WO1999065435A1

WO1999065435A1 - Hydrogel body

Info

Publication number: WO1999065435A1
Application number: PCT/GB1999/001721
Authority: WO
Inventors: David Monteith; John Francis Porter
Original assignee: Cenes Drug Delivery Limited
Priority date: 1998-06-17
Filing date: 1999-06-16
Publication date: 1999-12-23
Also published as: GB9812965D0; AU4377999A

Abstract

A solid hydrogel body containing no pharmaceutically active agent is used by itself for the treatment of bacterial or viral infection, particularly for vaginal, rectal or oral administration or as a wound packing. It may also be used to take a sample for diagnosis purposes.

Description

HVDPOΠEL BODY

TECHNICAL FIELD

The present invention relates to the use of a solid hydrogel body for the treatment of infection in mammals such as humans and animals. The solid hydrogel body is unmedicated in the sense that it contains no active agent effective in the treatment of the infection. It is particularly useful in the treatment of infection or infectious disease in body cavities such as the vagina or rectum, and also in the mouth, for example, for treating gum disease.

The hydrogel body may also be used as a vehicle for removal of a sample for testing from a body cavity.

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Hydrogels in solid form as delivery vehicles for pharmaceutically active agents are disclosed, for example, in patent specification EP0016652. The crystalline cross- linked polyurethane hydrogels disclosed therein have the ability to swell by uptake of water without losing their solid form. They are also able to absorb quantities of active agent which can subsequently be released in a controlled manner during swelling. Such hydrogels have therefore been proposed as vehicles for the sustained release over extended periods of time of pharmacologically active substances. Solid hydrogel pessaries adapted for the sustained release of prostaglandins are commercially available for intra vaginal treatments during childbirth.

US Patent 3,953,406 describes the use of solid hydrogel bodies to absorb lipids, such as cholesterol, lecithin and sodium cholate from bile.

Whilst the art has previously focused on the sustained release of pharmacologically active agents from solid hydrogel bodies, it has now been surprisingly discovered that the unmedicated hydrogel is effective in itself in the treatment of certain infections and infectious states.

SUMMARY OF THE INVENTION

Thus, the present invention provides a solid hydrogel body for use as a medicament for the treatment of infection; the hydrogel body containing no active agent effective in said treatment of said infection.

This surprising result was revealed in clinical trials using the unmedicated solid hydrogel body as a control. It was surprisingly found that the solid hydrogel body on its own was effective in treating the infection. Without wishing to be bound by any theoretical mode of action, it is believed that the solid hydrogel body is effective by a number of possible modes of action. One mode of action involves absorption of toxins or other molecules produced as a direct result of the infection, leading to an alleviation of symptoms. A second possible mode of action is the removal of low molecular weight amino acids and other growth-supporting factors such as carbon and nitrogen sources required for biosynthesis. A third potential mode of action is by dehydration and disruption of opportunistic infections, so as to allow the natural equilibrium to return. A fourth possible factor is the provision of a surface for macrophagous activity to clear the infection.

The solid hydrogel body is particularly applicable for administration by insertion into a body cavity, such as vaginal, rectal or oral administration. It may also be used as a wound packing for infected wounds. The solid hydrogel body may be shaped according to the shape of the body cavity into which it is to be inserted. Particularly preferred shapes include cylinders, flat strips, lozenge- shaped, kydney-shaped etc. It may also be in the form of beads or granules. Generally, the body will have rounded leading and/or trailing ends to facilitate insertion and removal. The hydrogel body of the present invention, of course, differs from conventional suppositories which generally melt or otherwise disintegrate once inside the body cavity. The solid hydrogel body of the present invention retains its solid integrity during the swelling process and is removed at a convenient point, either before or after full swelling has been achieved. Advantageously, the hydrogel body may be shaped such as to maximise its surface to volume ratio thereby enhancing uptake, e.g. by providing surface corrugations. In particular, cylindrical bodies may be provided with longitudinal flutes or crenellations .

In view of its absorptive properties, the hydrogel body also offers an attractive route to the acquisition of fluid samples from a body cavity (particularly, the vagina or rectum) for diagnosis purposes. This is particularly valuable for diagnosis based on the detection of toxins present. There are instances where it is necessary to take a sample for diagnosis of putative vaginal infection, but where the woman is reluctant to undergo medical examination in which direct visualisation of the vagina is necessary in order to take a swab.

In order to facilitate removal of the solid hydrogel body, particularly from the vagina, it is preferably provided with retrieval means, such as a net bag and retrieval cord, e.g. as disclosed in patent application EP92306296.2.

The hydrogel body may in principal be formed from any water-swellable hydrogel material which retains its solid integrity (i.e. does not dissolve or disperse) on uptake of water. Preferred materials include polyurethanes and other swellable materials such as polyacrylates and polymethacry lates ( for example polyhydroxyethyl ethacrylate) . Generally, these materials will be at least partially cross-linked so as to maintain their structural integrity when swollen. A particularly preferred material is disclosed in patent specification

EP0016652 which is a polyurethane formed by reacting a polyethylene oxide, metnane diphenyl di-isocyanate and trimethylol propane.

The solid hydrogel body containing no active agent has been found to be surprisingly effective in the treatment of infection, particularly in the vagina. Many infections are toxin-mediated. Micro-organisms present may include bacterial, protozoal and fungal infections. Particular infections include vaginal trichomoniasis, bacterial vaginosis (e.g. Gardnerella vaginalis) and vaginal candidiasis (e.g. Candida albicans) . Other infections, including viral infections may also be treated.

Our work has indicated that the anti-infection effect of the hydrogel body may operate by the absorption of low molecular weight compounds from the local microenvironment. Compounds of molecular weight less than 2000 Daltons, particularly less than 1000 Daltons appear to be preferentially absorbed from the local microenvironment by the hydrogel used in the tests. However, the hydrogel formulation and structure (e.g. degree of cross-linking) can be optimised for a wide range of molecular weights according to known techniques. Charged or polar molecules in particular are absorbed well. Therefore, as a hypothesis, it appears that the solid hydrogel body may be effective by absorbing toxins produced as a result of the infection and/or by removing low molecular weight growth- supporting factors. Many of the infective organisms concerned are present in the natural microflora of the body cavity. Infection can thus be an abnormal proliferation of one or more micro-organisms with respect to the normal state. This may be the result of a change in physiological conditions within the patient as a whole or in a specific region of the patient's body (e.g. a vaginal pH change). In fact, the absence of active agent in the hydrogel body of the present invention may be positively beneficial in maximising the number of absorptive sites available for absorption of low molecular weight species from the local microenvironment.

There may be instances where the administration of a pharmaceutically active agent may be undesirable, such as during pregnancy or where drug sensitivity or adverse reaction exists; where administration of the hydrogel body according to the present invention is therefore particularly desirable.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Embodiments of the present invention will now be described by way of example only with reference to the following Examples and Figures 1 to 7.

EXAMPLE 1 (Removal of Toxins and Nutrients)

The objective of this study was to assess the absorption potential of the hydrogel polymer.

This example presents data from in-vitro studies to investigate the absorption of a toxin, gliotoxin (mol.wt. 326) and three amino acids, tryptophan, tyrosine, and phenyl-analine. Gliotoxin is recognised as the agent causing reddening and swelling of "Che epithelial tissue during candidiasis infection. The amino acids are utilised for growth by fungi and bacteria, including opportunistic and pathogenic agents. The in-vitro system consisted of aqueous preparations of medium with known concentrations of solute. The hydrogel bodies were added and the concentrations of solutes in the medium measured over time. If there was a preferential uptake of solute by the hydrogel then the concentration in the surrounding solution would decrease as the hydrogel swelled. However, if there was no preferential uptake the concentration of solute would remain constant. If preferential exclusion occurred the concentration of the solute would increase accordingly in the surrounding medium.

(i) Test Solutions

Solutions of aqueous media were prepared in triplicate with gliotoxin (at pH 4 and 7) and in duplicate with individual amino acids. Hydrogel bodies were added and the solution concentrations measured with time.

Solution concentrations were measured at times 3 , 6 12, and 24 hours (gliotoxin) and 2, 4, 6, 8 and 24 hours (amino acids) .

Solutions containing solute alone were analysed to assess solution chemical stability. This would provide assurance that any apparent disappearance of solute would be due to absorption and not degradation.

(ii) Analytical Methods

The concentration of gliotoxin was measured by an HPLC method. The sample was applied onto a Supelcosil C-18 (150mm x 4.6mm i.d.) column employing a mobile phase which was a phosphate buffer (pH4) in methanol (35/65 v/v) at a flow rate of lml/min. The pump was a Hitachi 655 and injection was via a Reodyne manual injection device with 20μl loop. Detection was carried out at 254nm using a linear UV106 detector. The standard preparation comprised 600μg/ml of gliotoxin in methanol.

Amino acids were detected by UV absoption at 280nm.

(iϋ) Results

The data for gliotoxin absorption are presented in, Figure 1-Hydrogel absorption of gliotoxin at pH 7, Figure 2-Hydrogel absorption of gliotoxin at pH 4, Figure 3-Degradation of gliotoxin at pH 7, Figure 4-Degradation of gliotoxin at pH 4, and in Table 1 the data are presented as the half life, i.e. the time taken to reach 50% loss.

The data for amino acids absorption are presented in, Figure 5-Phenyl-alanine absorption, Figure 6-Tryptophan absorption, and Figure 7-Tyrosine absorption. (iv) Conclusion

The data indicate that gliotoxin concentration decreases with hydrogel present and without (control) . The decrease in concentration is more rapid at lower pH values. The decrease in concentration is more rapid with hydrogel present.

The amino acids tested all demonstrate a similar absorption of solute from solution.

There is thus an apparent preferential uptake of solute from solution.

Gliotoxin is produced during candidiasis (Thrush) by the yeast Candida albicans. The presence of gliotoxin in vaginal fluid has been associated with a number of clinical manifestations such as reddening and swelling of the epithelial tissue in the vaginal canal. The absorption of gliotoxin from the vaginal fluid as the hydrogel swells may reduce its concentration in the local environment and therefore reduce the clinical symptoms and/or manifestations .

The hydrogel has also been demonstrated to preferentially imbibe the low molecular weight amino acids. The removal of amino acids from the vaginal fluid during the disease states may affect the nutrient availability within the local microenvironment and resultantly affect the growth and survival of the disease-causing microorganism(s) . This may provide an opportunity for the normal vaginal microflora to re-colonise and aid a return to the non-diversified state. EXAMPLE 2 (Treatment of Vaσinal Candidiasis in-vivoϊ

Clinical studies were carried out on groups of patients reporting vaginal infection and presenting for treatment (intent-to-treat group) . From this group, a group (per protocol group) was selected where the patients had Candida infection alone and no other infection. The symptoms of vaginal candidiasis (itching, discharge and redness) in the per-protocol group were recorded at baseline and on days 3, 7 and 28. Assessments were made by a number of methods. At baseline date, each patient received two intra-vaginal hydrogel pessaries (cross-linked polyurethane) .

Table 2 shows primary efficacy data in the per- protocol group. The primary efficacy variables were the clinical and global assessments of vaginal candidiasis after three days of double-blind treatment. The global assessment was based on a patient questionaire and the appearance of the perineum. The outcome was recorded as cured, improved or not improved. Analyses were conducted on the per-protocol group and the intent-to-treat group. The clinical assessment was based on the clinician's examination.

The results show that on day 3 , in the global assessment, 10% of patients reported a cure whereas 90% reported failure. However, 90% reported an improvement and only 10% no improvement. Slightly better figures were reported for the clinical assessment. Table 3 shows the secondary efficacy data in the per- protocol group. The secondary efficacy variables were the following:

Clinical assessment of vaginal candidiasis after 7 and 28 days of double-blind treatment;

Global assessment (patient questionaire) after 7 days of double-blind treatment;

The microbiological assessment of vaginal candidiasis after 3 and 7 days of double-blind treatment;

The time to microbiological cure, and the time to clinical cure. The clinical assessment on day 28 was the patient's own assessment of itching, discharge and redness. Analyses were conducted on the per-protocol group and the intent-to- treat group. It can be seen that on day 3 by microbiological assessment, 60% of the patients considered their condition to be better and 40% no better. On day 7, 80% were better by global and clinical assessment and 55.6% were better by microbiological assessment. At day 28, 80% were better by clinical assessment.

Table 4 shows culture results from vaginal swabs in the per-protocol group. Vaginal swabs were taken at baseline, day 3 and day 7 of the study. It shows that at day 3, 50% of patients were cured (60% were cured or improved). At day 7, 57.1% were cured (71.4% cured or improved) .

Figure 5 shows a summary of primary efficacy and secondary efficacy results in the intent to treat group (including all vaginal infections) . It can be seen that there are significant rates of cure or improvement in all assessments.

The studies described above were carried out in parallel with analogous treatments employing two hydrogel pessaries containing an anti-fungal active agent (miconazole) . Although there appeared to be somewhat faster action in the case of the active-containing pessaries at day 3, by day 7 the results with the hydrogels containing no active were at least as good.

Table 2

Primary efficacy data and summaries of efficacy results (per-protocol population) .

* Better is cured and improved categories combined

# Not cured is improved and failed categories combined. TABLE 3

Secondary Efficacy data ^ d qntnmaries of Efficacy Results (per-protocol population) .

@ Missing patients were excluded from the percentage calculations in this table. * Micro-microbiological Table 4

Culture Results from Vaginal Swab (per-protocol population^

Missing values are not included in this table.

TABLE 5

ASSESSMENT VISIT (DAY) INTENT-TO-TREAT

Days Post Treatment

Primary Efficacy Cured 20.0% Global Assessment

Improved 60%

Improved or 80.0% cured

Cured 44.4%

Failure 16.7%

Clinical Cured 25.0% Assessment

Improved or 85.0% cured

Secondary Efficacy

Culture results Negative 5-> ll(day3) swab*

8/15

Clinical Cured

28 Treatment 35.0% Failure

Microbiological Not cured 60.0%

Treatment 46.7%(53.8%-day 7) Failure

Cured:not 5:8 cured

*Patients with negative baseline swab were not included in microbiological assessments. (Comparison with reported i n-vivo studies using active aαents)

The rates of cure and improvement according to the treatment of the present invention compare reasonably well with studies reported in the literature employing various active agents. Differences may depend on the definition of what constitutes "cure".

Brown D. Jr. et al., J Reprod Med 31(11)1045-1048 (1986) reported studies using butoconazole vaginal cream in the treatment of vulvovaginal candidiasis in comparison to miconazole and a placebo. The cure rate at 8 days and 30 days judged by mycological and clinical evaluation was 23% (placebo) , and 43 to 58% for butoconazole treatment at various treatment times and application rates. A cure rate of 54% was reported for miconazole treatment. The cure and improvement rates of the present invention are substantially greater than the placebo effect in Brown et al.

Thus, the results reported for the treatment of the present invention compare favourably with reported studies using various active agents applied intra-vaginally.

Claims

┬úLAIM┬ú

1. A solid hydrogel body for use as a medicament for the treatment of infection; the hydrogel body containing no active agent effective in said treatment of said infection.

2. A body according to claim 1 shaped for rectal or vaginal administration.

3. A body according to claim 2 having rounded leading and/or trailing ends to facilitate rectal or vaginal insertion.

4. A body according to any preceding claim, which retains its solid integrity during swelling.

5. A body according to any preceding claim, which is provided with surface corrugations.

6. A body according to any preceding claim which is provided with retrieval means for manual retrieval from a body cavity.

7. A body according to any preceding claim formed of a polyurethane which is the reaction product of a polyethylene oxide, methane diphenyl di-isocyanate and trimethylol propane.

8. A solid hydrogel body for use in the production of a medicament for the treatment of infection; the hydrogel body containing no active agent effective in said treatment of said infection.

9. A body according to claim 8 for the treatment of vaginal icrobial infection.

10. A body according to claim 9 for the treatment of toxin-mediated infection.

11. A body according to claim 9 or 10 for the treatment of vaginal trichomoniasis, bacterial vaginosis or vaginal candidasis.

12. A body according to any of claims 8 to 11 which preferentially absorbs low molecular weight compounds of molecular weight less than 2000 Daltons.

13. A body according to claim 12 which preferentially absorbs charged or polar molecules.

14. A body according to claim 12 or 13 which preferentially absorbs amino acids of molecular weight less than i╧ïO╧ï Daltons.

15. A body according to claim 9 or 10 which preferentially absorbs bacterial toxin.

16. A body according to any preceding claim for oral administration.

17. A body according to any preceding claim in the form of a packing for wounds.

18. A method of acquiring a sample from a body cavity which comprises introducing a solid hydrogel body into the cavity, maintaining the hydrogel body in the cavity for a time sufficient to absorb the sample and removing the hydrogel body and absorbed sample.