechanisms in the formulations.
[0137] The influence of the CP:ZnA complex was not as significant
for the formulations of the invention, the pseudoplastic flow
exhibited by the formulations of the invention suggesting that the
P&G formulations were significantly different from the
formulations of the invention. This was substantiated by the data
from part 2. The fact that addition of different amounts of water
to the P&G formulation made no difference to the rheological
properties of these formulations further suggested that the P&G
formulations and the formulations of the invention are
significantly different.
[0138] Thus, from the rheological data obtained, it could be
concluded that both the formulations of the invention and the
P&G formulations behave very differently in terms of the
mechanisms involved in the complexing of CP with Zn and the
resultant effect on the rheology.
EXAMPLE 3
Release Studies
[0139] In this Example, release rates of clindamycin from P&G
formulations were compared with release rates of formulations of
the present invention across a synthetic membrane.
[0140] The guidance based on SUPAC-SS for non sterile semisolid
dosage forms was followed [ZCG 31T; FDA (CDER), 1997, Guidance for
industry--SUPAC-SS Non-sterile Semisolid Dosage Form, Scale-up and
post-approval changes: Chemistry, manufacturing and controls; in
vitro release testing and in vivo bioequivalence documentation].
This guidance addresses nonsterile semisolid preparations such as
creams, gels, lotions and ointments intended for topical routes of
administration.
[0141] This Example was performed in three parts, and using
formulations as prepared in accordance with parts 1, 2 and 3 of
Example 2, above.
[0142] The pH of all the formulations to be studied was measured at
the beginning and end of the experiments. The testing of
formulations was conducted in accordance with the FDA's SUPAC In
Vitro Release Testing and In Vivo Bioequivalence guidelines
(supra).
[0143] Six Franz diffusion cell systems (18 mm diameter orifice)
system, fitted with a synthetic membrane (cellulose ester MWCO
3500) with deionised water as receiver fluid, were used for each
batch. An accurately weighed amount (300 mg) of the formulation,
corresponding to an infinite dose condition, was placed uniformly
on the membrane and occluded with Parafilm.RTM. to prevent solvent
evaporation and compositional changes. The Franz cells were placed
in a water bath at 32.degree. C. A sample (500 .mu.L) of the
receptor phase was removed at 1, 2, 3, 4, 5, 6 and 8 h. Any
aliquots removed from the receptor chamber were replaced with fresh
aliquot of receiver fluid (deionised water). Samples removed from
the receptor phase were analysed for drug content by high
performance liquid chromatography (HPLC).
10 HPLC Methodology Mobile Phase: 80:20, pH 2.5 phosphate
buffer:acetonitrile Column: Supelcosil LC-8, 25 cm .times. 4.6 mm,
5 .mu.m Detector: 210 nm Flow Rate: 1.0 mL/min Injection Volume:
100 .mu.L Temperature: 35.degree. C.
[0144] Preparation of buffer: potassium phosphate buffer (13.6
mg/mL), pH 2.5, will be prepared by dissolving 68 g of potassium
dihydrogen orthophosphate in 4 L of water. The solution will be
adjusted to pH 2.5 with orthophosphoric acid and water will be
added to 5 L. The buffer will be filtered as required.
[0145] Mobile phase: 80 parts by volume pH 2.5 phosphate buffer
will be mixed with 20 parts by volume HPLC grade acetonitrile. The
mobile phase will be filtered before use.
[0146] The percentage release was plotted against time. This
yielded a straight line, the slope of which represented the release
rate. The six samples yielded six slopes for each formulation,
providing in vitro release rates.
[0147] The pH's of all the complex and formulations of the
invention were determined, and are shown below.
11 Formulation pH before study pH after study Complex (CP:ZnA)
1:0.5 6.87 6.86 1:1 6.06 6.04 1:1.5 6.16 6.14 1:2 6.19 6.17
Formulation (CP:ZnA) 1:0.5 7.34 7.32 1:1 6.25 6.23 1:1.5 5.98 5.97
1:2 5.97 5.97
[0148] In addition, the pH's of the P&G formulations were taken
before testing, and were as follows:
12 Formulation pH before study Part 1 (CP:ZnA) 1:0.5 (6.3) 1:1
(5.1) 1:1.5 (6.1) 1:2 (5.5) Part 2 (CP:ZnA) 1:1.5 (6.2) Part 3 (w/w
% water) 0 (6.1) 5 5.7 15 5.5 40 4.9 Figures in brackets indicate
no pH, figure being an apparent pH produced by a pHmeter in the
absence of water in the preparation.
[0149] Figures in brackets indicate no pH, the figure being an
apparent pH produced by a pH meter in the absence of water in the
preparation.
[0150] Part 1
[0151] The release profiles of the each of the formulations tested,
at all CP:ZnA molar ratios, are shown in Table 4. It can be seen
that the different molar ratios of CP:ZnA significantly (p<0.05)
influence the rate of release of CP from all formulations across
the cellulose acetate membrane, but with the formulations of the
invention ("Formulation" in the Table below) exhibiting little
change. It is notable that the lowest level of release is for the
formulation of the invention at a molar ratio of CP:ZnA of 1:1, in
accordance with a preferred aspect of the present invention.
13TABLE 4 The release rates of CP from P&G, Complex of the
invention and formulation compared at similar molar ratios. Release
rate (%/h) P value compared to Formulation Mean .+-. s.e. (n = 5,6)
Formulation CP:ZnA (1:0.5) P&G formulation 0.657 .+-. 0.088 P
< 0.05 Complex of the invention 0.356 .+-. 0.040 P < 0.05
Formulation 0.207 .+-. 0.025 CP:ZnA (1:1) P&G formulation 0.276
.+-. 0.045 P < 0.05 Complex of the invention 0.221 .+-. 0.023 P
< 0.05 Formulation 0.140 .+-. 0.009 CP:ZnA (1:1.5) P&G
formulation 0.182 .+-. 0.041 P < 0.05 Complex of the invention
0.195 .+-. 0.016 P < 0.05 Formulation 0.223 .+-. 0.020 CP:ZnA
(1:2) P&G formulation 0.098 .+-. 0.026 P < 0.05 Complex of
the invention 0.108 .+-. 0.008 P < 0.05 Formulation 0.245 .+-.
0.031
[0152] Part 2
[0153] The results of this part are shown in Table 5 and FIG. 4.
FIG. 4 shows the effect of CP release from P&G II, P&G IV,
complex of the invention and formulation of the invention (CP:ZnA,
1:1 molar ratio) over time, mean.+-.s.e (n=5,6).
[0154] The results demonstrate that the rate of release of the
P&G IV formulation was more an two-fold greater than P&G II
formulation. Both of the P&G formulations were found to produce
significantly greater CP release than the either the complex or the
formulation of the invention. This data suggests that the release
of CP through the cellulose ester membrane was enhanced when
polyethylene glycol 400 in P&G II was replaced with ethanol
(P&G IV) even at half the CP concentration.
14TABLE 5 The release rates of CP from P&G, Complex of the
invention and formulations. Release rate (%/h) P value compared to
Formulation Mean .+-. s.e. (n = 5,6) Formulation P&G II 0.276
.+-. 0.035 P < 0.05 P&G IV 0.612 .+-. 0.050 P < 0.05
Complex of the invention 0.221 .+-. 0.023 P < 0.05 (CP:ZnA, 1:1)
Formulation of the 0.140 .+-. 0.009 invention (CP:ZnA, 1:1)
[0155] Part 3
[0156] The results are shown in Table 6 and FIG. 5. FIG. 5
demonstrates the effect of the addition of water at 5, 15 and 40%
to the P&G formulation at a Cp:ZnA 1:1.5 molar ratio, compared
to complex and formulation of the invention (CP:ZnA, 1:1). The
release rate of CP from the P&G formulation (at all water
contents) was found to be significantly greater (p>0.05) than
the formulations of the invention (CP:ZnA, 1:1), which provide
longer duration of delivery, in accordance with a preferred aspect
of the present invention.
15TABLE 6 The effect of water on the release rates of CP from
P&G (CP:ZnA, 1:1.5 molar ratio) compared to complex and
formulation of the invention (CP:ZnA, 1:1) Release rate (%/h)
Formulation Mean .+-. s.e. (n = 5,6) CP:ZnA (1:1.5) P&G
formulation (0% H.sub.20) 0.182 .+-. 0.041 P&G formulation (5%
H.sub.20) 0.301 .+-. 0.073 P&G formulation (15% H.sub.20) 0.435
.+-. 0.036 P&G formulation (40% H.sub.20) 0.672 .+-. 0.093
CP:ZnA (1:1) Complex of the invention 0.221 .+-. 0.023 Formulation
of the invention 0.140 .+-. 0.009
[0157] From Example 2, at a CP:ZnA molar concentration of 1:1.5,
the non-aqueous P&G formulation was found not to be
significantly different (p>0.05) from the aqueous systems of the
complex of the invention. Therefore, the addition of water to the
P&G formulation would not be expected to alter the rate of
release of CP from the P&G formulation. However, the release
rate of CP was found to increase significantly, as the percentage
of water was increased from 0% to 40%, suggesting that the release
rate of CP from the P&G formulation is very much affected by
water. Furthermore, the formulation of the invention contains
approximately 40% water, but only has a release rate of
approximately 20% of that of the P&G formulation (with a
similar amount of water) indicating that the two formulations
behave very differently.
[0158] Therefore, from the diffusion data observed, it could be
concluded that both the formulations of the invention and P&G
formulations behave very differently in terms of the mechanisms
involved in the complexation of CP with Zn and the resultant effect
on the thermodynamic activity of CP (drug release).
* * * * *