Ultrasound enhanced delivery of materials through skin

description

Technical Field

This invention relates generally to the field of drug delivery. More particularly, the invention relates to a method of increasing the permeation rate of topically, transmucosally or transdermally applied materials using high frequency ultrasound.

Background

Drug release through the skin (transdermal drug release, or TDD) provides many advantages; First, such a release means is a comfortable, convenient and non-invasive mode of drug administration. The variable rates of absorption and metabolism encountered in oral treatment are avoided and other inherent drawbacks - for example gastrointestinal and other irritations - are similarly eliminated. Transdermal drug release also makes possible a high degree of control over the blood concentrations of any particular drug.

The skin is a structurally complex, relatively impermeable membrane. Molecules and any material on their surface, moving from the middle into and through intact skin, must first penetrate the stratum corneum. They should then penetrate the epidermis in good condition, the dermis papillae, and the capillary walls into the bloodstream or lymphatic channels. To be absorbed in this way, molecules must overcome the different resistance to penetration in each type of tissue. Transport across the skin membrane is thus a complex phenomenon. However, it is stratum corneum, a layer of thickness approximately 5-15 micrometers covering most of the body, which presents a barrier to absorption of transdermally administered topical compositions. It is believed to be the high degree of inner keratinization of their cells, as well as their dense disposition and orderly cementation, semicrystalline lipids, which in many cases constitute a substantial barrier to drug penetration. The applicability of transdermal drugs is thus limited at present because the skin is thus an excellent barrier to the ingress of topically applied materials. For example, many of the new peptides and proteins now produced as a result of the biotechnology revolution cannot be released through the skin in sufficient quantities due to their naturally low skin permeation rate.

the first or release waterproof drugs

Various methods have been used to increase skin permeability, and in particular to increase stratum corneum permeability (i.e., as well as to obtain increased skin penetration of drugs to be transdermally released). The first center of interest has been the use of chemical enhancers, that is, wherein the drug is co-administered with a penetration enhancing agent (or permeation enhancers). While such compounds are effective in increasing the rate at which each drug is released through the skin, there are disadvantages with many permeation enhancers which limit their use. For example, many permeation enhancers are associated with deleterious effects on the skin (eg, irritation). Also, controlling drug release with chemical increase can be quite difficult.

Iontophoresis has also been used to increase skin drug permeability and involves (1) the application of an external electric field, and (2) topical release of an ionized form of the drug (or a neutral drug carried with the flow of associated with ion transport, ie via electroosmosis). While increased permeation via iontophoresis, as with chemical enhancers, has been effective, there are problems with controlling drug release and the degree of irreversible skin damage induced by transmembrane current passage.

The presently discovered and claimed method involves the use of ultrasound to decrease the barrier functions of stratum corneum and thereby increase the rate at which the drug can be released through the skin. Ultrasound is defined as mechanical pressure waves with a frequency above 20,000 Hz (see, for example, H. Lutz et al., Manual of Ultrasound: 1. Basic Physical and Technical Principles (Berlin: Springer-Verlag, 1984)).

As discussed by P. Tyle et al. In Pharmaceutical Research 6 (5); 355-361 (1989), drug penetration, obtained via sonophoresis ”(the movement of drugs through the skin on the influence of an ultrasonic disturbance; see DM Skauen and G.

M. Zentner, Int. J. Pharmaceutics 20; 235-245 (1984), it is believed that chemical, mechanical and thermal changes of biological tissues result by application of ultrasonic waves. Unlike iontophoresis, the risk of skin damage appears to be low.

The application of ultrasound to drug release has been discussed in the literature. See, for example, P. Tyle et al., Supra (which provides an overview of sonophoresis); S. Miyazaki et al., J. Pharm. Pharmacol, 40: 716-717 (1988) (Controlled insulin release of a polymer implanted using ultrasound); J. Cost et al., Proceed. Intern Symp. Control King Bioact. Mater. 16 (141); 294-295 (1989) (overview of the effects of ultrasound on the permeability of human skin and synthetic membranes); H. Benson et al., Physical Therapy 69 (2): 113-118 (1989) (effects of ultrasound on percutaneous absorption of benzidamine); E. Novak, Arch. Phys. Medicine & Rehab. 45: 231-232 (1964) (increased penetration of lidocaine through intact skin using ultrasound); JE Griffin et al., Amer. J. Phys. Medicine 44 (1): 20-25 (1965) (ultrasonic penetration of cortisol in pig tissues); JE Griffin et al., J. Amer. Phys. Therapy Assoe. 46: 18-26 (1966) (overview of the use of ultrasonic energy in drug therapy); JE Griffin et al., Phys. Therapy 47 (7): 594-601 (1967) (ultrasonic hydrocortisone penetration); JE Griffin et al., Phys. Therapy 48 (12): 1336-1344 (1968) (ultrasonic penetration of cortisol in pig tissues); JE Griffin et al., Amer. J. Phys. Medicine 51 (2): 62-72 (1972) (same); JC McElnay, Int. J. Pharmaceutics 40: 105-110 (1987) (the effects of ultrasound on percutaneous absorption of fluocinolone acetonide); and C. Escoffier et al., Bioeng. Skin 2; 87-94 (1986) (in vitro studies of ultrasound velocity in the skin).

In addition to the aforementioned art, Kost, U.S. Patent Nos. 4,767,402 and 4,780,212 specifically refer to the use of specific ultrasound frequencies to increase the permeation rate of a drug across human skin or across human skin. a synthetic membrane.

While the application of ultrasound in conjunction with drug release is thus known, the results have in most cases been disconcerting, ie the increase in skin permeability has been relatively low.

Summary of the invention

The present invention provides a novel method for increasing the permeation rate of a given material across an intact area selected from an individual's body surface. The method comprises contacting a selected intact area with the material and applying ultrasound to the area

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contacted. The ultrasound preferably has a frequency of about 10 MHz, and continues at an intensity and for a period of time sufficient to increase the material's permeation rate into and across the body surface. Ultrasounds may also be used to pretreat the selected area of ​​the body surface in preparation for drug release, or for diagnostic purposes, i.e. to enable non-invasive cutting of samples of physiological material under the skin or surface. of the body.

In addition to increasing the permeation rate of a material, the present invention involves increasing the permeability of the biological membrane, such as stratum corneum, by applying ultrasound having a frequency above 10 MHz to the membrane at an intensity and sufficient time to allow increased membrane permeability. Once the membrane permeability has been increased, it is possible to apply the material thereon and to obtain an increased flow rate of the material through the membrane.

It is therefore a primary object of the invention to overcome the aforementioned shortcomings of the prior art by providing a method of enhancing the permeability of biological membranes, and thus permitting an increased rate of material release therethrough.

It is another object of the invention to provide such an effective method with or without chemical permeation enhancers.

It is yet another object of the invention to minimize the time interval in such a method and to provide a relatively short total treatment time.

It is further another object of the invention to provide such a method wherein the drug release is effected using ultrasound.

It is a further object of the invention to enable the tissue sample to be cut under the skin or other body surface by applying high frequency (&gt; 10 MHz) ultrasound thereon.

A further feature of the invention is that it preferably involves ultrasound frequencies of greater than about 10 MHz.

Additional objects, advantages and novel features of the invention will be set forth below, in part from the following description, and in part will become apparent to those skilled in the art upon examination of the following, or may be understood by practice. of the invention.

Brief Description of the Figures

Figures ΙΑ, 1B and IC are theoretical graphs of energy dissipation within the skin barrier versus the frequency of applied ultrasound.

Figures 2, 3 and 4 are graphical representations of the amount of salicylic acid recovered from stratum corneum following ultrasound treatment at different frequencies.

Figures 5 and 6 represent the results of experiments similar to those summarized in Figures 2, 3 and 4, but with a shorter treatment time.

Figures 7, 8, 9 and 10 are graphs of the increase versus the number of skinned strips as described in the Example.

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Figure 11 illustrates the effect of ultrasound on systemic availability of salicylic acid following topical application.

Detailed Description of Preferred Settings

Prior to describing and disclosing the present method of increasing the permeation rate of a material across the biological membrane and increasing the permeability of membranes using ultrasound, it should be understood that this invention is not limited to the particular process steps and materials described. here, how such materials and process steps can, of course, change. It should also be understood that the terminology used herein is only used for the purpose of describing particular embodiments and is not intended to be limiting, assuming that the scope of the present invention will be limited only by the appended claims.

It should be noted that, as used in this specification and the appended claims, the singular forms one and the include plural references, unless the context clearly states otherwise. Thus, for example, reference to a drug includes mixtures of drugs and their pharmaceutically acceptable salts, reference to an ultrasound device includes one or more ultrasound devices of the type necessary to carry out the present invention, and reference to the method of Administration includes one or more different methods of administration known to those skilled in the art, or which will become known to those skilled in the art upon reading this description.

In one aspect of the invention, a method is provided for increasing the permeation of a particular material, such as a drug, pharmacologically active agent, or diagnostic agent into and / or across a biological membrane or a body surface of the subject. which method comprises (a) contacting the membrane with the chosen material in a pharmaceutically acceptable carrier; and (b) applying ultrasound with an intensity and for an effective treatment time to produce release of material through the membrane. The material is preferably a drug, and it is preferable to obtain a desired level of a drug in the blood of the subject. Ultrasound is of an effective frequency and intensity to increase the permeability of the selected area to the applied drug, greater than would be achieved without ultrasound. Ultrasounds preferably have a frequency of more than 10 MHz, and may be applied either continuously or by pulse, preferably continuously. Ultrasound may be applied to the skin both before and after application of the drug medium as long as the administration of the ultrasound and the drug medium is relatively simultaneous, that is, the ultrasound is applied at about 6, more preferably at about 4. even more preferably within about 2 minutes of drug application.

The invention is useful for performing transdermal permeation of pharmacologically active agents which would otherwise be quite difficult to release through the skin or other body surface. For example, proteinaceous drugs and other high molecular weight pharmacologically active agents are ideal candidates for transdermal, transmucosal or topical release using the presently disclosed method.

In an alternative embodiment, agents useful for diagnostic purposes may also be released into and / or across the body surface using the present method.

The invention is also useful as a noninvasive diagnostic technique, that is, by providing for cutting samples of physiological material from under the skin or other body surface and into a collection (and / or evaluation) chamber.

Unless otherwise indicated, the present invention will use conventional pharmaceutical methodology and, more specifically, conventional methodology used in conjunction with transdermal delivery of pharmaceutically active compounds and enhancers.

In describing the present invention, the following terminology will be used in accordance with the following definitions.

A biological membrane means a membrane material present in a living organism that separates one area of ​​the organism from another and, more specifically, that separates the organism from its external environment. The skin and mucous membranes are thus included.

Increased penetration or increased permeation as used herein refers to an increase in skin permeability to a material, such as a pharmacologically active agent, that is, to increase the rate at which the material penetrates in and through of the skin. The present invention involves increasing permeation through the use of ultrasound, and in particular through the use of ultrasound having a

Xfrequency greater than 10 MHz.

Transdermal (or percutaneous) will mean passage of a material into and through the skin to achieve effective therapeutic blood levels or deep tissue therapeutic levels. While the invention is described herein primarily in terms of transdermal administration, it will be appreciated by those skilled in the art that the presently claimed and discovered method also contains transmucosal and topical administration of drugs using ultrasound. Transmucosal is intended to mean the passage of any given material through a mucous membrane of a living organism and, more specifically, will refer to the passage of a material from the outside of the organism through a membrane and into the organism. Transmucosal administration thus includes drug delivery through either the mouth or nasal tissue. By topical administration is meant local administration of a pharmacologically active topical agent to the skin, for example in the treatment of various skin diseases or administration of a local anesthetic. Topical release may involve penetration of a drug into the skin but not through it, ie topical administration does not involve actual passage of a drug into the bloodstream.

Carriers or carriers, as used herein, refer to non-pharmacologically active carrier materials which are suitable for administration with other pharmacologically active materials, and include any type of material known in the art, for example any liquid, gel, solvent,

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liquid diluent, solubilizers, etc. which is non-toxic and does not interact with the drug to be administered in a detrimental manner. Examples of carriers suitable for use herein include water, mineral oil, silicone, inorganic gels, aqueous emulsions, liquid sugars, waxes, petroleum jelly and a variety of other polymeric oils and materials.

By the term pharmacologically active agent or drug as used herein is meant any chemical material or compound suitable for transdermal or transmucosal administration that may (1) have a prophylactic effect on the body and prevent an undesired biological effect such as preventing infection, (2) alleviate a condition caused by an illness, such as pain relief caused as a result of an illness; or (3) alleviate or completely eliminate the disease from the body. 0 The effect of the agent may be local, such as providing a local anesthetic effect, or may be systemic. Such substances include the broad class of compounds normally released through body surfaces and membranes, including the skin. In general, it includes: anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations; anorexics; anthelmintics; anti-arthritics; anti-asthmatic agents; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihistamines; anti-inflammatory agents; anti-migraine preparations; antinauseants; antineoplastic drugs, antiparquinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations, including potassium and calcium channel blockers, beta blockers and antiarrhythmics; antihypertensives; diuretics; vasodilators, including general, coronary, peripheral and cerebral; central nervous system stimulants; cold and cough preparations, including decongestants; hormones, such as estradiol and other steroids, including corticosteroids; hypnotics; immunosuppressants; muscle relaxants; parasympatholytic, psycho-stimulating; sedatives and tranquilizers. By the method of the present invention, both ionized and nonionized drugs can be released as they can have both high and low molecular weight.

Proteinaceous and polypeptide drugs represent a preferred class of drugs for use in conjunction with the presently discovered and claimed invention. Such drugs generally cannot be administered orally as they are often destroyed in the gastrointestinal tract or metabolized in the liver. In addition, due to the high molecular weight of most polypeptide drugs, conventional transdermal delivery systems are generally not effective. It is also desirable to use the method of the invention in conjunction with drugs for which skin permeability is relatively low, or which give rise to a large time interval (ultrasound application as described herein has been found to significantly reduce the delay involved. with transdermal administration of most drugs).

By a therapeutically effective amount of a pharmacologically active agent is meant a non-toxic but sufficient amount of a compound to provide the effect.

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desired therapeutic The therapeutically desired effect may be a prophylactic, disease prevention effect, an effect that alleviates a disease system, or a curative effect that both eliminates and aids in the elimination of the disease.

As noted above, the present invention relates to a method for increasing the permeation rate of a drug across an intact area of ​​an individual body surface, preferably human skin. The method involves transdermal administration of a selected drug in conjunction with ultrasound.

Ultrasound causes thermal, mechanical and chemical changes of ι

biological tissue, and thereby increase the permeation rate of a given material through it.

While not intended to be limited by theory, the applicants propose that the use of high frequency ultrasound, as discovered herein, specifically increases drug permeation through the outer layer of the skin, ie stratum corneum, because it causes momentary and reversible disturbances. inside (and thus short term reversible reduction in barrier function) of the stratum corneum layer. It will be appreciated by those skilled in the art of transdermal drug delivery that a number of factors related to the present method will vary with the drug to be administered, the disease or injury to be treated, the age of the selected subject, the skin site in the which drug is applied, etc.

As noted above, ultrasound is ultrasonic radiation of frequency above 20,000 Hz. As can be deduced from the literature cited above, ultrasound used in most medical purposes typically employ a range of frequencies.

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from 1.6 to about 10 MHz. The present invention, by contrast, uses higher ultrasound frequencies of about 10 MHz, preferably in the range of about 15 to 50 MHz, and more preferably in the range of 15 to 25 MHz. The idea that these ranges are intended to be merely illustrative of preferred embodiments should be reinforced; In some cases higher or lower frequencies may be used.

Ultrasound can be either pulse or continuous, but continuos are preferred when low frequencies are used. For very high frequencies, pulse applications will generally be preferable to allow dissipation of the heat generated.

The preferred intensity of the applied ultrasound is less than about 5.0 W / cm²more preferably is in the range of 0.01 to 5.0 W / cm²and most preferably is in the range of 0.05 to 3.0 W / cm². Total treatment time, that is, the period during which the drug and ultrasound are administered, will vary depending on the drug administered, the disease or wound treated, etc., but will generally be in the order of about 30 seconds to 60 minutes. preferably 5 to 45 minutes, more preferably 5 to 30 minutes, and most preferably 5 to 10 minutes. It should be noted that the above ranges represent suggested or preferred treatment times, but are in no way intended to be limiting. Longer or shorter times may be possible and in some cases desirable. Virtually any type of device can be used to deliver ultrasound, ensuring that the device is capable of producing the highest frequency ultrasonic waves required by

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present invention. A device will typically have a power source such as a small battery, a transducer, a reservoir in which the drug medium is stored (and may or may not be rechargeable), and a means of attaching the system to the desired skin location.

Because ultrasound does not transmit well in the air, a liquid medium is usually required to efficiently and quickly transmit ultrasound between the ultrasound applicator and the skin. As explained by P. Tyle et al., Cited above, the selected medium of the drug should contain a coupling or contacting agent, typically used in conjunction with ultrasound. 0 Coupling agent should have an absorption coefficient similar to that of water, and, moreover, do not bruise, be non-irritating to the skin, and dry gently. It is clearly preferred that the coupling agent retains a paste or gel consistency over the duration of ultrasound administration, provided that this contact is maintained between the ultrasound source and the skin. Examples of preferred coupling agents are mixtures of mineral oil and glycerine and propylene glycol, oil / water emulsions, and a water based gel. A non-crystalline solid state polymeric film having the above characteristics may also be used. The drug medium may also contain a carrier or a vehicle as defined alone.

A transdermal patch as is well known in the art may be used in conjunction with the present invention, that is, to deliver the drug medium to the skin. The plaster, however, must have the properties of the coating agent.

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coupling as described in the preceding paragraph to enable the transmission of ultrasound from the applicator through the patch to the skin.

As noted at the beginning of this section, virtually any chemical material or compound suitable for topical, transmucosal or transdermal administration may be administered using the present method. Again, the present invention is particularly useful for enhancing the release of proteinaceous and other high molecular weight drugs.

The method of the invention is preferably embodied as follows. The drug medium, that is, containing the selected drug or drugs together with the coupling agent and, optionally, a carrier or carrier material, is applied to an intact body surface area. Ultrasound, preferably having a frequency greater than about 10 MHz, may be applied before or after application of the drug medium, but is preferably immediately prior to application of the drug so as to pre-treat the skin prior to drug administration.

It should also be noted that the present method may be used in conjunction with a chemical permeation enhancer as known in the art, where ultrasound enables the use of much lower concentrations of the permeation enhancer - thus minimizing skin irritation and other problems. often associated with such compounds - which will be possible in the absence of ultrasound. The permeation enhancer may be incorporated into the drug medium or may be applied to a conventional transdermal patch after ultrasound pretreatment of the body surface.

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The present invention may also be used in conjunction with iontophoresis for drugs which are particularly difficult to administer through the skin, that is, due to the low permeability of stratum corneum for such drugs. The selected body surface area is ultrasonically pretreated and the drug is then administered using conventional iontophoresis techniques.

With respect to the skin site, virtually any area of ​​the body surface may be selected as long as it is intact, but, however, the thickness and permeability of the skin at the exposure site will affect treatment conditions, ie intensity, frequency, contact time. , exposure time, and others. The area of ​​skin through which the drug medium and ultrasound are administered may again vary strongly, but will typically be in the range of 1 to 100 cm.², more typically 50 to 100 cm², and in most cases typically on the order of 10 to 50 cm².

Example

Based on the present inventors' theoretical analysis of the propagation of ultrasonic energy in the tissue and the insulating properties of the skin, it was concluded that higher frequencies of ultrasound could be more effective in increasing the flow of drug molecules through the skin. This conclusion, assuming that the increase is proportional to the amount of energy dissipation within the barrier, is supported by Figure 1, which suggests that within the first millimeter of skin ultrasonic energy dissipation increases exponentially with frequency.

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To test the hypothesis that high frequencies (&gt; 10 MHz) could produce greater increases, in vivo experiments were performed on naked guinea pigs. The embodiment of the experiment consisted of a function generator, transducers tuned to different frequencies and a power meter 14. C-labeled salicylic acid was used as the model labeled drug molecule. A saturated TM solution of unlabelled salicylic acid in water was prepared. Carbopol (BF Goodrich), a polymer, was added to this solution to make a gel containing salicylic acid at a concentration of 0.57 wt%. This gel was then spiked with a known amount of radiolabelled salicylic acid (approx. 2.27 gCi / mg gel). Approximately 30 mg of gel per square centimeter of transducer cross-sectional area was then applied to the skin surface of guinea pig flanks. This gel served as a drug reservoir and coupling medium between the transducer and the skin surface. The frequencies of 1, 7.5 and 16 MHz were tested using an intensity of 0.25 w / cm² and treatment periods (drug and ultrasound skin exposure time) of 10 and 20 minutes. At the treatment site, ultrasound released by the transducer at the appropriate frequency during the designated period. At the control site, on the contralateral flank, the transducer was positioned on the skin but not activated. Thus each animal served as its own control.

The increase was quantified in two ways: (1) by skinning on outer skin strips at treatment and control sites immediately after the experimental period (radioactivity on skinned strips was then determined by liquid scintillation counting), and (2) by measuring the accumulated amount of C excreted in the animals' urine up to 14 hours after the start of the experiment.

(1) Strip skinning procedure: It has been established that the outermost layer of the skin, stratum corneum (SC), offers most resistance to drug penetration. It was therefore decided to compare the amount of radioactivity present in the SC after ultrasound treatment with this after the control experiment (passive diffusion without ultrasound). Figures 2, 3 and 4 show a comparison of the total amount of salicylic acid that had penetrated the SC with exposure to 1, 7.5 and 16 MHz for 20 minutes without exposure to ultrasound. As can be seen, the use of 16 MHz resulted in a significantly higher drug level in SC compared to the control. Figures 5 and 6 are comparable to Figures 3 and 4, but here the treatment was 10 minutes, preferably 20 minutes. Each skinned strip removed a certain amount of SC. Therefore, as the number of skinned strips increased, the posterior tissue furthest from the surface was examined. Accordingly, a graph of the amount of drug in each strip against the number of strips reflects the gradient of drug concentration in SC. Such graphs are shown in Figures 7, 8, 9 and 10. The ordinate is the ratio of the amount of radioactivity on the strips after treatment to the amount on the strip after control.

(2) Urinary excretion: To confirm that the amount of drug recovered from SC reflected the amount of drug penetrated, radioactivity excreted in the urine was monitored.

Figure 11 graphically illustrates a change in the total amount of radioactivity excreted in the urine 14 hours after a 20 minute treatment using 16 MHz and the corresponding control. At least five times more drugs entered the systemic circulation with ultrasound than without them.

While the present invention has been described with reference to specific embodiments thereof, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit of the scope of the invention. In addition, many modifications may be made to adapt a particular ultrasound device, drug, excipient material, process, process step or steps to the purpose, spirit and scope of the present invention. All such modifications are intended to be within the scope of the appended claims.