FIELD OF THE INVENTION

This invention relates to apparatus and a method for controlling permeation of a compound through a membrane and ha3 particular, but not exclusive application to the controlled release of a therapeutic agent into a patient.

BACKGROUND TO THE INVENTION

It has previously been proposed to package a biologically active agent in a lipid bilayer vesicle and to implant the vesicle into a patient so as to produce a slow release of the agent into the patient through the bilayer over a long period of time e.g. six months to one year. Contraceptives have been administered in this manner.

A disadvantage of this arrangement is that the rate of release of the biologically active agent cannot be controlled easily once the vesicle has been implanted in the patient. The present invention seeks to provide a more controllable release of such a biologically active agent.

SUMMARY OF THE INVENTION

The present invention provides apparatus for controlling permeation of a compound such as a biologically active agent through a 3emi-permeable membrane in which an electromagnetic field is applied to the membrane in such as manner as to control or modify the rate of permeation of the compound through the membrane.

In a preferred method according to the invention, vesicles formed of a lipid biylayer are implanted into the subcutaneous tissue of a patient and thereafter a rf electromagnetic field is applied to the patient from a portable battery driven transmitter device which may be strapped to the skin of the patient externally. The rf field is typically selected to be in the 26 MHz

range and is of a field strength which does not produce significant bulk tissue heating. Typically the field

strength is of the order of 100 microwatts cm _2

measured at the 3kin of the patient. A suitable form of transmitter device which can be applied externally to the sking of the patient is disclosed in my US

Patent No. 4 429 698; 4 412 540; 4 471 787.

A vesicle formed of a lipid bilayer is known as a liposome and is described for example in "The Design and Characterisation of Temperature-Sensitive Liposomes ¹¹ Majin R. L. and einstein J. N. "Liposome Technology 1984 volume 3 p.p. 137-155 CRC Press, Florida, USA. The membrane of lipids molecules is arranged in such a manner that they display a semi-permeable characteristic to certain compounds ' contained within the bilayer envelope.

BRIEF DESCRIPTION OF THE DRAWINGS

In order that the invention may be more fully understood embodiments thereof will now be described by

way of example, with reference to the accompanying drawings in which:-

Figure 1 is a schematic drawing of a liposome containing a biologically active agent;

Figure 2 shows treatment of an arm of a patient with an rf transmitter so as to control release of a biologically active agent from a liposome;

Figure 3 is a magnified sectional view of the arm of the patient; and

Figure 4 is a schematic diagram of the transmitter shown in Figure 3.

DESCRIPTION OF EMBODIMENTS

Referring to Figure 1, a liposome is shown in schematic section. It consists of a lipid bilayer consisting of layers 1, 2. The liposome is shown in cross section so as to illustrate the position of the lipids 3 within the inner and outer layers. The liposome contains a biologically active agent 4 selected to perform a

particular treatment as will be explained in more detail hereinafter.

In use, one of more liposomes is inserted under the skin of a patient by the use of a local anaesthetic. Typically, this is achieved by forming a subcutaneous pouch by surgery, inserting the liposome into the pouch and then closing the wound. The puch may conveniently by formed in a limb, e.g. an arm as shown in Figure 2.

Referring now to Figure 3 _> this shows a section taken along the line X-X of Figure 2. The patients skin consists of the outer layer or epidermis 5, the underlying dermis 6, adipose tissue 7 and subcutaneous tissue 8. Liposomes 9 of the type shown in Figure 1 are placed in the subcutaneous tissue by the surgical procedure just described.

In accordance with the present invention it has been appreciated that by application of a rf electromagnetic field to the liposomes 9, it is possible to control the rate at which the biologically active agent 4 is r.eleaaed. through the semi-permeable membrane formed by the vesicle bilayer 1, 2. Thus, the liposome may be

configured so that in the absence of an applied rf field, a very low rate of release of the biologically active agent 4 occurs through the lipid bilayer. However, when a rf field of a a predetermined strength is applied, the rate of release of the agent 4 is increased substantially. Thus, by the application of the rf field, it is possible to control the rate of release and hence the biological effect of the agent 4.

Conveniently the rf transmitter device is a portable battery driven device carried by the patient on his or her skin. A convenient form of device is disclosed in my US Patents mentioned hereinbefore. Alternatively, a non-portable rf device may be utilised for example at the bedβide if the patient is hospitalised.

A schematic circuit diagram for the transmitter device shown in Figure 3 is given in Figure 4. The device is driven by a battery 10 and includes an oscillator 11 which may run at a frequency of 24.2 MHz. The output of the oscillator 11 is fed to a modulator 12 which may be used to pulse modulate the output so a,s to increase efficacy of the treatment. Use of the modulator is optional. The output of the modulator is fed to a

timer circuit which may cause the rf field to be applied only at particular times during the day. The timer circuit 13 is described in more detail in my Patents aforesaid.

The output of the timer is fed to an antenna which conveniently is in the form of a printed circuit or a coaxial cable loop attached to the skin of the patient. Furthermore, the circuit may be controlled by a monitor 15 which is used to monitor the amount of agent 4 released into the patient. The monitor 15 can operate in a variety of different ways depending on the treatment being effected. For example, if the biologically active agent 4 is selected for treatment of diabetes e.g. insulin, the monitor 15 can test urine content. Other non-infasive or semi-infasive means may be used for monitoring the release of the agent 4.

In certain situations, the patient is able to determine themselves from their own physical feeling that treatment should be started, for example, the patient may start palpitations, sweating etc depending on the patients condition to be treated. The patient would then in response to these physical conditions switch on

the transmitter device so as to cause release of the therapeutic agent 4 to treat the condition.

The battery 10 may be rechargeable or exchangeable depending on the treatment required.

It will be appreciate that the invention permits an improved control of slow release drug treatments and will bring relief to many hardened sufferers of chronic pharmaceutical ingestion. The invention is believed also to have benefit to injection treatment patients such as insulin in diabetics. The controlled treatment according to the invention permits a way of ensuring that the patient may receive the correct prescribed treatment without recourse to the patients memory. Thus, the timer 13 can arrange for predetermined release periods for a drug throughout the day. This is particularly useful for the elderly who may either not take treatments that are necessary on a regular basis of conversely they may take too much because they cannot recally how many pills have been swollowed.

In some circumstances, such as for example anti-cancer drug treatment where a more ordered delivery of drug may be required or where the drug is not itself eaβily amenable to continuous slow release, the ability of the rf device to affect the permeability of the liposome and thus the dose level in the blood stream has a very significant advantage in treatment management. In case where the anti-cancer drug therapy is temporarily modulated with other forms of a treatment such as hypothermia or radio-therapy, the present invention advances the efficiency of drug delivery very considerably.

The invention also permits a far greater freedom for patients when only intermittent treatment is required for example once a week or once a day. The ability to control the does by altering the permeability of the liposome affords a much safer margin of management of the patient than has been possible hitherto.

Clinical examples of pathologies for which the present invention has application are as follows:

Diabetes, steroid treatment, hormone treatment, anti- cancer treatment, pain relief, long term antibiotic treatment, non-steroidal preparations in joint disease and other conditions, growth hormone and anti- hypertensive treatments.

Whilst in the foregoing, the semi-permeable membrane is exemplified by a liposome, other forms Of semi- permeable membrane may be utilised.