HK1119675B - Stabilized compositions of volatile alkylating agents and methods of using thereof - Google Patents

Description

Stable compositions of volatile alkylating agents and methods of use thereof

Technical Field

The present invention relates generally to a composition and method for topical treatment of skin disorders, and more particularly to a stabilized nitrogen mustard composition and method for topical treatment of skin disorders.

Background

Cutaneous T-cell lymphoma (CTCL) is a malignancy of T-helper (CD4+) cells of the immune system. CTCL is also known as Mycosis Fungoides (MF), a leucoma that affects primarily the skin and only secondarily (secondary affect) elsewhere. The disease involves uncontrolled proliferation of lymphocytes called helper T cells, so named for their role in the immune response. Helper T cells are characterized by the presence of a protein receptor called CD4 on their surface. Thus, helper T cells are referred to as CD4 +.

Proliferation of helper T cells results in penetration or invasion of these abnormal cells into the epidermal layer of the skin. The skin response is a mild ichthyoid lesion with itching, although the most invasive site is not necessarily the lesion. The lesions most often appear on the torso, but may appear on any part of the body. The punctate lesions progress to palpable plaques with deep red color and more distinct edges during the most common course of the disease. The disease progresses to skin tumor with the deterioration of the disease, and the skin tumor generally takes the shape of mushroom, so the disease is named mycosis fungoides. Finally, the tumor develops into an external melanoma (extracutaneous), often occurring in lymph nodes or internal organs.

CTCL is a rare disease with an annual incidence of approximately 0.29 per 100,000 in the united states, about half of the incidence in eastern europe. However, this difference may be due to a difference in the physician's knowledge of the disease rather than a real case difference. In the United states, there are approximately 500-. CTCL is commonly found in older adults; the median age at diagnosis was 55-60 years. Twice as many cases are in men as in women. The average life expectancy of diagnosed patients is 7-10 years, even without treatment.

The most common side effect of treatments applied to the skin is the skin sensitivity of the drug. There is a need for improved compositions and methods for skin disorders to avoid or reduce skin irritancy of drugs.

Disclosure of Invention

In a first aspect the present invention provides a composition for use in the treatment of a skin disorder, the composition comprising: a nitrogen mustard or an HX salt of a nitrogen mustard, wherein the nitrogen mustard or the HX salt of a nitrogen mustard is present in a non-aqueous carrier (vehicle or carrier), wherein the non-aqueous carrier does not include petrolatum or ethanol, wherein the nitrogen mustard is represented by the structure:

wherein R is₁、R₂、R₃...R₃₄(R₁-R₃₄) Each independently selected from the group consisting of a hydrogen atom, a straight chain alkyl group having from 1 to 6 carbon atoms, a branched alkyl group having from 2 to 12 carbon atoms, a cycloalkyl group having from 3 to 17 carbon atoms, a fluorinated straight chain alkyl group having from 2 to 12 carbon atoms, a fluorinated branched alkyl group having from 2 to 12 carbon atoms, a fluorinated cycloalkyl group having from 3 to 17 carbon atoms, an aryl group, an aralkyl group, an alkaryl group, a cycloalkyl group, a bicycloalkyl group, an alkenyl group, an alkalkenyl group, an alkenylalkyl group, an alkynyl group, an alkalkynyl group, an alkynylalkyl group, a trifluoropropyl group, a cyanopropyl group, an acryloyl group, an arylacryloyl group, an acryloylaryl group, an alkanoyl group, an arylacyl group, an alkenylacyl group and an alkynoyl group, wherein n is 1, 2 or 3, wherein p is 0, 1 or 2, wherein n +₁-R₃₄Can be connected to form aA three to eight membered cyclic group.

A second aspect of the invention provides a method for treating a patient having skin disease, the method comprising: topically applying a nitrogen mustard or an HX salt of a nitrogen mustard to affected skin, wherein the nitrogen mustard or the HX salt of a nitrogen mustard is present in a non-aqueous carrier, wherein the non-aqueous carrier does not include petrolatum or ethanol, wherein the nitrogen mustard is represented by the following structure:

wherein R is₁、R₂、R₃...R₃₄(R₁-R₃₄) Each independently selected from the group consisting of a hydrogen atom, a straight chain alkyl group having from 1 to 6 carbon atoms, a branched alkyl group having from 2 to 12 carbon atoms, a cycloalkyl group having from 3 to 17 carbon atoms, a fluorinated straight chain alkyl group having from 2 to 12 carbon atoms, a fluorinated branched alkyl group having from 2 to 12 carbon atoms, a fluorinated cycloalkyl group having from 3 to 17 carbon atoms, an aryl group, an aralkyl group, an alkaryl group, a cycloalkyl group, a bicycloalkyl group, an alkenyl group, an alkalkenyl group, an alkenylalkyl group, an alkynyl group, an alkalkynyl group, an alkynylalkyl group, a trifluoropropyl group, a cyanopropyl group, an acryloyl group, an arylacryloyl group, an acryloylaryl group, an alkanoyl group, an arylacyl group, an alkenylacyl group and an alkynoyl group, wherein n is 1, 2 or 3, wherein p is 0, 1 or 2, wherein n +₁-R₃₄May be linked to form a three to eight membered cyclic group.

A third aspect of the present invention provides a method of stabilizing a volatile alkylating agent, the method comprising: providing a non-aqueous flowable (flowable) ointment or cream, wherein the non-aqueous flowable ointment or cream does not comprise petrolatum or ethanol; reconstituting the HX salt of the volatile alkylating agent in an anhydrous solvent (recornstitute); the non-aqueous flowable ointment or cream is combined with the HX salt of the volatile alkylating agent by mixing.

In a fourth aspect the invention provides a device having walls defining a chamber, wherein said walls are formed from a material which is impermeable to a mixture of a pharmaceutically acceptable nitrogen mustard HCl and a non-aqueous carrier which does not include petrolatum or ethanol.

Drawings

The features of the invention are set forth in the appended claims. The invention itself, however, will be best understood by reference to the following detailed description of an illustrative embodiment when read in conjunction with the accompanying drawings, wherein:

FIG. 1 illustrates a method of using a composition having a stable alkylating agent for treating skin disorders in accordance with an embodiment of the present invention;

FIG. 2 shows a front cross-sectional view of a device having a chamber partially enclosed by walls, according to an embodiment of the invention;

FIG. 3 shows a device having a plug that mechanically closes an opening portion of a wall, in accordance with an embodiment of the present invention; and is

Figure 4 shows a device in which the heat seal is serrated to allow easy removal of the stopper, according to an embodiment of the invention.

Detailed Description

In one embodiment, MF patients topically treated with nitrogen mustard incorporated into polypropylene glycol (PPG, molecular weight from about 300 to about 2500), Propylene Glycol (PG), polyethylene glycol (PEG, molecular weight from about 100 to about 1000), or ethylene glycol ointment or cream do not show any signs of systemic toxicity.

A summary of the response rate and toxicity involved in the topical treatment of MF patients with mechlorethamine in Propylene Glycol (PG) is given in Table 1 below.

Table 1: topical administration of nitrogen mustard to Mycosis Fungoides (MF) patients: summary of clinical results & toxicity.

^*General toxicity history&Physical examination and experimental study monitoring.

Abbreviations: PTS ═ patient study; F/U is follow-up; CR is complete response; PG ═ propylene glycol, PCR ═ partial response; NR is no record.

Can be absorbed by whole body

There is no evidence that topical administration of nitrogen mustard results in clinically significant systemic absorption. Chronic topical administration of mechlorethamine to MF patients no systemic toxicity due to percutaneous absorption was observed.

Genotoxicity-no genotoxicity was observed with topical application of nitrogen mustard. The study, in which peripheral blood lymphocytes from CTCL-MF patients were examined before and after topical nitrogen mustard treatment, did not reveal any effect on sister chromatid exchange, is the best demonstration.

Myelosuppression-based on continuous whole blood cell count monitoring, chronic topical use of nitrogen mustard has not been reported to have myelosuppression (anemia, leukoderma, or thrombocytopenia).

Hepatotoxicity (hepatotoxicity) -long-term topical NM use was not reported to be hepatotoxic based on continuous peripheral blood liver function test monitoring.

Nephrotoxicity-based on continuous monitoring of peripheral blood renal function tests, there was no report of nephrotoxicity with chronic topical application of nitrogen mustard.

Environmental pollution

Topical application of nitrogen mustard has also been shown to cause environmental pollution with minimal evidence.

Side effects of the skin

The melanogenesis effect of pigmentation, a direct production of nitrogen mustard, has been reported in a large proportion of treated patients. The pigmentation is reversible and will gradually decrease in most patients, even during continued topical treatment.

Contact dermatitis-a common complication of topical nitrogen mustard application. Irritant contact dermatitis is most common and occurs in up to 25% of individuals who use nitrogen mustard ointments topically, particularly when used on sensitive areas such as the face or skin folds. Allergic contact dermatitis is also observed in topical nitrogen mustard use.

Immediate (urticaria) response-rarely occurs.

Allergic contact dermatitis, delayed allergic reaction (DTH), is more common and shows dose-dependence. Higher concentrations of aqueous formulations correlate with a frequency of 10-67% DTH occurrence. Desensitization with lower concentrations of nitrogen mustard has been successfully used in patients who have a DTH response to nitrogen mustard. The use of lower concentrations of the ointment formulation significantly reduced the incidence of DTH reactions. Stanford university reported that in its consecutive nitrogen mustard ointment formulations, patients who initially received the nitrogen mustard ointment formulation had a 0% frequency of DTH reactions, and patients who previously had a history of HN allergy had a 8% frequency of DTH reactions.

For paediatrics

Topical application of nitrogen mustard has been reported for use in children and adolescents (< 18 years) with no significant difference in toxicity and use in adults.

Used during pregnancy

Although there is no evidence of transdermal absorption of topically applied nitrogen mustards, women during pregnancy and lactation should avoid topical application of nitrogen mustards based on past experience.

Skin canceration

There have been no reports of long-term topical application of nitrogen mustard to significantly increase the incidence of Squamous Cell Carcinoma (SCC) of the skin. Several groups have reported that patients with CTCL-MF with topical nitrogen mustard have an incidence of SCC of about 10% (4% -14%) and indicate a risk of skin canceration. However, these retrospective studies do not take into account mixed variables such as risk of second malignancy associated with CTCL-MF, previous treatment (e.g. radiation treatment of the skin), and no suitable control group.

In normal DNA strand replication, a DNA strand having deoxyribonucleosides, each of which may include the bases adenine (a), thymine (T), cytosine (C) and guanine (G), is replicated by linking each deoxyribonucleoside on the strand to another deoxyribonucleoside, where the typical linkage is the formation of an a-T bond between adenine (a) and thymine (T) and a C-G bond between cytosine (C) and guanine (G) of the original DNA strand and its replicating DNA strand.

Nitrogen mustard alkylating agents can act as anti-cancer agents by disrupting the natural DNA strand replication of cancer cells, allowing unnatural base-base linkages to occur, e.g., where a particular nitrogen mustard alkylating agent is a bifunctional alkylating agent, a guanine (G) base would be linked to another guanine (G) base. Hereinafter, the bifunctional alkylating agent is a nitrogen mustard having at least two 2-chloroethyl side chains, such as the bis- (2-chloroethyl) methylamine of structural formula I of reaction 1 below.

Reaction 1 below describes a reversible reaction represented by forward reaction 1a and reverse reaction 1b in reaction 1, wherein a nitrogen mustard alkylating agent having a 2-chloroethyl side chain, such as bis- (2-chloroethyl) methylamine, represented by structural formula I below, can undergo intramolecular cyclization to form a highly reactive aziridinium intermediate (aziridinium cation), represented by structure II below. The concentration of aziridinium cation, infra, of II can be compared with that of I, infraNitrogen mustard concentration balance, wherein the balance constant Keq: (_1a，1b)The velocity k of the forward reaction 1a can be used_1aVelocity k of reaction with reverse direction 1b_1bThe ratio of (a) to (b). Reaction 1: the formation of the aziridinium cation, represented by formula II, is described below.

In structure I, the carbon atom bound to chlorine may initially carry only a partial positive charge δ +, and the chlorine atom may initially carry only a partial negative charge δ -. In reaction I, the unshared electron pair of nitrogen can form a covalent bond with the δ + bearing carbon atom, releasing the chlorine atom as chloride and forming structure II.

Structural formula II above can be nucleophilically attacked by an electron donor, i.e., a nucleophile, resulting in alkylation of the nucleophile. The reaction with the nucleophile guanine (G) of structural formula III shown in reaction 2 above occurs to the greatest extent at the N-7 position of this guanine (G). Other sites of guanine (G) and other DNA bases such as adenine (A), cytosine (C), and thymine (T), as well as phospho-oxygens (phospate oxygens) may also be alkylated. Hereinafter, the structural formula III represents all stereoisomers and racemates of deoxyribonucleosides with any DNA base.

Reaction 2: nucleophilic attack by guanine of the labile aziridinium ring of structural formula II, resulting from intramolecular cyclization as shown in reaction 1 above.

Reaction 2 above results in the formation of an alkylated deoxyribonucleoside of structural formula IV. In reaction 2 above, nucleophilic attack of the aziridinium ring of formula II at the N-7 position of the guanine (G) base of the deoxyribonucleoside represented by structure III can result in alkylation of the aziridinium ring of formula III at the N-7 position of the guanine (G) base, which can be formed by intramolecular cyclization as represented in reaction 1 above. Hereinafter, structural formula IV represents all stereoisomers and racemates of deoxyribonucleosides having any DNA base.

Alkylating agents have four effects on nucleotides. First, the agent can cause cross-linking of DNA strands, interfering with DNA and RNA synthesis. This is believed to be the most important cause of the cytotoxic effect of the alkylating agent. Second, the reagent can alter the "side-chain groups" of the nucleotide base ring, which can lead to abnormal base pairing and point mutations in the synthesized DNA and RNA strands. Third, the alkylating agent can cleave the base ring at the nucleotide, which in turn blocks normal DNA and RNA synthesis. Finally, the alkylating agent can cleave the circular structure of the nucleotide base, which prevents base pairing in DNA and RNA synthesis.

In normal DNA strand replication, a DNA strand consisting of deoxyribonucleosides, each of which may include the bases adenine (a), thymine (T), cytosine (C) and guanine (G), is replicated by linking each deoxyribonucleoside on the strand to another deoxyribonucleoside, where the typical linkage is the formation of an a-T bond between adenine (a) and thymine (T) and a C-G bond between cytosine (C) and guanine (G) of the original and replicated DNA strands.

Nitrogen mustard alkylating agents can act as anti-cancer agents by disrupting normal DNA strand replication, allowing abnormal base-base linkages to occur, for example, where a particular nitrogen mustard alkylating agent is a bifunctional alkylating agent, a guanine (G) base would be linked to another guanine (G) base. Hereinafter, the bifunctional alkylating agent is a nitrogen mustard having at least two 2-chloroethyl side chains, such as the bis- (2-chloroethyl) methylamine of structural formula I above.

In reaction 2 above, the guanine (G) base of formula III has been alkylated with a 2-chloroethyl side chain of the deoxyribonucleoside represented by formula IV. In the following reversible reaction 3, the remaining 2-chloroethyl side chain of the deoxyribonucleoside of the structural formula IV is also subjected to intramolecular cyclization to form deoxyribonucleoside V having an aziridinium ring with high reactivity.

Reaction 3: the aziridinium cation is formed from the remaining 2-chloroethyl side chain of the deoxyribonucleoside of structural formula IV, see above.

Reaction 4 below describes the abnormal linkage of deoxyribonucleoside V, having a guanine (G) base and an activated aziridinium ring, to another deoxyribonucleoside III, also having a guanine (G) base, forming an abnormal guanine-guanine (G-G) bond of formula VI in the product. In the following, structure VI shows all stereoisomers and racemates of the product formed by the combination of two deoxyribonucleoside molecules represented by structure III at the N-7 position with the bifunctional alkylated nitrogen mustards represented by structure II above.

Reaction 4: abnormal linkage of deoxyribonucleoside V, having a guanine (G) base and an activated aziridinium ring, to another deoxyribonucleoside VI, also having a guanine (G) base.

The high instability and extremely short duration of action of nitrogen mustards in the presence of water may be due to the water decomposing the highly reactive aziridinium intermediate (aziridinium cation) represented by formula II in reaction 1 above, with the OH groupReplacing the chlorine atom of the 2-chloroethyl side chain of the nitrogen mustard. Nitrogen mustards are considered to be highly unstable and have an extremely short duration of action because they can react with water, resulting in the replacement of one or two chlorine atoms by a hydroxyl group (OH). Replacement of the chlorine atom can block the formation of the aziridinium cation and thus can prevent the nitrogen mustard from acting as an alkylating agent, e.g., at the N-2 position of the guanine base of DNA. Reaction 5 illustrates the competing equilibrium reactions, 1a and 1b and 5a and 5 b. In reactions 1a and 1b, the nitrogen mustard of structural formula I in free form can be in equilibrium with the aziridinium (aziridium) ion II, as described above for reaction 1. The equilibrium constants of reactions 1a and 1b are expressed as K above_eq(1a，1b). In the same way, the equilibrium constant K of reactions 5a and 5b_eq(5a，5b)Can be expressed as the ratio of the concentration of the HX salt of IX to the product of the concentration of the free form nitrogen mustard of structural formula I and the concentration of HX. Thus, in one embodiment, there may be one functional K_eq(1a，1b)/K_eq(5a，b)The equilibrium concentration of the aziridinium cation is shown even when the nitrogen mustard has been stabilized by converting the nitrogen mustard in its free base form, as shown in reaction 5 below, to its HX salt, which is shown by structural formula I below and by structural formula IX. Thus, formula III in reactions 2-4-the N-2 position of the guanine base of DNA-can be alkylated by HX salt IX as in reaction 5 below, since the concentration of the aziridinium cation in reaction 5 below can be a positive real number, equal to K_eq(1a，1b)/K_{eq (5a，5b)}. Hereinafter, the free base form of the nitrogen mustard is any non-salt form of the nitrogen mustard in which a lone pair of electrons on the nitrogen atom can be used to form the aziridinium ion II as in reaction 1 above. In embodiments of the present invention, the aziridinium cation of formula II above may be nucleophilically attacked by an electron donor, resulting in alkylation of the nucleophile. For example, reaction with the nucleophile guanine (G) of structural formula III at the N-7 position of the guanine (G) as shown in reaction 2 above occurs to the greatest extent. Other sites of guanine (G), and other DNA bases such as adenine (A), cytosine (C) and thymine (T), and phosphols may also be alkylated。

The present inventors have discovered that the oxygen on primary alcohols is often a nucleophile and thus may adversely affect the use of the free base or pharmaceutically acceptable HX salt IX as in reaction 5 below, because the nitrogen mustard free base or pharmaceutically acceptable HX salt IX is consumed in an undesirable side reaction in which the nucleophile is alkylated by the nitrogen mustard free base or pharmaceutically acceptable HX salt IX and is not able to fight T lymphoma cells in the form of an anticancer agent by, for example, disrupting normal DNA chain replication. Hereinafter, the pharmaceutically acceptable HX salt IX, as in reaction 5 below, refers to a salt form which is pharmacologically acceptable and which is substantially non-toxic to patients treated with the agent of the invention. Thus, secondary and tertiary alcohols, amines, amino alcohols having 1 to 20 carbon atoms are more preferred for the formulation of the free base of the nitrogen mustard or the pharmaceutically acceptable HX salt IX over primary alcohols having 1 to 20 carbon atoms when pharmaceutically acceptable inert ingredients, i.e. pharmaceutically acceptable excipients, are required to facilitate the dissolution of the free base of the nitrogen mustard or the pharmaceutically acceptable HX salt IX in a non-aqueous carrier that does not include petrolatum or ethanol.

Ethanol is not used to dissolve the nitrogen mustard or its HX salt because it is a nucleophile that degrades the nitrogen mustard or its HX salt by promoting the loss of chlorine. Isopropanol, cetyl alcohol, stearyl alcohol, cetostearyl alcohol (cetearyl) or dodecenyl alcohol are preferred as pharmaceutically acceptable excipients for dissolving (dissolve orthoke up) mechlorethamine or its HX salts. Alternatively, for example, for topical formulations, pharmaceutically acceptable adjuvants may include solvents, emollients, humectants, preservatives, emulsifiers, and pH agents. Suitable solvents include acetone, ethylene glycol, polyurethane and others known in the art. Suitable emollients include mineral oil, propylene glycol dicaprylate, lower fatty acid esters, lower alkyl ethers of propylene glycol, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, stearic acid, waxes and other materials known in the art. Suitable humectants include glycerin, sorbitol, and other materials known in the art. Suitable emulsifiers include glyceryl monostearate, glyceryl monooleate (glyceryl monoleate), stearic acid, polyoxyethylene cetyl ether, polyoxyethylene cetostearyl ether, polyoxyethylene stearyl ether, polyethylene glycol stearate, 1, 2-propylene glycol monostearate and others known in the art. Suitable pH agents include hydrochloric acid, phosphoric acid, diethanolamine, triethanolamine, sodium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, and other materials known in the art. Alternatively, the pH agent comprises from about 1 weight percent to about 15 weight percent acetic acid, citric acid, or lactic acid. Suitable preservatives include benzyl alcohol, sodium benzoate, parabens, and others known in the art.

The present inventors have disclosed that polyethylene glycol (PEG), Ethylene Glycol (EG), polypropylene glycol (PPG), Propylene Glycol (PG) and diethylene glycol mono-substituted ether (DGMSE) are useful pharmaceutically acceptable excipients. Polyethylene glycol (PEG), Ethylene Glycol (EG), polypropylene glycol (PPG), Propylene Glycol (PG) and diethylene glycol mono-substituted ether (DGMSE) may hydrogen bond to trace nucleophiles that may be contaminated in pharmaceutically acceptable excipients, thereby reducing the nucleophilic strength of the trace nucleophiles. Thus, diethylene glycol mono-substituted ether (DGMSE) or a siloxane, such as dimethicone or cyclomethicone, can be used as a pharmaceutically acceptable adjuvant to facilitate dissolution of the free base of the nitrogen mustard or, hereinafter, the pharmaceutically acceptable HX salt IX, in a formulation of the free base of the nitrogen mustard or, hereinafter, the pharmaceutically acceptable HX salt IX.

In an embodiment of the present invention, the pharmaceutically acceptable HX salts of nitrogen mustards of structural formula IX below are shown to be more stable and have a longer duration of activity than the respective free base by measuring their effective alkylation activity in a non-aqueous vehicle excluding petrolatum or ethanol, wherein the effective alkylation activity after three (3) years of the pharmaceutically acceptable HX salt of nitrogen mustards in the non-aqueous vehicle excluding petrolatum or ethanol is comparable to the effective alkylation activity after 3 months of the respective free base form of nitrogen mustards of structural formula I in the non-aqueous vehicle excluding petrolatum or ethanol. The non-aqueous carrier, excluding petrolatum or ethanol, in the formulation of the nitrogen mustard free base or the pharmaceutically acceptable HX salt of structural formula IX below does not include any grade of white or yellow petrolatum recognized in the art as suitable for human administration. Such non-aqueous carriers which do not include petrolatum or ethanol in the formulation of the nitrogen mustard free base or the pharmaceutically acceptable HX salt of structural formula IX below do not include such commercially available materials as Penreco Snow White Pet USP. Non-aqueous vehicles that do not include petrolatum or ethanol in the formulation of the nitrogen mustard free base or the pharmaceutically acceptable HX salt of structural formula IX below do not include hydrocarbon mixtures made from mineral oil in combination with paraffins of various melting points. The non-aqueous carrier not including petrolatum or ethanol does not include lipophilic emollients selected from petrolatum, fatty acid esters.

In the following, the effective alkylating activity of a pharmaceutically acceptable HX salt of structure IX below in a non-aqueous carrier that does not include petrolatum or ethanol is comparable to the effective alkylating activity of the free base form of the respective nitrogen mustard of structure I in a non-aqueous carrier that does not include petrolatum or ethanol, when the weight percent of the pharmaceutically acceptable HX salt of structure IX below in the non-aqueous carrier that does not include petrolatum or ethanol is substantially equal to the weight percent of the respective free base form of the nitrogen mustard of structure I in the non-aqueous carrier that does not include petrolatum or ethanol.

In an embodiment of the present invention, the use of a pharmaceutically acceptable HX salt of a nitrogen mustard of structural formula IX below in a non-aqueous carrier that does not include petrolatum or ethanol, can maintain its effective alkylation activity by reducing volatility as compared to the free base form, since the pharmaceutically acceptable HX salt of a nitrogen mustard generally has a lower vapor pressure than its corresponding free base form.

The reaction, represented by arrow 5c below, indicates the formation of the stable nitrogen mustard HX composition of the present invention, which is stabilized by the reaction of the nitrogen mustard and HX to convert the free form of the highly reactive nitrogen mustard alkylating agent into a pharmaceutically acceptable HX salt.

Reaction 5: formation of the nitrogen mustard HX is represented by structural formula IX, wherein the nitrogen mustard is represented by structural formula I in reaction 1 above.

In one embodiment, X^-May advantageously be a halide such as Cl^-、Br^-、I^-Or HSO₄ ^-Or NO₃Wherein HX can be HCl, HBr, HI or H respectively₂SO₄Or HNO₃. Alternatively, pharmaceutically acceptable HX salts include conventional acid addition salts or base addition salts formed from suitable non-toxic organic or inorganic acids or bases. Acid addition salts which may be mentioned as examples include derivatives of inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and derivatives of organic acids such as p-toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, isethionic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, 2-acetoxybenzoic acid, acetic acid, phenylacetic acid, propionic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, ascorbic acid, maleic acid, hydroxymaleic acid, glutamic acid, salicylic acid, sulfanilic acid and fumaric acid. Exemplary base addition salts include derivatives of ammonium hydroxide (e.g., quaternary ammonium hydroxides, such as tetramethylammonium hydroxide), derivatives of inorganic bases such as alkali or alkaline earth metal (e.g., sodium, potassium, lithium, calcium, or magnesium) hydroxides, and derivatives of non-toxic organic bases such as basic amino acids.

Hereinafter, a pharmaceutically acceptable nitrogen mustard or a pharmaceutically acceptable HX salt of a nitrogen mustard is the Active Pharmaceutical Ingredient (API). In one embodiment, the API may be provided in a weight ratio of 10: 1 NaCl to API. Alternatively, the weight ratio of NaCl to API may be about 100: 0.01 to 0.01: 100. Alternatively, the API may be formulated as any solid mixture containing one or more of the pharmaceutically acceptable HX salts mentioned above. The inventors have discovered that in theory the API in the form of its HX salt is stably present in a salt matrix because both the salt matrix and the HX salt of the API are ionic.

FIG. 1 depicts one embodiment of the present invention, method 1 for treating a dermatological patient, the method comprising: topically applying to the affected skin a pharmaceutically acceptable nitrogen mustard or a pharmaceutically acceptable HX salt of a nitrogen mustard, wherein the nitrogen mustard or the pharmaceutically acceptable HX salt of a nitrogen mustard is in a non-aqueous carrier that does not include petrolatum or ethanol, wherein the nitrogen mustard is represented by the following structural formula:

in one embodiment, R₁、R₂、R₃...R₃₄(R₁-R₃₄) Each independently selected from the group consisting of a hydrogen atom, a straight chain alkyl group having 1 to 6 carbon atoms, a branched alkyl group having 2 to 12 carbon atoms, a cycloalkyl group having 3 to 17 carbon atoms, a fluorinated straight chain alkyl group having 2 to 12 carbon atoms, a fluorinated branched alkyl group having 2 to 12 carbon atoms, a fluorinated cycloalkyl group having 3 to 17 carbon atoms, an aryl group, an aralkyl group, an alkaryl group, a cycloalkyl group, a bicycloalkyl group, an alkenyl group, an alkanyl group, an alkinyl group, an alkynyl group, a trifluoropropyl group, a cyanopropyl group, an acryloyl group, an arylacryloyl group, an acryloylaryl group, an alkanoyl group, an arylacyl group, an alkenylacyl group, and an alkynoyl.

In one embodiment, n is 1, 2 or 3.

In one embodiment, p is 0, 1 or 2 and n + p.ltoreq.3.

In one embodiment, any two R in the same molecule₁-R₃₄May be linked to form a three to eight membered cyclic group.

In one embodiment, the nitrogen mustard may advantageously be selected from bis- (2-chloroethyl) ethylamine, bis- (2-chloroethyl) methylamine, and tris- (2-chloroethyl) amine, and combinations thereof. Hereinafter, the structural formulae VII, VIII, IX and X (XI-XIV) may represent all racemates and stereoisomers in which the compounds may have optical activity.

Alternatively, in one embodiment, the nitrogen mustard may be advantageously derived from a nitrogen mustard prodrug represented by the following structural formula:

in one embodiment, R₃₅、R₃₆、R₃₇...R₇₈(R₃₅-R₇₈) Each independently selected from the group consisting of a hydrogen atom, a straight chain alkyl group having 1 to 6 carbon atoms, a branched alkyl group having 2 to 12 carbon atoms, a cycloalkyl group having 3 to 17 carbon atoms, a fluorinated straight chain alkyl group having 2 to 12 carbon atoms, a fluorinated branched alkyl group having 2 to 12 carbon atoms, a fluorinated cycloalkyl group having 3 to 17 carbon atoms, an aryl group, an aralkyl group, an alkaryl group, a cycloalkyl group, a bicycloalkyl group, an alkenyl group, an alkanyl group, an alkinyl group, an alkynyl group, a trifluoropropyl group, a cyanopropyl group, an acryloyl group, an arylacryloyl group, an acryloylaryl group, an alkanoyl group, an arylacyl group, an alkenylacyl group, and an alkynoyl. In one embodiment, any two R in the same molecule₁-R₅₇May be linked to form a three to eight membered cyclic group.

In one embodiment, each X group is a linking group selected from the group consisting of: straight or branched chain alkylene having 1 to 7 carbon atoms, cycloalkylene having 3 to 17 carbon atoms, alkylcycloalkylene having 4 to 20 carbon atoms, cycloalkylalkylene having 4 to 20 carbon atoms, arylene having 4 to 30 carbon atoms, alkylarylene having 4 to 30 carbon atoms, arylalkylene having 4 to 30 carbon atoms, and combinations thereof.

In one embodiment, each Ar group is a bifunctional aromatic linking group, wherein each Ar is selected from arylene, substituted arylene, and/or heteroarylene.

The compounds represented by structural formula XI, XII,.. XIV (XI-XIV) can be prodrug alternative forms of nitrogen mustards because they can be metabolized in vivo to produce the active nitrogen mustards. Hereinafter, a "prodrug" is a precursor (precursor) of the active nitrogen mustard. The prodrug can be chemically converted to the parent drug by metabolic processes, thereby becoming the active nitrogen mustard. In the following, the structural formulae XI, XII,. XIV (XI-XIV) can represent all racemic forms and stereoisomers in which the compounds can have optical activity.

For example, phosphatases and phosphoramidases can hydrolyze the P-N bond of structural formula XI, supra, e.g., cyclophosphamide of structure XIA, infra, or ifosfamide (ifosfamide) of structural formula XIB, infra, to form an intermediate aldphosphoramide, which can be degraded in a non-enzymatic manner to bifunctional phosphoramide mustard. In one embodiment, cyclophosphamide of formula XIA, supra, or ifosfamide of formula XIB, supra, can be oxidatively activated by cytochrome P-450.

In one embodiment, a compound of structural formula XII above, for example chlorambucil of structural formula XIIA below, may be a bifunctional alkylating agent of the nitrogen mustard type.

The compound of structural formula XII may be non-specific at the cell cycle stage, although it may also be cytotoxic to non-proliferating cells. Activation may be due to the formation of labile ethylenimonium ions that may alkylate or bind to many intracellular molecular structures including nucleic acids. Its cytotoxic effect may be due primarily to the cross-linking of the DNA strands that inhibit nucleic acid synthesis.

In one embodiment the compound of formula XIII above, such as 4-bis (2-chloroethyl) amino-L-phenylalanine of formula XIIIA below, i.e., phenylalanine mustard, may be a bifunctional alkylating agent of the nitrogen mustard type.

Similar to the nitrogen mustard prodrugs of structural formula XII, the prodrugs of structural formula XIII may be non-specific at the cell cycle stage, although they may also be cytotoxic to non-proliferating cells.

In one embodiment, a compound of structural formula XIV above, e.g., uracil mustard of structural formula XIVA below, can be a bifunctional alkylating agent of the nitrogen mustard type.

In one embodiment, the pharmaceutically acceptable HX salt of a nitrogen mustard may advantageously be selected from the group consisting of nitrogen mustard HCl, nitrogen mustard H₂SO₄Nitrogen mustard HNO₃Nitrogen mustard H₂SO₄Nitrogen mustard HBr, nitrogen mustard HI and combinations thereof.

In one embodiment, the non-aqueous vehicle ingredients, excluding petrolatum or ethanol, may be polyethylene glycol (PEG) or Ethylene Glycol (EG), polypropylene glycol (PPG) or Propylene Glycol (PG), diethylene glycol monosubstituted ether (DGMSE), HOCH₂CH₂OCH₂CH₂OR₇₉ (HO(CH₂CH₂O)₂R₇₉) Wherein R is₇₉Selected from the group consisting of straight chain alkyl having 1 to 6 carbon atoms, branched chain alkyl having 2 to 12 carbon atoms, cycloalkyl having 3 to 17 carbon atoms, fluorinated straight chain alkyl having 2 to 12 carbon atoms, fluorinated branched chain alkyl having 2 to 12 carbon atoms, fluorinated cycloalkyl having 3 to 17 carbon atoms, aryl, aralkyl, alkaryl, cycloalkyl, bicycloalkyl, alkenyl, alkanyl, alkenylalkyl, alkynyl, alkanyl, alkynylalkyl, trifluoropropyl, cyanopropyl, acryloyl, arylacryloylAcryloyl aryl, alkanoyl, arylacyl, alkenyl acyl and alkynoyl.

In one embodiment, each component of the non-aqueous carrier, excluding petrolatum or ethanol, may be selected from the group consisting of ethoxydiglycol reagent, hydroxypropylcellulose, buffer gel (buffer gel), menthol (mentholates) USP, di-t-butyl-p-cresol NF, glycerol USP, edetate disodium USP, decyl methyl sulfoxide, Kris-Ester236, and combinations thereof.

The buffer gel is selected from the group consisting of 2-Acrylic acid (2-Propeneic acid), Acrylate (Acrylate), Acrylic acid (Acrylic acid), Acrylate (Propeneate), vinyl formic acid (vinylic acid), Acrylic acid (Acroleic acid), Acrylic acid (Ethylenecarboxylic acid), Acrylic acid (Propeneic acid), CH2 ═ CHCOOH, Acrylic acid (Propenee acid), Glacial Acrylic acid (Kyseline akylova), Glacial Acrylic acid (Glacylic acid), Acrylic acid (Ethylenecarboxylic acid), Acrylic acid (Acrylic acid), Acide acylique [ French ], Acidoacrylic acid [ Spanish ], Glacial Acrylic acid (Glacylic acid), Kyseline akylo [ Czech ], Acrylic acid (Propeneacid), 2-Acrylic acid (2-Propeneic acid), Acrylic acid homopolymer, Acrylic acid (Acrylic acid), Acrylic acid (polymer), Acrylic acid (Acrylic acid), Acrylic acid (polymer), Acrylic acid (polymer (Acrylic acid), Acrylic acid (polymer (Acrylic acid), Acrylic acid (Acrylic acid), Acrylic acid (Acrylic acid), Acrylic acid, acrylic resin (Acrylic resin), Acrysol A1, Acrysol A3, Acrysol A5, Acrysol AC 5, Acrysol WS-24, Acrysol ase-75, Acrysol lmw-20X, Antiprex, Antiprex A, Arasorb 750, Arasorb S100F, Arolon, Aron A10H, Atactic poly (Acrylic acid) (Atomic poly (Acrylic acid)), CCRIS 3234, carbomer 1342, carbomer 910[ USAN ], carbomer 934p [ USAN ], carbomer 940[ USAN ], 941[ polN ], Carbopol 1342, Carbopol 910, Carbopol934, Carbopol P, Carbopol, Carbopol934, Carbopol 941, Carbopol 1, Carbopol 39961, Carbopol 39965, Carbopol 97961, Carbopol 39966, Carbopol 975, Carbopol 9750, Carbopol 39515, Carbopol 975, Carbopol 39966, Carbopol 975, Carbopol 4650, Carbopol 3, Carbopol 2, Carbopol 3, Dow Latex 354, G-Cure, Good-rite K37, Good-rite K702, Good-rite K732, Good-rite K-700, Good-rite K727, Good-rite WS 801, Haloflex 202, Haloflex 208, Joncryl 678, Junlon110, Jurimer AC 10H, Jurimer AC 10P, NSC 106034, NSC 106035, NSC 106036, NSC 106037, NSC 112122, NSC 112123, NSC 114472, NSC 165257, Nalfloc 636, Neocryl A-1038, OLD 01, P11H, P-11H, PA 11-11M, PAA-25, polyacrylic acid, Pemulen TR-1, Pemulen TR-2, poly (acrylic acid), Polyacrylate rubber (Polyacrylate rubber), cross-linked Polymer of pentaerythritol with acrylic acid (acrylic acid) and pentaerythritol Polymer of polyester ethers (acrylic acid of pentaerythritol polyamide 2, pentaerythritol cross-linked Polymer of pentaerythritol polyamide ethers 2, pentaerythritol cross-branched polyamide 2, and pentaerythritol cross-branched polyether, 2-allyl ether cross-linked polymers of acrylic acid and sucrose (Polymer of2-Propen acid, cross-linked with allyl ethers of sucrose or pentaerythritol), 2-allyl ether cross-linked polymers of acrylic acid and sucrose or pentaerythritol (Polymer of 2-Propeneic acid, cross-linked with allyl ethers of sucrose or pentaerythritol), allyl ether cross-linked polymers of acrylic acid and pentaerythritol (Polymer of acrylic acid, cross-linked with allyl ethers of pentaerythritol), allyl ether cross-linked polymers of acrylic acid and sucrose or pentaerythritol (Polymer of acrylic acid, cross-linked with allyl ethers of pentaerythritol), polymers of acrylic acid and sucrose or pentaerythritol (Polymer of acrylic acid, cross-linked with allyl ethers of acrylic acid, acrylic acid and sucrose or pentaerythritol), carboxy vinyl Polymerized acrylic acid (Polymer of acrylic acid, Polymer of acrylic, Rohagit SD 15, SokalanaPAS, Solidokoll N, Synthemul 90-588, TB 1131, Tecpol, Texcryl, Versicol E7, Versicol E15, Versicol E9, Versicol K11, Versicol S25, Viscalex HV 30, Viscon 103, WS 24, WS 801, XPA, 54182-57-9, 9007-20-9, carbomer [ INN-free ], carbomer [ INN-span ], carbomer [ INN-Latin ], Carbopol, Carboxypolymethylene (Carbopol), Carboxypolymethylene resin (Carbopol ethylene), 2-Acrylic acid (2-Propeneacid), Acrylic acid (Acylacic), Acrylic acid (Acrylic acid), Acrylic acid (Acrylic acid), Acrylic acid (Acrylic acid), Acrylic acid (Acrylic acid), Acrylic, Calcium diacrylate, acrylic acid (acrylic acid), 2-acrylic acid (2-Propenoic acid), AIDS-209945, AIDS209945, carbomer, Carbopol 934P, 2-acrylic acid (2-Propenoic acid), 2-methyl-, 2-hydroxyethyl ester, polymers of vinyl-1-acetate and 2-ethylhexyl 2-acrylate (2-ethylhexyl 2-propenoate).

In one embodiment, the pharmaceutically acceptable HX salt of the nitrogen mustard alkylating agent used to treat the skin disorder can be more stable and have a longer duration of activity because the pharmaceutically acceptable HX salt of the nitrogen mustard can be more resistant to attack by water than the respective free base form of the nitrogen mustard. In one embodiment, a pharmaceutically acceptable HX salt of a nitrogen mustard alkylating agent can be added to a non-aqueous carrier that does not include petrolatum. In one embodiment, the use of a pharmaceutically acceptable HX salt of a nitrogen mustard alkylating agent and/or its addition to a non-aqueous carrier that does not include petrolatum may result in a more stable and longer lasting effect in the treatment of skin disorders.

In one embodiment, the dermatological disorder is selected from the group consisting of psoriasis, eczema, actinic keratosis, lupus, sarcoidosis, alopecia, cutaneous T-cell lymphoma (i.e., mycosis fungoides), lymphoreticular tumors, pleural and peritoneal leaks, cutaneous B-cell lymphoma, cutaneous pseudolymphoma, squamous cell carcinoma, basal cell carcinoma, bronchial carcinoma, malignant melanoma, lymphosarcoma, chronic lymphocytic leukemia, polycythemia, lymphomatoid papulosis, Mucha-habberma disease (pliva), and combinations thereof. The method of administration is as in step 10 of method 1 and comprises topically applying to the human or animal a sterile solution or suspension containing the nitrogen mustard or nitrogen mustard HCl, wherein the dose contains an appropriate amount of the active ingredient. Topical solutions or suspensions are incorporated into a slow-release non-aqueous base for transdermal administration. In one embodiment, the dosage for a mammal is between about 0.0001 to about 2.0 percent of body weight of the active ingredient in a non-aqueous and non-petrolatum base per day. In another embodiment, the dosage for the mammal is between about 0.015 percent to about 0.04 percent of the body weight of the active ingredient in the non-aqueous and non-petrolatum base per day. In one embodiment, the dosage for a mammal is between about 0.015 and about 0.030 percent of body weight of the active ingredient in a non-aqueous and non-petrolatum medium per day. In the following, topical administration means the administration of a drug to a local area of the body or to the surface of a body part.

In an embodiment of the invention, a method of treating a patient having a skin disorder comprises: topically applying nitrogen mustard or mustard HCl to the affected skin. In one embodiment of the method, the non-aqueous vehicle, excluding petrolatum or ethanol, improves skin irritation due to the nitrogen mustard or its HX salt by providing an effective dose of the nitrogen mustard or nitrogen mustard HCl. Hereinafter, "improvement" means the reduction of pain and the reduction of skin irritation, resulting in an improvement due to the reduction of skin irritation. Hereinafter, an effective dose of nitrogen mustard or nitrogen mustard HCl may be sufficient to treat skin suffering from the above-mentioned diseases without causing allergic reactions, as disclosed in table 1 above.

In one embodiment of the present invention, a method of stabilizing a volatile alkylating agent comprises: providing a non-aqueous flowable ointment or cream, wherein the non-aqueous flowable ointment or cream does not contain petrolatum or ethanol; recovering the HX salt of the volatile alkylating agent in an anhydrous solvent that does not contain ethanol; the non-aqueous flowable ointment or cream is combined by mixing with a volatile alkylating agent HX salt. In one embodiment, in the method of stabilizing a nitrogen mustard or a nitrogen mustard HCl, the HX salt of the nitrogen mustard is nitrogen mustard HCl. In one embodiment of the method of stabilizing a nitrogen mustard or nitrogen mustard HCl, the duration of activity of the nitrogen mustard or HX salt of the nitrogen mustard is from about 3 months to about 3 years.

In one embodiment, in the method of stabilizing nitrogen mustard or nitrogen mustard HCl, the non-aqueous flowable ointment or cream comprises polypropylene glycol (PPG), Propylene Glycol (PG), polyethylene glycol (PEG), or Ethylene Glycol (EG). In one embodiment, in a method of stabilizing nitrogen mustard or nitrogen mustard HCl, the non-aqueous flowable ointment or cream consists essentially of propylene glycol, ethoxydiglycol reagent, hydroxypropylcellulose, menthol USP, di-tert-butyl-p-cresol NF, glycerol USP, edetate disodium USP, decyl methyl sulfoxide, and Kris-Ester 236. In one embodiment, in the method of stabilizing a nitrogen mustard or nitrogen mustard HCl, the nitrogen mustard or its HX salt is selected from the group consisting of bis- (2-chloroethyl) ethylamine, bis- (2-chloroethyl) methylamine, tris- (2-chloroethyl) amine, and combinations thereof.

In one embodiment, acceptable non-aqueous carriers for purposes of the present invention that do not include petrolatum or ethanol may be flowable non-aqueous pharmaceutical carriers, such as creams or ointments that do not include nucleophiles such as water or ethanol; as described above in reaction 5, nucleophiles may decompose nitrogen mustard or the HX salt of structural formula IX. In one embodiment, suitable pharmaceutically acceptable carriers include ethoxydiglycol reagent, hydroxypropylcellulose, menthol USP, di-t-butyl-p-cresol NF, glycerol USP, edetate disodium USP, decyl methyl sulfoxide, Kris-Ester236, propylene glycol, and ethylene glycol. In one embodiment, the polypropylene glycol (PPG), Propylene Glycol (PG), polyethylene glycol (PEG), or Ethylene Glycol (EG) may be about 15 to about 60 weight percent propylene glycol or ethylene glycol. The non-aqueous carrier excluding petrolatum or ethanol may contain adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers and agents used simultaneously with the sensitizer of the present invention.

In one embodiment of the invention, the sensitizers may also be used as adjuvant therapy in combination with existing treatments, such as hyperthermia in cancer therapy (management cancer therapy) of cancer patients.

Example 1

Preparation of bis- (2-chloroethyl) methylamine hydrochloride of formula IX described in reaction 5 above from about 0.001 to about 2.0.

The pharmaceutical preparation consists of a pharmaceutically acceptable nitrogen mustard hydrochloride in a topical ointment base which does not include petrolatum or ethanol. The compositions/ingredients are provided in table 2 below, assuming a batch size of 1 liter.

^aSlightly higher amounts than required may be used to offset losses in the manufacturing process.

^bCan be obtained from Merck&Obtained from co, West Point, PA 19486.

Manufacture of

Pharmaceutical formulations, for example, containing 0.001 to 2.0% by weight of a nitrogen mustard in the form of bis- (2-chloroethyl) methylamine-HCl of structural formula IX in reaction 5 above, may be prepared by the following general method:

preparation of ointments

All dry adjuvant ingredients were collected and weighed out according to the formula in table 2 and placed in suitable containers. Hereinafter, an adjuvant is an inert substance added to the free form of nitrogen mustard or its pharmaceutically acceptable HX salt to increase its volume. Hereinafter, the dry adjuvant ingredients are described in terms of the weight of solid added, e.g., grams, i.e., gm.

The particles of the dried material are reduced to a uniform size by trituration. About 15 to about 60 weight Percent Polypropylene Glycol (PPG), Propylene Glycol (PG), polyethylene glycol (PEG) or Ethylene Glycol (EG) is then added to obtain a smooth paste by the principle of geometric dilution. Once a smooth paste is obtained, the addition of propylene glycol or ethylene glycol is continued until a volume is reached at which the fluid-like nature is maintained.

The entire contents were then transferred to a larger beaker, a stir bar was added and the beaker placed on a magnetic stir plate to begin mixing.

While the mixture was continuously stirred, glycerol was added. During agitation of the mixture, the original container was washed with about 15 to about 60 weight percent ethoxydiglycol and the washed contents of the container were added to the agitated mixture in a beaker.

After the addition of ethoxydiglycol, kris-ester was added to the stirred mixture. The mixture is then stirred for about 1 to 2 hours. After stirring was complete, the mixture was covered and allowed to stand overnight.

The next day, the mixture was mixed with a high shear mixer to a uniform consistency with minimal to no air. Air and moisture may be removed during mixing by applying a vacuum of about 0.01 to about 0.1 torr. The mixture was then brought to ambient pressure by the addition of dry nitrogen.

Adding nitrogen mustard

The nitrogen mustard is reconstituted with anhydrous ethanol (200 proof) at the appropriate concentration and quantity and then added to an appropriate quantity of a non-aqueous carrier, wherein the non-aqueous carrier does not include petrolatum or ethanol, and mixed to a uniform consistency by stirring for 60-90 seconds. For example, in one embodiment, the concentration of pharmaceutically acceptable nitrogen mustard HCl in the non-aqueous carrier excluding petrolatum or ethanol is advantageously between about 1mg nitrogen mustard HCl per 100ml non-aqueous carrier and about 2000mg nitrogen mustard HCl per 100ml non-aqueous carrier on a mg/ml basis. In one embodiment, the concentration of nitrogen mustard HCl in the non-aqueous carrier excluding petrolatum or ethanol, on a mg/ml basis, is advantageously between about 10mg nitrogen mustard HCl per 100ml non-aqueous carrier excluding petrolatum or ethanol and about 40mg nitrogen mustard HCl per 100ml non-aqueous carrier excluding petrolatum or ethanol. In one embodiment, the concentration of nitrogen mustard HCl used in the non-aqueous carrier excluding petrolatum or ethanol is advantageously between about 15mg nitrogen mustard HCl per 100ml non-aqueous carrier excluding petrolatum or ethanol and about 30mg nitrogen mustard HCl per 100ml non-aqueous carrier excluding petrolatum or ethanol. The mixture was then injected into 50ml of flip-top plastic tubing and provided to the appropriate patient.

Cleaning of

All containers used in this process were placed in a water wash of sodium thiosulfate (bath). After standing in the washing solution for two hours, the contents were released and then washed. The wash liquor is then discarded in a conventional manner. Note that: sodium thiosulfate reacts with nitrogen mustard to produce a non-toxic, safe mixture that can be discarded in a conventional manner.

Example 2

Preparation of bis- (2-chloroethyl) methylamine hydrochloride of formula IX described previously in reaction 5 from about 0.001 to about 2.0.

The pharmaceutical preparation consists of a pharmaceutically acceptable nitrogen mustard hydrochloride in a topical ointment base. The compositions/ingredients are provided in table 3 below, assuming a batch size of 1 liter.

^aSlightly higher amounts than required may be used to offset losses in the manufacturing process.

^bCan be obtained from Merck&Obtained from co, West Point, PA 19486.

Non-aqueous carriers for purposes of the present invention which do not include petrolatum or ethanol may be flowable non-aqueous pharmaceutical carriers which do not include petrolatum or ethanol, for example creams or ointments which do not include nucleophiles such as water or ethanol; as described above in reaction 5, the nucleophile may decompose nitrogen mustard or its HX salt of structural formula IX; the non-aqueous carrier may be a dimethicone liquid, such as substantially moisture free dimethicone or cyclomethicone. Hereinafter, the dimethylsilicone fluid means a low viscosity silicone, that is, polydimethylsiloxane having a viscosity of about 1 to 1000cps at 25 ℃, hexamethyldisiloxane, CAS # 107-46-0, pure silicone 1cSt (purosilicone 1cSt), volatile silicone (volalite silicone), volatile polydimethylsiloxane, low temperature silicone (low temperature silicone), skin care silicone (skin care silicone), octamethyltrisiloxane, CAS # 107-51-7, CAS 107-51-7, decamethylmethylsiloxane, (CAS # 141-62-8, dodecamethylpentasiloxane CAS # 141-63-9, trisiloxane, low viscosity dimethylsilicone fluid, volatile dimethylsilicone fluid, cosmetic dimethylsilicone fluid (cosmetic dimethylsilicone fluid), Cosmetic base solutions, silicone for sunscreen solutions (sun lotion), antiperspirant silicone, hair care silicone, low surface tension silicone, and low evaporation silicone. Hereinafter, the cyclomethicone is Cyclopentasiloxane (Cyclopentasiloxane), volatile polydimethylsiloxane (silicone), CAS 541-02-6, CAS #541-02-6, low surface tension silicone (low surface tension silicone), volatile silicone (silicone), D5 silicone, Dow Corning 245fluid, DC 245fluid, 245 silicone, skin cream silicone (skin cream silicone), antiperspirant silicone (antiperspirant silicone), silicone for sunscreen (sun deposition silicone), silicone for skin (silicone for skin), silicone for skin (skin silicone), silicone for body care (silicone 1202), silicone for body wash (bath silicone), SF 631202 silicone, SF 56 Cyclopentasiloxane (Cyclopentasiloxane D), Cyclopentasiloxane (silicone D5), silicone for skin care (silicone for skin), silicone for body care (silicone 1202), silicone for body wash (bath silicone 1202), SF 6335 silicone for silicone, and 5. Generally, simethicone and cyclomethicone are simethicones having good lubricity, strong moisturizing properties and moisture retention properties. Simethicone and cyclomethicone have very low water contents, i.e., < 0.1% by weight water, because they are methyl terminated (stop) polymers, not OH terminated polymers.

Manufacture of

Pharmaceutical formulations, such as those containing 0.001-2.0% by weight of nitrogen mustard in the form of bis- (2-chloroethyl) methylamine-HCl of structural formula IX as described in reaction 5 above, in dimethicone or cyclomethicone ointments, may be prepared by the following general procedure:

preparation of dimethicone or cyclomethicone ointment

a) All dry adjuvant ingredients were collected and weighed out according to the formula in table 3 and placed in suitable containers.

b) The particles of the dried material are reduced to a uniform size by trituration.

c) Then about 10 to about 60 weight percent dimethicone or cyclomethicone is added to get a smooth paste by the principle of geometric dilution. Once a smooth paste is reached, simethicone or cyclomethicone is added continuously until a volume is reached at which the fluid-like nature is maintained.

d) The entire contents were then transferred to a larger beaker, a stir bar was added and the beaker placed on a magnetic stir plate to begin mixing.

e) While the mixture was continuously stirred, glycerol was added. During the stirring of the mixture, the original container was washed with from about 10 to about 16 weight percent ethoxydiglycol and the washed contents of the container were added to the stirred mixture in the beaker.

f) After the addition of ethoxydiglycol, about 0.01 to 15% by weight of a pH regulator, for example citric acid, lactic acid or of the formula C_nH_(2n+2)An aliphatic acid of COOH (n ═ 1-6) was added to the stirred mixture. The mixture is then stirred for about 1 to 2 hours. After stirring was complete, the mixture was covered and allowed to stand overnight.

g) The next day, the mixture was mixed with a high shear mixer to a uniform consistency with minimal to no air. Air and moisture may be removed during mixing by applying a vacuum of about 0.01 to about 0.1 torr. The mixture was then brought to ambient pressure by the addition of dry nitrogen.

Combination of nitrogen mustard with the non-aqueous carrier of dimethicone or cyclomethicone excluding petrolatum or ethanol in step g) above.

In one embodiment, 1) a suitable amount of an API that has been rejuvenated with an anhydrous secondary or tertiary alcohol, such as isopropanol, wherein ethanol has been rigorously removed from the secondary or tertiary alcohol, such as isopropanol; 2) an amount of non-aqueous carrier not including petrolatum or ethanol in step g) above, wherein the non-aqueous carrier does not include petrolatum or ethanol; the above 1) substance and 2) substance can be mixed by agitating using a high shear mixer for 60-90 seconds to produce a pharmaceutically acceptable nitrogen mustard HCl of substantially complete uniform consistency. For example, in one embodiment, the concentration of pharmaceutically acceptable nitrogen mustard HCl in the non-aqueous carrier excluding petrolatum or ethanol is advantageously between about 1mg nitrogen mustard HCl per 100ml non-aqueous carrier and about 2000mg nitrogen mustard HCl per 100ml non-aqueous carrier on a mg/ml basis. In another embodiment, the pharmaceutically acceptable nitrogen mustard HCl is used in a non-aqueous carrier that does not include petrolatum or ethanol at a concentration, on a mg/ml basis, advantageously between about 10mg nitrogen mustard HCl per 100ml non-aqueous carrier that does not include petrolatum or ethanol and about 40mg nitrogen mustard HCl per 100ml non-aqueous carrier that does not include petrolatum or ethanol. In another embodiment, the pharmaceutically acceptable nitrogen mustard HCl is used in a non-aqueous carrier that does not include petrolatum or ethanol at a concentration, on a mg/ml basis, advantageously between about 15mg nitrogen mustard HCl per 100ml non-aqueous carrier that does not include petrolatum or ethanol and about 30mg nitrogen mustard HCl per 100ml non-aqueous carrier that does not include petrolatum or ethanol. The mixture was then injected into 50ml of flip-top plastic tubing and provided to the appropriate patient.

The inventors have discovered that a relatively small volume container of from about 0.01 to about 0.2ml, from about 0.1 to about 0.5ml or from about 0.1 to about 1ml can be advantageously used to provide 1-10 administrations of the pharmaceutically acceptable nitrogen mustard HCl, which is shorter than the use cycle with a 50ml plastic flip-top tube; thus, less nucleophile, such as ambient water or other environmental nucleophiles such as methanol or ethanol, may be introduced into the smaller volume container than a 50ml flip-top plastic tube would be exposed to the ambient environment during 100 to 1000 applications. The present inventors contemplate that storage of a pharmaceutically acceptable nitrogen mustard in a smaller volume container suitable for about 1-10 administrations will reduce decomposition of the nitrogen mustard in free form or its HX salt of formula IX in reaction 5 above. In theory, the chlorine of the free form of the nitrogen mustard or its HX salt could be replaced by, for example, water or ethanol by nucleophilic attack, resulting in the replacement of Cl by OH. Such decomposition of the free form of the nitrogen mustard or its HX salt can be avoided by isolating the nitrogen mustard from trace amounts of water, ethanol or other nucleophiles in the environment. The apparatus 20 illustrated in fig. 2 below describes such a smaller volume container.

FIG. 2 depicts a front cross-sectional view of a device 20 that can be used to contain a pharmaceutically acceptable nitrogen mustard HCl or a stabilized volatile alkylating agent or a stabilized HX salt of a volatile alkylating agent in a non-aqueous carrier that does not include petrolatum or ethanol, the device comprising: a chamber 25 surrounded by a wall 31. The wall 31 includes an outer surface 28 and an inner surface 23, ends 24 and 21, and openings 30. The first chamber 25 can be injected with the substantially completely homogeneous mixture of the above pharmaceutically acceptable nitrogen mustard HCl through the opening 30. The opening 30 may be closed with a plug 22. The stopper 22 may be made of the same material as the wall 31 or of a lower melting plastic or wax-like material.

Fig. 3 depicts the device 20 after forming heat seals 26 and 27 by heating the stopper 22 and ends 21 and 24 to their melting points, wherein the heating physically and mechanically joins the ends 21 and 24, forming heat seals 26 and 27 with strong mechanical strength.

FIG. 4 depicts the apparatus 20 after forming the serrated apertures 33 and 34 in the plug 22 using a crimping tool (crimping tool) or other suitable device for forming the serrated apertures 33 and 34. The serrated apertures 33 and 34 weaken the heat seals 21 and 24 so that their mechanical strength is weakened, creating a tear line for removal of the plug 22 for patients who wish to administer a pharmaceutically acceptable nitrogen mustard HCl to the affected or treated area. Alternatively, a sharp-edged tool, such as scissors, safety blade, or knife, may be used to pierce stopper 22 to restore opening 30 in wall 31 of device 20.

In one embodiment, a patient desiring to administer a pharmaceutically acceptable nitrogen mustard HCl to an affected area or treatment area can remove plug 22 from wall 31 of device 20 to restore opening 30 in wall 31. Squeezing or applying pressure to wall 31 reduces the volume of chamber 25, causing the pharmaceutically acceptable nitrogen mustard HCl to flow out of chamber 25 through opening 30, thereby allowing the topically acceptable nitrogen mustard HCl to be administered to the affected area or the treatment area.

In one embodiment, the concentration of pharmaceutically acceptable nitrogen mustard HCl in the carrier excluding petrolatum or ethanol in compartment 25 is between about 1mg nitrogen mustard HCl per 100ml of non-aqueous carrier and about 2000mg nitrogen mustard HCl per 100ml of non-aqueous carrier. In another embodiment, the pharmaceutically acceptable nitrogen mustard HCl concentration in the carrier exclusive of petrolatum or ethanol is between about 10mg nitrogen mustard HCl per 100ml non-aqueous carrier exclusive of petrolatum or ethanol and about 40mg nitrogen mustard HCl per 100ml non-aqueous carrier exclusive of petrolatum or ethanol. In another embodiment, the concentration of pharmaceutically acceptable nitrogen mustard HCl in a carrier that does not include petrolatum or ethanol is advantageously between about 15mg nitrogen mustard HCl per 100ml of the non-aqueous carrier that does not include petrolatum or ethanol and about 30mg nitrogen mustard HCl per 100ml of the non-aqueous carrier that does not include petrolatum or ethanol. An opening or opening 30 may be made by forming an opening in the outer wall 31 through which opening 30 the mixture of nitrogen mustards may then be provided to the patient for treatment by the physician's prescription.

The outer wall 31 of the apparatus 20 is impermeable or impermeable to the mixture and/or reconstituted nitrogen mustard solution of step g) or 9) above. Hereinafter, "impermeable" or "impermeable" means that the wall 31 prevents the mixture of step g) or 9) above and/or the reconstituted nitrogen mustard solution from passing or diffusing through the wall 31. By "impermeable" is meant, hereinafter, that the mixture and/or reconstituted nitrogen mustard solution of step g) or 9) above is not allowed to pass through the wall 31, or that the wall 31 is not allowed to be acted upon by the mixture and/or reconstituted nitrogen mustard solution of step g) or 9) above. The wall 31 may be made of aluminum foil, plastic or resin coated aluminum foil, elastomeric materials including ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone elastomers, medical polydimethyl siloxane, neoprene, polyisobutylene, chlorinated vinyl chloride, polyvinyl chloride, vinyl chloride vinyl acetate copolymers, polymethacrylate polymers (hydrogels), polyvinylidene chloride, polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene vinyl alcohol copolymers, ethylene vinyl oxyethanol (ethylene vinyl oxyethanol) copolymers; siloxane copolymers, polysiloxane-polycarbonate copolymers, polysiloxane-polyethylene oxide copolymers, polysiloxane-polymethacrylate copolymers, polysiloxane-olefin interpolymers, polysiloxane-ethylene copolymers, polysiloxane-olefin silane copolymers, polysiloxane-vinylsilane copolymers, cellulosic polymers, methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, cellulose esters, polycarbonates, polyesters, polytetrafluoroethylene, starch, gelatin, natural gums, synthetic gums, and combinations thereof.

Cleaning of

All containers used in this process were placed in a water wash of sodium thiosulfate. After standing in the washing solution for two hours, the contents were released and then washed. The wash liquor is then discarded in a conventional manner. Note that: sodium thiosulfate reacts with nitrogen mustard to produce a non-toxic, safe mixture that can be discarded in a conventional manner.

The foregoing description of the embodiments of the invention has been presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise form disclosed, and obviously, many modifications and variations are possible.

Claims (11)

1. A topical pharmaceutical composition comprising:

bis- (2-chloroethyl) methylamine or an HX salt of bis- (2-chloroethyl) methylamine in a non-aqueous carrier, wherein said non-aqueous carrier does not comprise petrolatum or ethanol, and wherein the non-aqueous carrier is selected from HOCH₂CH₂OCH₂CH₂OR₇₉Wherein R is₇₉Selected from the group consisting of straight chain alkyl groups having 1 to 6 carbon atoms and branched chain alkyl groups having 2 to 12 carbon atoms; and wherein HX is HCl, HBr, HI, H₂SO₄Or HNO₃。

2. The composition of claim 1, comprising:

bis- (2-chloroethyl) methylamine or an HX salt of bis- (2-chloroethyl) methylamine in a non-aqueous carrier, wherein said non-aqueous carrier does not comprise petrolatum or ethanol, wherein the non-aqueous carrier component is ethoxydiglycol reagent; and wherein HX is HCl, HBr, HI, H₂SO₄Or HNO₃。

3. The composition of claim 1 or 2, wherein the composition comprises from 0.015 to 0.030 weight percent bis- (2-chloroethyl) methylamine or its HX salt.

4. The composition of claim 2, further comprising: hydroxypropyl cellulose, menthol USP, di-t-butyl-p-cresol NF, glycerol USP, edetate disodium USP, decyl methyl sulfoxide or Kris-Ester236, propylene glycol and ethylene glycol.

5. The composition of claim 1 or 2, wherein the composition comprises from 0.0001 to 2.0 weight percent of bis- (2-chloroethyl) methylamine or its HX salt.

6. The composition of claim 1 or 2, wherein the composition comprises from 0.015 to 0.04 wt.% of bis- (2-chloroethyl) methylamine or its HX salt.

7. The composition of claim 1 or 2 for use in a method of treatment of a skin disorder selected from the group consisting of psoriasis, eczema, actinic keratosis, lupus, sarcoidosis, alopecia, cutaneous T-lymphoma, mycosis fungoides, lymphoreticular tumors, pleural and peritoneal leaks, cutaneous B-cell lymphoma, cutaneous pseudolymphoma, squamous cell carcinoma, basal cell carcinoma, bronchial carcinoma, malignant melanoma, lymphosarcoma, chronic lymphocytic leukemia, polycythemia, lymphomatoid papulosis, muca-Habberman disease, pliva, and combinations thereof.

8. Use of bis- (2-chloroethyl) methylamine or an HX salt of bis- (2-chloroethyl) methylamine as defined in any one of claims 1 to 6, in the manufacture of a medicament for the treatment of skin disorders, in combination with a non-aqueous carrier.

9. The use of claim 8, wherein the skin disease is selected from the group consisting of psoriasis, eczema, actinic keratosis, lupus, sarcoidosis, alopecia, cutaneous T-cell lymphoma, mycosis fungoides, lymphoreticular tumors, pleural and peritoneal leaks, cutaneous B-cell lymphoma, cutaneous pseudolymphoma, squamous cell carcinoma, basal cell carcinoma, bronchial carcinoma, malignant melanoma, lymphosarcoma, chronic lymphocytic leukemia, polycythemia, lymphomatoid papulosis, macha-Habberman disease, pliva, and combinations thereof.

10. A topical pharmaceutical composition as defined in any one of claims 1 to 6 for use in a method of treatment of a skin disorder.

11. The composition of claim 10, wherein the dermatological disorder is selected from the group consisting of psoriasis, eczema, actinic keratosis, lupus, sarcoidosis, alopecia, cutaneous T-cell lymphoma, mycosis fungoides, lymphoreticular tumors, pleural and peritoneal leaks, cutaneous B-cell lymphoma, cutaneous pseudolymphoma, squamous cell carcinoma, basal cell carcinoma, bronchial carcinoma, malignant melanoma, lymphosarcoma, chronic lymphocytic leukemia, polycythemia, lymphomatoid papulosis, macha-Habberman disease, plava, and combinations thereof.