BACKGROUND OF THE INVENTION

Field of the Invention

[0001] The present invention relates to pharmaceutical compositions for the treatment of hemorrhoids, sheets for applying the composition, methods of making and using the same.

Description of the Related Art

[0002] Hemorrhoids are swollen veins in the anal canal. Veins can swell inside the anal canal to form internal hemorrhoids or near the opening of the anus to form external hemorrhoids. Patients may have both. Excess pressure on the veins in the pelvic and rectal area can cause hemorrhoids. Normally, tissue inside the anus tills w ith blood to help control bowel movements. Increased pressure during bowel movements can cause the veins in this tissue to swell and stretch leading to hemorrhoids. Diarrhea or constipation also may lead to straining and can increase pressure on veins in the anal canal. Pregnant women can get hemorrhoids during the last 6 months of pregnancy because of increased pressure on the blood vessels in the pelvic area. Straining during labor can make hemorrhoids worse. Being overweight can also lead to hemorrhoids. WebMD Hemorrhoids Guide (2015).

[0003] Common symptoms of both internal and external hemorrhoids include: bleeding during bowel movements, discomfort, skin irritation, itching, rectal pain. Internal hemorrhoids often are small, swollen veins in the wall of the anal canal. I -Menial hemorrhoids can get irritated and clot under the skin, causing a hard painful lump called a ihmmbuMAl. or dolled, hemorrhoid.

(0001 Current medicines thai can help relieve symptoms o! hemorrhoids include ointments, wipes, suppositories, and nonprescription pain relievers. WebMD Hemorrhoids Guide (2015).

[0005] Ointments that protect the skin, such as zinc oxide or petroleum jelly, can prevent further injury and reduce itching by forming a barrier over hemorrhoids. Medicated ointments may contain 1% or 2.5% hydrocortisone that may relieve inllammation and itching. Other products contain a local anesthetic that numbs the anal region for relief of pain associated with hemorrhoids. WebMD Hemorrhoids Guide (2015).

|0006| Suppositories, Preparation H® or Tucks® (formerly Anusol), may last for 7 to 10 days to relieve irritation and to lubricate the anal canal during bowel movements. Some of these products contain substances that can harm anal tissues if they are used for too long. WebMD Hemorrhoids Guide (2015). pain. Aspirin and other nonsteroidal anti-inflammatory drugs ( NSAl Ds) such as Motrin® (ibuprofen) and Aleve® (naproxen) can offer patients rel ief from pain and swell ing. WebMD Hemorrhoids Guide (201 5).

|0()08) Commercially-available products for the treatment of hemorrhoids include Preparation H® Wipes which have 50% Witch Hazel (astringent) as an active ingredient and aloe barbadensis leaf juice, anhydrous citric acid, capryl/capramidopropyl betaine, diazolidinyl urea, glycerin, methyl paraben. propylene glycol, propyl paraben, purified water, and sodium citrate as inactive ingredients. Similarly. Preparation I f® Medicated Wipes for Women which have 20% Witch Hazel (astringent) as an active ingredient and aloe barbadensis leaf juice, anhydrous citric acid, capryl/capramidopropyl betaine, chamomi l la recutita (matricaria) flower extract, cucumis sativus (cucumber) fruit extract, diazolidinyl urea, dipropylene glycol. DM DM hydantoin, edctatc disodium, fragrance, glycerin, methylisothia/olinone. methyl paraben, PEG-75 shea butter glycerides. phenoxyelhanol, polysorbate 20 ( Polyoxyethylene (20) sorbitan monolaurate), propylene glycol, propyl paraben. purified water, sodi um citrate, and vitamin E acetate as inactive ingredients. Preparation H® Maximum Strength Pain Relief Cream which comprises 14.4% glycerin. 0.25% pheny lephrine MCI. 1 % pramoxine MCI. and 1 5% white petrolatum. Preparation 1 1® Wipes; Preparation H® Medicated Wipes for Women; and Preparation H® Maximum Strength Pain Relief Cream product information (20 1 5).

]0009| Tucks® Medicated Cooling pads comprise 50% Witch Hazel (astringent) as an active ingredient and water, glycerin, alcohol, propylene gy lcoL sodium citrate, diazolidinyl urea, citric acid, methyl paraben. and propy l paraben as inactive ingredients. Tucks® Medicated Cooling pads product information (201 5).

(0010] Nelsons Medicated Wipes comprise Aesculus Uippocastanum - 6 C, Calendula

Officinalis - 6 C. Collinsonia Canadensis - 6 C. Hamainelis Virginiana - 6 C, Paeonia Officinalis - 6 C as active ingredients and aloe vera, butylparaben. citric acid, diazol idinyl urea, disodium eocoamphodiacetate, ethy Iparaben. glycerin, isobuty lparaben. methyl paraben, phenoxyethanol. polysorbate 20. propylene glycol, propyl paraben. purified w ater, sodium hydroxide, and tocopherol as inactive ingredients. Nelsons Medicated Wipes product information (201 5).

(0011 ] CVS® Maximum Strength Formula Medicated wipes comprise 50% W ^; itch Hazel (astringent) as an active ingredient and aloe barbadensis leaf juice, 2-bromo-2-nitropropane- l ,3- lanolin, propylene glycol, sodium citrate, and water as inactive ingredients. CVS Pharmacy website (201 5).

[0012] Walgreens® P e -Moistened Medicated Wipes comprise 50% Witch Hazel (astringent) as an active ingredient and alcohol, citric acid, glycerin, phenoxyethanol. potassium sorbate, purified water, and sodium citrate as inactive ingredients. W algreens Website (201 5).

[0013| The commercial ly avai lable preparations may not provide sufficient relief to patients with hemorrhoids. Accordingly, there is a need in the art f r an improved hemorrhoid treatment preparation.

BRIEF SUMMARY OF THE INVENTION

[0014] In numerous embodiments, this invention provides a pharmaceutical composition comprising an analgesic, vasoconstrictor, emoll ient, and cooling agent.

[0015] In one embodiment, the analgesic may be pramoxine hydrochloride, benzocaine; benzyl alcohol, dibucaine, dibucaine hydrochloride, dyclonine hydrochloride, lidocaine, pramoxine hydrochloride, tetracaine, tetracaine hydrochloride, or a mixture thereof.

[0016] In most embodiments of this invention, the analgesic is pramoxine hydrochloride. In numerous embodiments of this invention, the analgesic may be in an amount of about 0.5% to about 2.0% by weight of the composition. In various embodiments of this invention, the analgesic may be in an amount of about 0.75%. 1 .0%. 1 .25%. or 1 .50% by weight of the composition. In most embodiments of this invention, the analgesic may be benzocaine at about 5 to 20 percent by weight: benzyl alcohol at about 1 to 4% by weight; dibucaine at about 0.25 to 1 % by weight; dibucaine hydrochloride at about 0.25 to 1 % by weight: dyclonine hydrochloride at about 0.5 to 1 % by weight; lidocaine at about 2 to 5% by w eight: pramoxine hydrochloride at about 1 % by weight; tetracaine at about 0.5 to 1 % by weight; tetracaine hydrochloride at about 0.5 to 1 %; or a mixture thereof.

J0017] The compositions of this invention may comprise water as a solvent.

[0018| In most embodiments of this invention, the composition may comprise mixtures of water, glycerin, propylene glycol, and/or low molecular weight polyethylene glycols (PEGs) as a solvent. In many embodiments, the composition may comprise about 1 0-40% glycerin by weight, preferably 1 0%, 1 5%. 20%. 25%. 30%, 35%. or 40% glycerin by weight, more about 1 - 10% propylene glycol by weight, preferably about 1 %. 1 .5%, 2%, 2.5%. 3%, 5%, 6%, 7%, 8%, 9%, or 1 0% propylene glycol by weight, more preferably about 2% propylene glycol by weight. In particular embodiments, the composition may comprise about 1 -5% polyethylene glycol by weight, preferably about 1 %, 1 .5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5%

polyethylene glycol by weight, more preferably about 2% polyethylene glycol by weight.

|0()19| In some embodiments, the said polyethylene glycol may have an average molecular weight of 100-600. I n many embodiments, the polyethylene glycol may be PEG 1 00, PEG200, PEG300, PEG400. PEG 500, PEG600 or a mixture thereof. I n many embodiments, t ic polyethylene glycol may be PEG400, PEG600, or a mixture thereof. In many embodiments, the composition may comprise a mixture of water:propylene glyco PEG in a ratio of 1 : 1 : 1 to 3:2: 1 . In many embodiments, the composition may comprise a mixture of watenpropylene

glyco PEG 100 in a ratio of I : I : I . I n many embodiments, the composition may comprise a mixture of water.propylene glycol :PEG600 in a ratio of 3 :2: 1 .

[0020| In particular embodiments, the solvent may be in an amount of about 70% to about 90% by weight of the composition. In particular embodiments, the solvent may be in an amount of about 71 ). 72%o, 73%, 74%, or 75% by weight of the composition. |

|0021] In most embodiments of this invention, the vasoconstrictor may be ephedrine sulfate, epinephrine, epinephrine hydrochloride, phenylephrine hydrochloride, or a mixture thereof. In particular embodiments, the vasoconstrictor may be phenylephrine hydrochloride. In many embodiments, the vasoconstrictor may be in an amount of about 0.005% to about 1 .25% by weight of the composition. In particular embodiments, the vasoconstrictor may be in an amount of about 0.20%, 0.25%, 0.30%, or 0.35% by weight of the composition. I n particular embodiments, the vasoconstrictor may be an amount of about 0. 1 to 1 .25% by weight. In particular embodiments, the vasoconstrictor may be ephedrine sul ate at about 0.1 to 1 .25% by weight; epinephrine at about 0.005 to 0.01 % by weight; epinephrine hydrochloride at about 0.005 to 0.01 %) b weight; phenylephrine hydroch loride at about 0.25%: or a mixture thereof. In another embodiment, the vasoconstrictor may be epinephrine in an amount of about 0.10% to about 0.50% by weight of the composition.

[0022] In many embodiments, the emollient may be glycerin, propylene glycol, dipropylene glycol, hexylene glycol, butylene glycol, or a combination thereof. I n many embodiments, the many embodiments, the emoll ient may be in an amount of about 1 .0% to about 40% by weight of the composition. In particular embodiments, the emollient may be in an amount of about 2.0%, 5.0%, 1 0%. 1 5%, 20%,, 25%, 30%. 35%.. or 40% by weight of the composition.

[0023] In many embodiments, the composition may comprise a surfactant which is preferably a nonionic surfactant. In many embodiments, the nonionic surfactant may be ethoxylated castor oil. Polysorbate 20. Polysorbate 60, Polysorbate 80. or a combination thereof. In many embodiments, the composition may comprise a surfactant which is Polysorbate 80 (polyethylene glycol sorbitan monooleate).

[0024] In many embodiments, the surfactant may be in an amount of about 0.5% to about 5% by weight of the composition. In particular embodiments, the surfactant may be in an amount of about 1 .0%, 1 .5%, 2.0%o. 3.0%, 3.5%. or 5.0% by weight of the composition.

[0025] In many embodiments, the cooling agent may be menthol, cucalyptol. camphor, juniper tar, or a combination thereof. In many embodiments, the cooling agent may be menthol. In many embodiments, the cooling agent may be in an amount of about 0.05%> to about 0. 1 % by weight of the composition. In particular embodiments, the cool ing agent may be in an amount of about 0.05%, 0.06%, 0.07%. 0.08%, or 0.09% by weight of the composition.

[0026] I n many embodiments, the composition may further comprise an antioxidant, acidulant, preservative, chelating agent, or a combination thereof.

[0027] In many embodiments, the antioxidant may comprise butylated hydroxyanisole, butylated hydroxy! toluene, propyl gallate. or a combination thereof. I n many embodiments, the antioxidant may be in an amount about 0.0 1 % to about 0.1 0% by weight of composition. In particular embodiments, the antioxidant may be in an amount about 0.03%o. 0.04%), 0.05%, 0.06%. or 0.07% by weight of composition.

[0028] In many embodiments, the acidulant may be sodium citrate, citric acid, or a combination thereof. In many embodiments, the acidulant may be in an amount about 0.10% to about 0.50% by weight of composition. In particular embodiments, the acidulant may be in an amount about 0.20%), 0.25%, 0.30%), 0.35%. or 0.40% by weight of composition.

[0029] In many embodiments, the preservative may be sodium bcnzoate. methyl paraben, propyl paraben, or a combination thereof. I n many embodiments, the preservative may be is in an amount about 0.01 % to about 0.25% by weight of composition. I n particular embodiments, the 0.18%, 0.20%. or 0.25% by weight of composition.

[0()3()| In many embodiments, the chelating agent may be disodium 1ZDTA. In many

embodiments, the chelating agent may be in an amount about 0.05% to about 0.20% by weight of composition. In particular embodiments, the chelating agent may be in an amount about 0.08%, 0.09%.0.10%.0.11 %, 0.12%, or 0.13% by weight of composition.

[0031] In many embodiments of the method of this invention, the pharmaceutical composition described herein will not contain petrolatum.

10032] In many embodiments of the method o this invention, the pharmaceutical composition described herein will not contain witch hazel.

10033] In many embodiments of the method ofthis invention, the pharmaceutical composition described herein will not contain cctyl alcohol.

|0034] In many embodiments of the method ofthis invention, the pharmaceutical composition described herein may be formulated as a suspension.

|0035] In a further embodiment, the invention provides for a pharmaceutical composition comprising a solvent, emollient, analgesic, vasoconstrictor, antioxidant, acidulant, surfactant, preservative, chelating agent, and a cooling agent/penetrating agent. In another embodiment, the pharmaceutical composition may comprise water, glycerin, pramoxine hydrochloride, phenylephrine hydrochloride, propylene glycol, butylated hydroxyanisole, trisodium citrate dihydrate, TWl_.£N ^J( 80 (Polysorbate 80). citric acid (anhydrous), sodium benzoate, disodium EDTA. methyl paraben. propyl paraben. and L-menthol crystals. In a particular embodiment, the pharmaceutical composition may comprise about 73% water by weight, 20% glycerin by weight, 1% pramoxine hydrochloride by weight.0.25% phenylephrine hydrochloride by weight, 2% propylene glycol by weight.0.05% butylated hydroxyanisole by weight.0.35% trisodium citrate dihydrate by weight.2% TWEIZN* 80 (Polysorbate 80) by weight, 0.25% citric acid (anhydrous) by weight, 0.1 % sodium benzoate by weight.0.1 % disodium I TA by weight, 0.18% methyl paraben by weight.0.02% propyl paraben by weight, and 0.07% [.-menthol crystals by weight.

[0036] In many embodiments ofthis invention, a cream ma comprise the pharmaceutical composition described herein. In many embodiments ofthis invention, a lotion may comprise the pharmaceutical composition described herein. composition described herein. I n certain embod iments, the sheet may comprise absorbent cellulose based fibers, absorbent synthetic fibers, or a m ixture thereof. The fibers may be cross- linked. The absorbent cel lulosic fiber may be in sheet form. H uff form, or a combination thereof. The absorbent cellulose fiber may be in the form of a stabi l ized resi n-bonded or thermal-bonded non-woven mat. The absorbent cel lu lose fi ber ma be a wood pulp fiber obtained from a Kraft or sulfite chemica l process. The wood pu lp fiber may be obta ined from a hardwood ce llulose pulp, a softwood cel l ulose pu lp, or a combi nation or mixture thereo f. The composition may be appl ied to the sheet to provide from about 0.00 1 weight % to about 600% weight % composition on fiber, based on the tota l weight of the fiber. The composition may be appl ied to the sheet to provide from about 6.0 gram solution per sheet of cloth .

[0038] In many embodiments of th is invention, a method of making a sheet may comprise applying the pharmaceutical composition described herein to absorbent fibers. The composition may be applied by spraying, dipping, or rol l ing. The composit ion may be appl ied by a puddle press, size press, or a blade-coater.

[0039] I n many embodiments of this invention, a method of making the pharmaceutical composition described herein may comprise (a) m ix 131 IA, polysorbate 80, and propylene glycol for form a first mixture; (b) add methyl paraben. propyl paraben. and menthol to said first mixture to form a second mixture; (c) mix w ater and glycerin to form a third mixture; (d) add EDTA, sodium benzoate. sodium citrate, and citric ac id to said third mixture to form a fourth mixture; (e) add pramoxine I IC I and phenylephrine MC I to sa id fourth m ixture to form a fifth mixture; and (0 add said second mixture to said fi fth mi xture to form a hemorrhoid treatment composition.

[0040] I n many embod iments of th is invention, a method of treating hemorrhoids may comprise administering one or another embodiment of the pharmaceutical composition described herein a patient in need thereof. The composition is appl ied by the patient to the source of the pain, redness or swel l ing. This area of application may be the hemorrhoid itself or the tissue adjacent to the hemorrhoid.

[0041 ] In many embodiments of this invention, a method of treating hemorrhoids comprises applying the sheet described herein to a hemorrhoid on patient in need thereof. vasoconstrictor, and a cooling agent.

[0043] In one embodiment, the use of a composition comprising analgesic, solvent,

vasoconstrictor, emollient, surfactant, and cooling agent, ma be used in the manufacture of a composition for treating hemorrhoids.

DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 depicts an exemplary flow chart of manufacturing hemorrhoid treatment compositions.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

[0045] Commercially available hemorrhoid treatment preparations provide partial relief to hemorrhoid sufferers. Further, commercially available hemorrhoid treatment preparations have lipophilic skin protectants which delay the action of the anorectal drugs. Specifically, the addition of oleaginous additives such as shark liver oil. garlic oil. petrolatum, mineral oil, stearyl alcohol, cetyl alcohol, and tocopherol have occlusive properties that delay the onset of water soluble drugs and are often uncomfortable for patients to use due to greasiness.

[0046J The hemorrhoid treatment compositions described herein comprise multiple ingredients, which may include analgesic, vasoconstrictor, hydrophilic skin protectant, penetration enhancer, especially hydrophilic penetration enhancer, surfactant, and cooling agent. The hemorrhoid treatment compositions described herein may comprise about 1% pramoxine HCl (analgesic), 0.25% phenylephrine 1101 (vasoconstrictor).20% glycerin (hydrophilic skin protectant), 2% propylene glycol (hydrophilic penetration enhancer), 2% TWEKN® 80 (polyethylene glycol sorbitan monooleate).0.07% D.L-menthol (cooling agent/penetration agent), and water to balance. See, e.g., Table 1.

[0047] The inherent solubility parameter of skin lipids (6s) is about 10 (cal/cnr ¹ ) ¹⁷² , where water the δν is 23.4. The inherent solubility parameter for lipophilic ingredients of prior art preparations include shark liver oil/squalene (δν - 6.1 ), petrolatum (δν= 7.3), mineral oil (δν = 7.09). stearyl alcohol (δν =- 8.90). and cetyl alcohol (δν ^; 8.94) which are added to provide skin protection. These lipophilic skin protectants have occlusive properties that can act to delay the onset of action for w ater soluble drugs, especially w hen the inflamed area is located deep inside propylene glycol (δν = 14.5) and glycerin (δν = 16.26) are capable of distributing within the stratum corneum and increasing the tlux (enhancing penetration) of water soluble drugs, thereby acting as penetration enhancers. Menthol (δν = 9.94) is capable of distributing with the stratum corneum and increasing the flux of water soluble drugs.

10048] A single agent may act as both cooling agent and penetration enhancer, e.g.. menthol. Obata. et al. reported that percutaneous absorption of hydrophi l ic diclofenac sodium was substantially enhanced in the presence of l-menthol. Obata. ei al. Drug Design. Del.. 6, 3 19, 1 90. The combined effect of menthol and elhanol as skin penetration enhancers was also studied by obayashi. el al. Pharm Res.. 1 1 . 96. 1 94.

[0049] The inventors surprisingly discovered that menthol acts synergistically both as a cool ing agent and a penetration enhancer to improve the delivery of water soluble active ingredient through the mucous membrane of a hemorrhoid. The menthol is preferably solubilized in a micro-emulsion of a surfactant, e.g. , TW EEN® 80 (polyethylene glycol sorbitan monooleate). Other surfactants that may be used are nonionic surfactants such as ethoxylated castor oil, Polysorbate 20 (Polyoxyethylene (20) sorbitan monolauratc). and/or Polysorbate 60

(polyoxyelhylene (60) sorbitan monostearate). The hemorrhoid treatment compositions described herein improve the efficacy of the hemorrhoid preparation through the synergistic action of analgesic (e.g. , pramoxine NCI), vasoconstrictor (e.g.. phenylephrine 1 IC1) and penetration enhancer (e.g. , methanol, propylene glycol, and glycerin ), further, the hemorrhoid treatment compositions described herein do not contain l ipophil ic sk in protectants that slow down the action of the water soluble drugs.

(0050] The pharmaceutical compositions described herein may comprise water, glycerin, propylene glycol, and/or low molecular weight polyethylene glycols (PEGs) as a solvent. For example, the pharmaceutical compositions described herein may comprise about 10-40% glycerin by weight. The pharmaceutical compositions described herein may comprise. 10%. 1 5%, 20%. 25%. 30%, 35%, or 40% glycerin by weight, preferably about 20% glycerin by weight. The pharmaceutical compositions described herein may comprise about 1 - 10% propylene glycol by weight. The pharmaceutical compositions described herein may comprise, about 1 %. 1 .5%. 2%, 2.5%, 3%. 5%. 6%, 7%. 8%. 9%. or 10% propylene glycol by weight, preferably about 2% propylene glycol by weight. 1 he pharmaceutical compositions described pharmaceutical compositions described herein may comprise, about 1%, 1.5%.2%.2.5%, 3%, 3.5%.4%.4.5%. or 5% polyethylene glycol, preferably P CJ400. by weight, preferably about 2% polyethylene glycol, preferably PEG400, by weight.

|()051| Analgesics that may be used in compositions of this invention include but are not limited to benzocaine; benzyl alcohol; dibucaine; dibucaine hydrochloride; dyclonine hydrochloride; lidocaine; pramoxine hydrochloride; tetracaine; tetracaine hydrochloride; or a mixture thereof.

[0052] Λ preferred analgesic is pramoxine HCl.

[0053] The analgesics may be in an amount of about 0.25 to 20% by weight. For example, benzocaine may be at about 5 to 20% by weight; benzy l alcohol may be at about 1 to 4% by weight; dibucaine may be at about 0.25 to 1% by weight; dibucaine hydrochloride may be at about 0.25 to 1% by weight; dyclonine hydrochloride may be at about 0.5 to 1% by weight; lidocaine may be at about 2 to 5% by weight: pramoxine hydrochloride may be at about 1 percent by weight; tetracaine may be at about 0.5 to 1% by weight; tetracaine hydrochloride may be at about 0.5 to 1%; or a mixture thereof.

[0054] The A preferred analgesic is pramoxine I Id may be in an amount of about 0.5% to about 2.0% by weight of the composition. For example, pramoxine I ICI may be in an amount of about 0.75%. 1.0%.1.25%, or 1.50% by weight of the composition.

[0055] Vasoconstrictors used in compositions of this invention include ephedrine sulfate, epinephrine, epinephrine hydrochloride, phenylephrine hydrochloride, or a mixture thereof. The vasoconstrictor may be present in an amount of about 0.005 to 1.25% by weight. The vasoconstrictor may be ephedrine sulfate at about 0.1 to 1.25% by weight; epinephrine at about 0.005 to 0.01% by weight; epinephrine hydrochloride at about 0.005 to 0.01 % by weight;

phenylephrine hydrochloride at about 0.25% ; or a mixture thereof.

[0056] A preferred vasoconstrictor is phenylephrine HCl. The preferred vasoconstrictor phenylephrine HCl may be in an amount of about 0.10% to about 0.50% by weight of the composition. For example, the compositions described herein may comprise phenylephrine HCl in an amount of about 0.20%.0.25%.0.30%, or 0.35% by weight of the composition.

[0057] The compositions of this invention may comprise an emollient. Examples of suitable emollients a e dipropylene glycol, hexylene glycol, butylene glycol which are used at percentages low enough to ensure solubility in the preparation.

[0059] The emollient may be propylene glycol. The emol lient may be glycerin.

[0060] The emollient may be in an amount of about 1 .0% to about 40% by weight of the composition. The emol lient may be in an amount of about 2.0%. 5.0%, 10%), 1 5%, 20%>, 25%, 30%, 35%), or 40% by weight of the composition. For example, the composition may comprise about 1 -40% glycerin by weight of the composition, preferably about 2.0%. 5.0%, 10%. 1 5%. 20%, 25%, 30%. 35%. or 40% by weight of the composition. The composition may comprise about 1 -40% propylene glycol by weight of the composition, preferably about 2.0%, 5.0%. 10%. 1 5%, 20%, 25%. 30%. 35%. or 40% by weight of the composition.

[0061 ] The compositions described herein may further comprise an antioxidant, acidulant, preservative, chelating agent, or a combination thereof.

[0062] The compositions of this invention will typically comprise acidulants. such as citric acid and sodium citrate, as wel l as preservatives, such as methyl paraben, propyl paraben, sodium benzoate, diazol idinyl urea, and butylated hydroxyanisole. The compositions may also include chelating agents. Compositions of this invention also comprise an aqueous solvent.

]0063] The antioxidant may be butylated hydroxyanisole, butylated hydroxy! toluene, propyl gallate. or a combination thereof. The antioxidant, preferably butylated hydroxyanisole, may be in an amount about 0.01 % to about 0. 10% by weight of composition, preferably about 0.03%, 0.04%, 0.05%, 0.06%). or 0.07% by weight of composition.

[0064) The acidulant may be sodium citrate, citric acid, or a combination thereof.

|0065| The acidulant may be in an amount about 0. 1 0% to about 0.50% by weight of composition, preferably in an amount about 0.20%. 0.25%. 0.30%. 0.35%, or 0.40% by weight of composition.

[0066] For example, the composition may comprise water as a solvent. The composition may comprise a mixture of water/glycerin/propylene glycol/low molecular weight polyethylene glycols (PEGs) as a solvent. The composition may comprise a solvent is in an amount of about 70% to about 90% by weight of the composition. For example, the composition may comprise a solvent, preferably water, that is in an amount of about 7 1 %. 72%, 73%, 74%. or 75% by weight of the composition. amount of about 70% to about 90% by weight of the composition. For example, the solvent may be in an amount of about 71 %. 72%, 73%, 74%), or 75% by w eight of the composition.

(0068) The pharmaceutical composition may comprise mixtures of w ater, glycerin, propylene glycol, and/or low molecular weight polyethylene glycols ( PEGs ) as a solvent. The

pharmaceutical composition may comprise about 1 0-40% glycerin by weight, preferably 1 0%, 1 5%, 20%, 25%, 30%, 35%, or 40% glycerin by weight, more preferably about 20% glycerin by weight. The pharmaceutical composition may comprise about 1 - 1 0% propylene glycol by weight, preferably about 1 %, 1 .5%. 2%. 2.5%, 3%, 5%, 6%. 7%, 8%, 9%. or 10% propylene glycol by weight, more preferably about 2% propylene glycol by weight. The pharmaceutical composition may comprise about 1 -5% polyethylene glycol by weight, preferably about 1 %, 1 .5%. 2%. 2.5%. 3%, 3.5%. 4%. 4.5%, or 5% polyethylene glycol by weight, more preferably about 2% polyethylene glycol by w eight.

(0069] The polyethylene glycol may have an average molecu lar weight of 100-600. The polyethylene glycol may be PEG 1 0. PEG200. PEG300. PEG400, PEG 500, PEG600 or a mixture thereof. The polyethylene glycol may be PEG400. PEG600, or a mixture thereof. Ratio of the mixtures depend on the average molecular weight of PHG where the number denotes the molecular unit, e.g. , PEG 400 has an average molecular weight of 400. In the compositions described herein, water soluble PEGs can vary from PEG 1 00 to PEG 600. As the molecular weight of the PEG increases, the proportion of the PEG in the mixture may decrease. For example, the ratio of a suitable mixture of water: propylene gly col: PEG 1 00 = 1 : 1 : 1 and the ratio of a suitable mixture of water: propylene glycol: PEG 600 = 3 :2: 1 The pharmaceutical composition may comprise a mixture of waterpropylene glyco PEG in a ratio of 1 : 1 : 1 to 3:2: 1 . For example, the water:propy1ene glycoh PEG 100 may be a ratio of 1 : 1 : 1 . The water:propylene glycol:PEG60() may be a ratio of 3 :2: 1 .

(0070] The solvent may be in an amount of about 70% to about 90% by weight of the composition. For example, the solvent may be in an amount of about 71 %. 72%>, 73%, 74%, or 75%) by weight of the composition.

(0071 ) The compositions described herein may comprise a nonionic surfactant. The nonionic surfactant may be ethoxy lated castor oil. Polysorbate 20. Polysorbate 60, Polysorbate 80. or a combination thereof. The surfactant may be Polysorbate 80 ( polyethylene glycol sorbitan monooleate), may be in an amount of about 0.5% to about 5% by weight of the composition, preferably in an amount of about 1 .0%. 1 .5%. 2.0%. 3.0%, 3.5%. or 5.0% by weight of the composition.

[0072 J Cooling agents used in the compositions of this invention include menthol, eucalyptol, camphor, juniper tar, or a combination thereof. Λ preferred cool ing agent is menthol.

[0073] The cooling agent, preferably menthol, may be an amount of about 0.05% to about 0.1 % by weight of the composition, preferably about 0.05%, 0.06%. 0.07%, 0.08%, or 0.09% by weight of the composition.

[00741 The preservative is a pharmaceutically-acccptablc preservative suitable for topical use. For example, the preservative may be sodium bcnzoale. methy l paraben, propyl paraben, or a combination thereof. The preservative may be in an amount about 0.01 % to about 0.25% by weight of composition. For example, the preservative may be in an amount about 0.01 %. 0.02%, 0.03%. 0.05%, 0.1 0%, 0.1 5%, 0. 16%, 0. 1 8%. 0.20%. or 0.25% by weight of composition.

[0075] The chelating agent may be disodium EDTA in an amount about 0.05%o to about 0.20% by weight of composition, preferably in amount about 0.08%. 0.09%. 0. 1 0%, 0.1 1 %, 0.12%. or 0.1 3% by weight of composition.

[0076] The compositions described herein do not contain petrolatum. The compositions described herein do not contain witch hazel. The compositions described herein do not contain acycl ic alcohol or a monohydric al iphatic alcohol. The compositions described herein do not contain cetyl alcohol . The compositions described herein may be formulated as a suspension, cream, lotion, or applied to a sheet.

[0077] The hemorrhoid treatment compositions described herein have rapid onset action because, in part, it is a solution and not a cream which reaches the affected areas faster than a petrolatum-containing cream. A lso, the hemorrhoid treatment compositions described herein contain menthol which has instant cooling action that provides the patient rapid relief from pain associated with hemorrhoids. Also, the hemorrhoid treatment compositions described herein comprise a penetration enhancer— menthol— that al lows for better access of the active ingredients to the intlamed tissue. The hemorrhoid treatment compositions described herein use glycerin ( ?.#. , 20%) and not petrolatum which gives the compositions better skin protectant effect. The hemorrhoid treatment compositions described herein has a rapid synergistic effect a dual penetration enhancer/cooling agent that causes ihe active agents to penetrate the affected area and provide long lasting relief from the pain and discomfort of hemorrhoids. Menthol, a penetration agent, improves the analgesic action of the pramoxine HCI as a topical analgesic and phenylephrine HCI as a topical vasoconstrictor. The improvement in action is related to the fact that neutral molecules such as menthol have the exact solubility characteristics that improve the passage of ionic molecules through mucous membranes.

[0078] Also, the hemorrhoid treatment compositions described herein do not contain any petrolatum and are non-greasy with a better feel after application. Additionally, the

microemulsion created by the addition of at least 2% w/w TWT.FN" 80 forms micelles that solubilize menthol.

[0079] A clear microemulsion is inherently stable due to the formation of submicron sized micelles that are also referred to as isotropic solutions. The surfactants which make up microemulsions are too large themselves to penetrate into the dermis.

J0080| The hemorrhoid treatment preparations described herein may be formulated as a suppository, topical solution, ointment, cream, or impregnated into a wipe. Further, the hemorrhoid treatment preparations described herein may be delivered by a pump spray, squeeze tube (with or without nozzles), or disposable applicators. The dose may be metered by the pump spray or disposable applicator. In certain embodiments, the composition of this invention may be produced by mixing methol with surfactant(s) and preservatives, then adding this mixture to an aqueous solution which contains all of the other ingredients of the composition. Figure I shows an exemplary manufacturing scheme. This final mixture may then be impregnated into a non- woven sheet for use as a wipe.

[0081] A sheet may be impregnated with the composition described herein. The sheet may be absorbent cellulose based fibers, absorbent synthetic fibers, or a mixture thereof. Further, the fibers of the sheet may be cross-linked. The cellulosic absorbent liber may be in sheet form, fluff form, or a combination thereof. The absorbent cellulose fiber is may be in the form of a stabilized resin-bonded or thermal-bonded non-woven mat. ^' I ^' he absorbent cellulose fiber may be a wood pulp fiber obtained from a Kraft or sulfite chemical process. The wood pulp fiber may be obtained from a hardwood cellulose pulp, a softwood cellulose pulp, or a combination or mixture spraying, rolling, or a combination thereof.

[0082] Preferred cloths are those which are dispersible. Dispersibility is a desirable

characteristic for cloths due to the concern about the potential blockage of sewer drains and septic systems. Specific tests proposed by the National Sanitary Association are performed in order for a cloth to be designated as "dispersible".

[0083] Proceeding now to a description of the drawing, FIG 1 shows an exemplary method of manufacturing the composition described herein. The composition is formulated as two separate formulations 104, 203 and then mixed together into a final composition 302. BIIA is added to polysorbate 80 and propylene glycol 100. This composition is mixed with moderate shear 101. Then methyl paraben. propyl paraben, and menthol are added 102. This mixture is then mixed with moderate shear 103 to form a first mixture 104.

[0084] The amount of shear should be sufficient to create a vortex in the solution such that the BHA, methyl paraben, propyl paraben, and menthol will be dissolved in a reasonable period of time, preferably less than 1 hour. This amount of mixing can be achieved with a 6' ^' -12 ^" propeller mixer running at 600 - 1200 PM. For example, in a 100 gallon tank a 6 ^" blade running at 600 RPM may be used to achieve dissolution in about I hour. As the size of the tank increases, the mixer speed and/or the size of the blade may need to be increased in order to achieve adequate mixing in a reasonable amount of time, preferably less than I hour. [Or example, the mixer speed may be increased to 1200 RPM and the size of the blade may be increased to 12" in order to achieve dissolution in about 1 hour.

[0085] Ross. Silverson. or Gaulin mixers may be used. For example, moderate shear may be 400 rpm (rotations per minute) of the 4 blade rotor head against a static stator with a 10 micron gap allowing the mixture to pass through in a ROSSK) High Shear Mixer (Laboratory Model). The time required for mixing w ill depend upon the size of the batch and the number of passes through the mixer head in one hour, usually at least 3 - 5 passes per hour are required to achieve dissolution. Slight heating will accelerate the mixing process, but heat is not required to achieve mixing.

[0086] In a separate tank, water and glycerin are added together 200. Then EDTA, sodium benzoale. sodium citrate, citric acid are added and propeller mixed until dissolved 201. Then pramoxine HCl, phenylephrine HCl are added and the mixture is propeller-mixed until dissolved mixture 203 and propeller mixed in the reaction vessel that held the second mixture 301. This produces the final formulation 302, a composition for treating hemorrhoids.

[0087] Further embodiments of the present invention will now be described with reference to the following examples. The examples contained herein are offered by way of illustration and not by any way of limitation.

EXAMPLE 1

[0088| Table I— Non-optimal hemorrhoid treatment preparation

[008 J Clear microemulsions are inherently stable solutions. The preparation shown in Table 1 was made with 1.3% w/w TVVEEN* 80 and was not clear, therefore the microemulsion was not completely formed. Some of the menthol and eucalyptol remained undissolved. Also, is preparation was found to be sticky while drying on the skin.

EXAMPL 2

J0090) Table 2— on-optimal hemorrhoid treatment preparation μπειιν ic|)iii m n uiuemunuc vasoconsiricior

propylene glycol emollient 2.00% butylated hydroxyanisole antioxidant 0.02% trisodium citrate dihydrate acidulant 0.35%

TWEEN * 80 surfactant 1.50% (Potysorbate 80)

citric acid (anhydrous) acidulant 0.25% sodium benzoate preservative 0.10% di sodi m EDTA chelating agent 0.10%

Methyl para ben preservative 0.18%

Propyl paraben preservative 0.02%

Eucalyptol cooling agent/ 0.02%

penetrating agent

L-menthol crystals cooling agent/ 0.07%

penetrating agent

[00911 As shown in Table 2, a preparation was made with 1.5% vv/w TWEEN* 80 and was initially clear, but became cloudy over time. Compared to the preparation of Table 1, the preparation of Table 2 was less sticky while drying on the skin.

EXAMPLE 3

[0092] Table 3— Exemplary hemorrhoid treatment preparation of this invention

clear, and maintained clarity over the shell ^" lite of two years. Compared to the preparation of Table 1. the preparation of [ able 3 was less sticky while ing on the skin.

[0094] All publications (e.g.. Non-Patent Literature), patents, patent application publications, and patent applications mentioned in this specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All such publications (e.g., Non-Patent Literature), patents, patent application publications, and patent applications are herein incorporated by reference to the same extent as if each individual publication, patent, patent application publication, or patent application was specifically and individually indicated to be incorporated by reference.

10095] While the foregoing invention has been described in connection with this preferred embodiment, it is not to be limited thereby but is to be limited solely by the scope of the claims which follow.