DELTA <9> TETRAHYDROCANNABINOL ( DELTA <9> THC) SOLUTION METERED DOSE INHALERS AND METHODS OF USE

Abstract: The present invention provides therapeutic formulations for solutions of DELTA <9>-tetrahydrocannabinol ( DELTA <9> THC) to be delivered by metered dose inhalers. The formulations, which utilize non-CFC propellants, provide a stable aerosol-deliverable source of DELTA <9> THC for the treatment of various medical conditions, such as: nausea and vomiting associated with chemotherapy; muscle spasticity; pain; anorexia associated with AIDS wasting syndrome; epilepsy; glaucoma; bronchial asthma; and mood disorders.

Description: Δ 9 TETRAHYDROCANNABINOL ( Δ 9 THC) SOLUTION METERED DOSE INHALERS AND METHODS OF USE DESCRIPTION BACKGROUND OF THE INVENTION Field of the Invention The invention is generally related to the therapeutic use of Δ 9 Tetrahydrocannabinol (Δ 9 THC). In particular, the invention provides a metered dose inhaler (MDI) for the aerosol administration of Δ 9 THC to patients suffering from nausea and vomiting associated with cancer chemotherapy, muscle spasticity, pain, anorexia associated with AIDS wasting syndrome, epilepsy, glaucoma, bronchial asthma, mood disorders, and the like. Background Description "Medical Marijuana" is a timely and controversial subject that is currently receiving widespread public attention. While marijuana is usually thought of as an illegal "recreational" drug, it also has a long history as a medicine. In 1997, the National Institutes of Health (NIH) released a review of the scientific data concerning potential therapeutic uses for marijuana. In that review, the NIH found that marijuana may indeed have beneficial medicinal effects and recommended that researchers develop alternative dosage forms for the drug, such as a "smoke free" inhaled delivery system (1). Table 1 summarizes the findings of several studies (references 2-18) that have documented therapeutically beneficial medicinal uses of the major active component of marijuana, Δ 9 tetrahydrocannabinol (Δ 9 THC ). TABLE 1. The Use of Δ 9 THC for the Treatment of Assorted Clinical Conditions Condition and Administration Findings Reference Number of Route and Dose Patients AIDS-associated Oral placebo, 2.5 mg THC Long term THC Beal et al., anorexia and cachexia; once or twice daily treatment was well- 1997 94 patients; increasing to 20 mg daily tolerated; THC 12 months improved appetite and only tended to increase weight compared to controls AIDS-associated Oral placebo or 2.5 mg 57% and 69% of vehicle Beal et al., anorexia and cachexia; THC twice daily and THC patients were 1995 139 patients; evaluable for efficacy. 42 days Appetite increased 38% over baseline for THC group compared to only 8% for the placebo group. THC also decreased nausea. No significant changes were found between the groups for weight change. Nausea and emesis due Oral THC, 15mg/m 2 Reduction in McCabe et al., to cancer chemotherapy-induced 1988 chemotherapy; nausea and vomiting in 36 patients who had 64% of patients given experienced severe THC compared to nausea and vomiting prochloperazine; side that was refractory to effects included prochlorperazine or dysphoria; authors thiethylperazine recommend initial THC dose of 5 m /πr When marijuana is used illegally as a recreational psychoactive drug, the active ingredient Δ 9 THC is usually delivered to the lungs as an impure non-pharmaceutical aerosol in the form of marijuana smoke. Aerosolized Δ 9 THC in the inhaled smoke is absorbed within seconds and delivered to the brain efficiently. Table 2 and references 19-20 describe the pharmacokinetics of the administration of Δ 9 THC. As can be seen, inhalation is the preferred route of delivery for Δ 9 THC. When compared to oral delivery, inhalation provides a more rapid onset of pharmacological action and peak plasma levels. The effects achieved via inhalation are comparable to those achieved when the drug is administered intravenously, but inhalation is a much less invasive technique. Currently, the sources of Δ 9 THC for patients who could benefit from the drug are very limited. An oral form of Δ 9 THC (MARINOL) is marketed as a treatment for nausea and vomiting related to cancer chemotherapy, and as an appetite stimulant in patients suffering from AIDS wasting syndrome. In MARINOL, pharmaceutical grade Δ 9 THC is dissolved in sesame oil, encapsulated in gelatin capsules and delivered orally. However, when the drug is taken orally, the absorption is slower and more variable than when inhaled, with an onset of action between 30 minutes and 2 hours (Table 2). Alternatively, some cancer patients do manage to obtain and smoke marijuana in order to alleviate such conditions as nausea and vomiting due to chemotherapy. This is, however, technically illegal and is thus obviously a less than ideal treatment protocol. There is no currently available pharmaceutically acceptable aerosol form of Δ 9 THC. It would be advantageous to have available a form of pharmaceutical grade Δ 9 THC that could be administered as an aerosol. This would provide a means for rapid uptake of the drug without resorting to the illegal practice of smoking marijuana. Also, the potential adverse side effects encountered by smoking marijuana would be avoided. Further, an aerosol preparation of pharmaceutically pure Δ 9 THC could be administered in known, controlled dosages. In 1976, Olsen et al. described a chlorofluorocarbon (CFC) propelled MDI formulation of Δ 9 THC (21). However, Δ 9 THC is known to deteriorate during storage, and the stability of Δ 9 THC in this formulation is suspect. In addition, the ethanol content in this formulation was so high (-23%) as to create an aerosol with droplets too large to be effectively inhaled (22). The Δ 9 THC CFC formulations were tested for use in treating asthma but were shown to be only moderately effective (23, 24). Moreover, CFC propellants have since been banned so that such a formulation is now useless. It would clearly be advantageous to develop a new aerosol formulation in which the Δ 9 THC is stable, the droplets are of a size that can be effectively inhaled, and which utilizes a non-CFC propellant. SUMMARY OF THE INVENTION It is an object of the present invention to provide a stable aerosol-dispensable pharmaceutical composition comprising a non-CFC propellant and a pharmaceutically effective concentration of Δ 9 THC. More particularly, it is an object of the present invention to provide a stable aerosol-dispensable pharmaceutical composition comprising a hydro fluoroaikane propellant, (for example, HFA 227 or HFA 134a) and Δ 9 THC. The propellant is present in the range of approximately 78 to 100% by weight, and more particularly the propellant is present in the range of approximately 85 to 100% by weight. An organic solvent such as ethanol can be used to assist in solubilizing the Δ 9 THC in the propellant but is not required. If a solvent is used, preferably less than 20%> by weight will be required, and most preferably less than 15% by weight will be required. The pharmaceutically effective concentration of Δ 9 THC is preferably in the range of 0.05 to 10% by weight, and most preferably in the range of 0.1 to 6% by weight. The pharmaceutical composition of the present invention can be used to treat a variety of medical conditions including nausea and vomiting associated with cancer chemotherapy, muscle spasticity, pain, anorexia associated with AIDS wasting syndrome, anorexia associated with cancer chemotherapy, epilepsy, glaucoma, bronchial asthma, mood disorders, migraine headaches. DETAILED DESCRIPTION OF THE DRAWINGS Figure 1. Δ 9 THC MDI characterization summary before and after storage at 40°C and 82% relative humidity (RH). Figure 2. Generalized schematic drawings of a Δ 9 THC MDI. DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT OF THE INVENTION The instant invention provides a series of non-ozone depleting pressurized metered dose inhaler formulations of Δ 9 THC. In preferred embodiments of the invention, the formulations contain the pharmaceutically acceptable, non-ozone depleting hydro fluoroaikane propellants HFA 134a (1,1,1,2-tetrahydrofluoroethane) and HFA 227 (1,1,1,2,3,3,3-heptafluoropropane), or a mixture thereof. When the propellant is a hydrofluoroalkane, it has been discovered that the propellant may be used with or without a solvent such as ethanol. Higher percentages of solvent generally allow higher levels of dissolution of Δ 9 THC. However, higher percentages of solvent also cause droplet size to increase. In preferred embodiments of the invention, the range of propellant compositions, as shown in Table 3, may be from 100%) propellant and 0% solvent to 85% propellant and 15 %> solvent. Within this range of percentages, pharmaceutically useful concentrations of Δ 9 THC can be achieved and droplet size is still small enough (<5.8μm) to provide excellent aerosol delivery of the drug. While these ratios reflect preferred embodiments of the invention, it will be recognized by those of skill in the art that the exact ratio of propellant to solvent (e.g. ethanol) may vary according to the desired final concentration of Δ 9 THC and droplet size. Any ratio of propellant to solvent that results in appropriate sized droplets and adequate dissolution of the Δ 9 THC may be used in the practice of this invention, and this will generally be in the range of from 100 to 80% propellant and 0 to 20%) solvent. It is expected that a wide variety of solvents, such as ethanol, propanol, propylene glycol, glycerol, polyethylene glycol, etc. may be used in the preparation of formulations contemplated by this invention. Those skilled in the art will also recognize that the "respirable dose" (or mass of Δ 9 THC in particles with aerodynamic diameters small enough to be delivered to and absorbed by the lungs) (Figure 1 ) may be increased by choosing MDI spray nozzles of different design and smaller orifice diameters. Respirable doses may also be increased by extending the mouthpiece of the MDI in such a way as to create an integral or separate aerosol spacer or reservoir attached to the mouthpiece of the MDI. This promotes an increase in droplet evaporation and hence in the percentage of the dose in smaller "respirable" particles or droplets. Generally, the optimal size of a respirable droplet is less than 10μm in size. A distinct advantage of the present formulations is that, surprisingly, the use of surface active agents or "surfactants" as valve lubricants and solubilizers is not necessary. This is in contrast to the invention of Purewal and Greenleaf (European Patent 0,372,777; reference #25) which provides HFA 134a/ethanol mixtures to produce stable formulations of pharmaceuticals in the presence of lipophilic surface active agents. Lipophilic surface active agents are incorporated in that invention in order to suspend undissolved material and to ensure adequate valve lubrication of the MDI. Without adequate valve lubrication, the useful life of the MDI and its ability to deliver an accurate dose of drug are severely attenuated. However, probably due to the inherent lubricity of the formulations of the present invention, the use of such surface active agents is unnecessary. This simplifies the composition and thus is an advantage with respect to cost and the elimination of potentially deleterious interactions between components of the formulations and the agents. A major consideration in the formulation of any drug is its stability. Δ 9 THC is known to deteriorate upon storage so that the effective concentration decreases and the purity is vitiated. The stability of the formulations of the present invention were tested according to accelerated storage testing protocols. The results are given in Figure 1 and Tables 4 A and 4B. The formulations of the present invention were shown to be stable with respect to the release of aerosolized Δ 9 THC in reproducible doses following accelerated storage testing. Apparently, the containment of Δ 9 THC in solution in the non-aqueous formulations of the present invention is excellent with respect to chemical degradation, making possible the construction of a multidose inhaler with a good shelf life prognosis. Further, lipophilic materials like Δ 9 THC are generally known to partition into the elastomers of the valves in MDI formulations. (Δ 9 THC is highly lipophilic as reflected in its octanolrwater partition coefficient of 6000:1). Over time, this partitioning results in a decrease in the emitted or delivered dose of a lipophilic drug. Thus, this phemonemon also decreases the useful shelf-life of such preparations. However, the data presented in Figure 1 and Table 4 show that this is not the case with the formulations of the present invention. The emitted or delivered doses were constant over the time period tested. This may be due to the somewhat surprising preference of Δ 9 THC for the formulation itself, rather than for the valve elastomers. TABLE 4A. Formulation and aerosol characteristics of Δ 9 THC pressurized metered dose inhalers in ethanol/hydrofluoroalkane (HFA) propellant blends. a Mean (Standard Deviation) of five determinations. b Mass of Δ 9 THC aerosol particles <5.8 μm aerodynamic diameter *SS: Stability Sample ** RH: relative humidity *** Aproximate spray nozzle diameter = 0.2 mm. TABLE 4B. Formulation and aerosol characteristics of Δ 9 THC pressurized metered dose inhalers in ethanol/hydrofluoroalkane (HFA) propellant blends. a Mean (Standard Deviation) of five determinations. b Mass of Δ 9 THC aerosol particles with <5.8 μm aerodynamic diameter *SS: Stability Sample ** RH: relative humidity ND: not determined *** Approximate spray nozzle diameter = 0.2 mm The final concentration of Δ 9 THC in a given formulation may be varied by adjusting the ratio of propellant to solvent and thus the solubility of the Δ 9 THC. Higher percentages of solvent (e.g. ethanol) generally allow a higher amount of Δ 9 THC to be dissolved. For example, in preferred embodiments of the invention, the apparent solubility of Δ 9 THC ranged from 0.147% w/w to 5.94%> w/w as the propellant composition varied from 100% HFA 227 to 85% HFA 227 and 15% ethanol. Thus, the dose of Δ 9 THC in a given metered volume may be selected by changing the formulation. Further, as stated above, the "fine particle dose" or "respirable dose" of a drug dispensed with an MDI is a function of the spray nozzle diameter. In Figure 1 and Tables 4A and 4B, the spray nozzle diameter is 0.4mm. The "fine particle dose" or "respirable dose" of the formulations of the present invention was shown to be unaffected by storage. The Δ 9 THC of the present invention is pharmaceutically pure. That is, its form is the nonionized resinous drug substance (6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9- trimethyl-3-pentyl-6H-dibenzo[b,d]-pyran-l-ol. Although its preferred embodiment in this invention is not a salt or ester, it will be readily understood by those of skill in the art that other appropriate forms of Δ 9 THC may be synthesized (e.g. esters and salts) and thus used in the practice of this invention. The desired final concentration of Δ 9 THC in a patient's serum will vary from patient to patient depending on, for example, the nature and severity of the condition being treated, and the patient's overall condition, weight, gender and response to the drug, etc. But the desired range will generally be 10-100ng/ml at 15 minutes following inhalation. The level of Δ 9 THC in a patient's serum can be readily and reliably monitored by gas chromatography/mass spectrophotometry (GC/MS). The exact treatment protocol to be used may vary from patient to patient depending on the circumstances. For example, in a preferred embodiment of the invention, a patient receiving chemotherapy may have one dose of Δ 9 THC prescribed via inhalation, to be administered 15 minutes before chemotherapy and 4-8 times daily following chemotherapy. In another preferred embodiment, a patient suffering from anorexia associated with AIDS wasting syndrome may have Δ 9 THC by inhalation prescribed 3-5 times daily, 30 minutes before each meal or snack. In other preferred embodiments, a patient suffering form cancer pain, or spasticity related to either multiple sclerosis or spinal cord injury may have Δ 9 THC by inhalation prescribed 3-6 times daily. Those skilled in the art will readily recognize that the treatment protocol may be crafted so as to address the particular needs of each individual patient on a case by case basis. Δ 9 THC may be used alone or in combination with other medications. Those skilled in the art will readily recognize that, for example, in the case of AIDS wasting syndrome, the patient will likely also be taking drugs that combat the AIDS virus. Similarly, those skilled in the art will readily recognize that patients receiving chemotherapy for cancer may also receive other antiemetics, and cancer patients seeking to relieve pain are likely to receive opioids as well as nonsteroidal anti- inflammatory agents. The containers for the formulations of the instant invention may be any that are suitable for the efficacious delivery of aerosol inhalants. Several containers and their method of usage are known to those of skill in the art. For example, MDIs can be used with various dose metering chambers, various plastic actuators and mouthpieces, and various aerosol holding chambers (e.g. spacer and reservoir devices), so that appropriate doses of Δ 9 THC reach and deposit in the lung and are thereafter absorbed into the bloodstream. In addition, a lock mechanism such as that shown in U.S. Patent 5,284,133 to Burns and Marshak, which is herein incorporated by reference, can be used to prevent overdose or unauthorized consumption of Δ 9 THC. Figure 2 provides a generalized drawing of an MDI containing the composition of this invention and provides the advantage of delivering metered quantities of Δ 9 THC on a repetitive basis. The MDI includes a container 100 for holding the composition and a valve delivery mechanism 102 for delivery of aerosolized Δ 9 THC. While the invention has been described in terms of its preferred embodiments, those skilled in the art will recognize that the invention can be practiced with modification within the spirit and scope of the appended claims. REFERENCES 1. Workshop on the medical utility of marijuana. National Institutes of Health, August 1997. 2. 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(1980) Antiemetics in patients receiving chemotherapy for cancer: a randomized comparision of Δ 9 THC and prochlorperazine. N. Engl. J. Med. 302:135-138. 7. Frytak, S., Moertel, C.G., O'Fallon, J.R., Rubin, J., Creagan, E.T., O'Connell, M.J., Schutt, A.J. and Schwartau, Ν.W. (1979) Delta-9-tetrahydrocarmabinol as an antiemetic for patients receiving cancer chemotherapy: a comparison with prochlorperazine and a placebo. Ann. Inter. Med. 91 :825-830. 8. Chang, A.E., Shiling, D.J., Stillman, R.C., Goldgerg, Ν.H., Seipp, C.A., Barofdky, I., Simon, R.M. and Rosenberg SA (1979) Δ 9 THC as an antiemitic in cancer patients receiving high-dose methotrexate. Ann. Internal. Med. 91:819-824. 9. Sallan, S.E.. Zinberg, N.E.and Frei, I.E. (1975) Antiemetic effect of Δ 9 THC in patients receiving cancer chemotherapy. New Engl. J. Med. 293:795-797. 10. Noyes, J.R., Brunk, S.F., Baram, D.A. and Canter, A. (1975) The analgesic properties of Δ 9 THC and codeine. J. Clin. Pharmacol. 15:139-143. 11. Noyes, R., Jr., Brunk, S.F., Baram, D.A. and Canter, A. (1975) Analgesic effect of Δ 9 -tetrahydrocannabinol. J. Clin. Pharmacol. 15:139-143. 12. Brenneisen, R., Egli, A., Elosohlly, M.A., Henn, V. and Spiess, Y. (1996) The effect of orally and rectally administered Δ 9 THC on spasticity: a pilot study with 2 patients. Int. J. Clin. J. Pharmocol. Ther. 34:446-452. 13. Ungerleider, J.T., Andyrsiak, T.F.L., Ellison, G.W. and Myers, L.W. (1987) Δ 9 THC in the treatment of spasticity associated with multiple sclerosis. Adv. Alcohol Subst. Abuse 7:39-50. 14. Clifford, D.B. (1983) Tetrahydrocannabinol for tremor in multiple sclerosis. Ann. Neurol. 13:669-171. 15. Petro, D.J. and Ellenberger, C. (1981) Treatment of human spasticity with delta 9 -tetrahydrocannabinol. J. Clin. Pharmacol. 2 413S-416S. 16. Maurer, M., Henn, V., Dittrich, A. and Hofman, A. (1990) Delta 9- tetrahydrocannabinol shows antispastic and analgesic effects in a single case double- blind trial. Eur. Arch. Psychiatry Neurol. Sci. 240:1-4. 17. Merritt, J., Crawford, W., Alexander, P., Anduze, A. and Gelbart, S. (1980) Effects of marihuana on intra ocular and blood pressure in glaucoma. Opht. 87:222- 228. 18. Cooler, P. and Gregg, J.M. (1977) Effect of delta 9-Δ 9 THC on intra ocular pressure in humans. South. Med. J. 70:951-954. 19. PDR (1995) Physician's Desk Reference (49) Montvalek, New Jersey: Medical Economics Data Production Co., pp.2787. 20. Ohlsson, A., Lindgren, J.E., Wahlen, A., Agurall, S., Hollister, L.E. and Gillespie, H.K. (1980) Plasma Δ 9 THC concentrations and effects after oral and intravenous administration and smoking. Clin. Pharmacol. Ther. 28:409-416. 21. Olsen, J.L., Lodge, J.W., Shapiro, B.J. and Tashkin, D.P. (1976) An inhalation aerosol of Δ 9 - tetrahydrocannabinol. J Pharmacy and Pharmacol. 28:86. 22. Dalby, R.N. and Byron, P.R. (1988) Comparison of output particle size distributions from pressurized aerosols formulated as solutions or suspensions. Pharm. Res. 5:36-39. 23. Tashkin, D.P., Reiss, S., Shapiro, B.J., Calvarese, B., Olsen, J.L. and Lidgek, J.W. (1977) Bronchial effects of aerosolized Δ 9 - tetrahydrocannabinol in healthy and asthmatic subjects. Amer. Rev. of Resp. Disease. 115:57-65. 24. Williams, S.J., Hartley, J.P.R. and Graham, J.D.P. (1976) Bronchodilator effect of delta-9-THC administered by aerosol to asthmatic patients. Thorax. 31 :720-723. 25. European Patent 0, 12,111 (Riker Laboratories). Medicinal aerosol formulations.

Claims: CLAIMS We claim: 1. An aerosol-dispensable pharmaceutical composition, comprising: a hydrofluoroalkane propellant; and Δ 9 - tetrahydrocannabinol present in a pharmaceutically acceptable form and at a pharmaceutically effective concentration dissolved in said hydrofluoroalkane propellant. 2. The aerosol dispensable pharmaceutical composition of claim 1 wherein said Δ 9 - tetrahydrocannabinol is dissolved in said hydrofluoroalkane propellant without the use of a solubilizing agent selected from the group consisting of solvents and surfactants. 3. The aerosol-dispensable pharmaceutical composition of claim 1 wherein said hydrofluoroalkane is selected from the group consisting of: HFA 134a and HFA 227. 4. The aerosol-dispensable pharmaceutical composition of claim 3 wherein said hydrofluoroalkane is present in an amount in excess of 85% by weight. 5. The aerosol-dispensable pharmaceutical composition of claim 1 further comprising an organic solvent. 6. The aerosol-dispensable pharmaceutical composition of claim 5 wherein said organic solvent is ethanol present in an amount ranging up to 15% by weight. 7. The aerosol-dispensable pharmaceutical composition of claim 1 wherein said pharmaceutically effective concentration of Δ 9 -tetrahydrocannabinol ranges from 0.05 to 10% by weight. 8. The aerosol-dispensable pharmaceutical composition of claim 1 wherein said pharmaceutically effective concentration of Δ 9 -tetrahydrocannabinol ranges from 0.1 to 6% by weight. 9. The aerosol-dispensable pharmaceutical compositon of claim 1 wherein Δ 9 - tetrahydrocannabinol is present in pure form. 10. A solvent free pharmaceutical composition consisting essentially of 1,1,1,2,3,3,3-hydrofluoropropane (HFA 227) and Δ 9 - tetrahydrocarmabinol. 11. A solvent free pharmaceutical composition consisting essentially of 1,1,1 ,2-hydrofluroethane (HFA 134a) and Δ 9 - tetrahydrocannabinol. 12. A method of treating a patient in need thereof with an aerosolized pharmaceutically acceptable form of Δ 9 - tetrahydrocannabinol, comprising the step of: administering an aerosolized dose of a pharmaceutically acceptable form of Δ 9 -tetrahydrocannabinol as respirable droplets to a patient's lung from a composition comprised of a hydrofluoroalkane propellant and said pharmaceutically acceptable form of Δ 9 - tetrahydrocannabinol. 13. The method of claim 12 wherein said composition comprises a pharmaceutically acceptable solvent. 14. The method of claim 12 wherein said composition is solvent-free. 15. The method of claim 12 wherein said aerosolized dose is sufficient to reduce nausea. 16. The method of claim 12 wherein said aerosolized dose is sufficient to reduce vomiting. 17. The method of claim 12 wherein said aerosolized dose is sufficient to reduce pain. 18. The method of claim 12 wherein said aerosolized dose is sufficient to relieve muscle spasticity. 19. The method of claim 12 wherein said aerosolized dose is sufficient to relieve migraine headaches. 20. The method of claim 12 wherein said aerosolized dose is sufficient to relieve movement disorders. 21. The method of claim 12 wherein said aerosolized dose is sufficient to increase appetite in patients suffering from cachexia. 22. The method of claim 12 wherein said pharmaceutically acceptable form of Δ 9 - tetrahydrocannabinol is pure Δ 9 - tetrahydrocannabinol and said hydrofluoroalkane is selected from the group consisting of HFA 134a and HFA 227. 23. A metered dose inhaler, comprising, a housing; a metering valve connected to said housing; and, an aerosol-dispensable pharmaceutical composition which includes a hydrofluoroalkane propellant and Δ 9 - tetrahydrocannabinol present in a pharmaceutically effective concentration dissolved in said hydrofluoroalkane propellant.

Inventors: BYRON PETER, LICHTMAN ARON, MARTIN BILLY, PEART JOANNE, BYRON, PETER, LICHTMAN, ARON, MARTIN, BILLY, PEART, JOANNE
Applicants: UNIV VIRGINIA COMMONWEALTH, VIRGINIA COMMONWEALTH UNIVERSITY
Application year: 1999
Main classification: A61K
IPC codes: A61K9, A61K31, A61K47, A61M13, A61M15, A61P1, A61P21, A61P25, A61P43