Topical wipes containing nifedipine and lidocaine

Abstract

In particular, the present disclosure provides pharmaceutical compositions, kits, and methods for the treatment of anal fissures using medicated topical wipes containing nifedipine and lidocaine.

Description

[Technical field]

[0001] cross reference This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 63 / 169,768, entitled “Topical Wipe Containing Nifedipine and Lidocaine,” filed April 1, 2021, the contents of which are incorporated herein by reference in their entirety.

[0002] The present invention relates to the field of treating soft tissue injuries, and more specifically to topical wipes for the delivery of therapeutic compounds in the treatment of anal fissures. [Background technology]

[0003] Human body organs and soft tissues, generally defined as tissues that do not harden by ossification or calcification, comprise the majority of the human body's composition. Such tissues include muscles, tendons, ligaments, fat, skin, and the like. Soft tissues are generally very elastic materials and can undergo significant deformations without failure and return to their original configuration. In any case, under certain forces and loads, even soft tissues can undergo failure and tear. While many such tears are minor and heal naturally over time, some are more severe and can result in discomfort and pain. Furthermore, some tears in sensitive areas can be particularly painful and can interfere with daily life activities. Soft tissue damage in certain parts of the body can also be embarrassing or difficult for patients to discuss due to taboos and other social attitudes.

[0004] One such example is anal fissures, which are generally defined as small tears in the tissue lining the anus. Although such tears are most common in infants and young children, they occur in people of all ages, and can affect approximately 1 in 350 adults. As with most soft tissue injuries, shallow or superficial fissures usually heal naturally on their own, and simple treatments can sometimes reduce the associated discomfort and even speed up healing. However, in some cases, severe cases may not heal naturally and may require medicine or surgery.

[0005] Medications such as nitroglycerin ointment and calcium channel blockers such as nifedipine, diltiazem, and indoramin have been used to treat anal fissures. Golfam et al. (Acta medica Iranica, Vol. 48, No. 5, 2010, pages 295-299) treated chronic anal fissures with a cream containing 0.5% nifedipine for four weeks and found that 70% of patients experienced healing. Wise (U.S. Patent No. 10,543,201) uses a topical composition containing 0.3% nifedipine to treat the internal anal sphincter and / or pelvic floor. The internal anal sphincter is located deep within the anal canal (more than 1 cm away from the anal canal), so topical compositions cannot be applied to the tissue without the use of an applicator device or by deep finger penetration. Gels or creams are typically applied by the patient with a finger or with a syringe or suppository. The patient covers the finger with a plastic wrap or disposable glove, squeezes a prescribed amount of ointment onto the covered finger, and then spreads the ointment with the finger over the affected area. This type of application is not always practical or comfortable. Some patients do not have the versatility or dexterity to apply ointment in this manner. Patients who are able to apply ointment often find the process uncomfortable. This can lead to improper or incomplete application, limiting the effectiveness of the treatment or discouraging the patient from applying the treatment altogether.

[0006] Summary of the Invention In one aspect, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of 0.15% to 7.5% by weight, and nifedipine and its salts in a concentration of 0.15 to 1.5% by weight.

[0007] In a related aspect, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of 1.5% to 7.5% by weight, and nifedipine and its salts in a concentration of 0.3 to 1.5% by weight.

[0008] In a related aspect, the disclosure provides a method for the preparation of a medicament for use in a pharmaceutical composition comprising administering to the patient a medicament for which the medicament has been administered, the medicament being administered at a concentration of 0.15%, or 0.2%, or 0.25%, or 0.3%, or 0.35%, or 0.4%, or 0.45%, or 0.5%, or 0.8%, or 1%, or 1.2%, or 1.5%, or 1.8%, or 2%, or 2.2%, or 2.5%, or 2.8%, or 3%, or 3.2%, or 3.5%, or 3.8%, or 4%, or 4.2%, or 4.5%, or 4.8%, or 5%, or 5.2%, or 5.4%, or 5.6%, or 5.8%, or 6%, or 6.5%, or 6.8%, or 7%, or 7. A topical wipe is provided that includes a fibrous substrate moistened with a solution comprising 0.5% by weight of lidocaine and salts thereof (e.g., lidocaine HCl) and nifedipine and salts thereof in the following concentrations by weight: 0.15%, or 0.18%, or 0.2%, or 0.22%, or .25%, or .28%, or .3%, or 0.32%, or 0.35%, or 0.38%, or 0.4%, or 0.42%, or 0.45%, or 0.5%, or 0.55%, or 0.6%, or 0.65%, or 0.7%, or 0.75%, or 0.80%, or 0.85%, or 0.90%, or 0.95%, or 1%, or 1.2%, or 1.5%.

[0009] In a related aspect, the disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and salts thereof (e.g., lidocaine HCl) in a concentration of 1.5%, or 1.8%, or 2%, or 2.2%, or 2.5%, or 2.8%, or 3%, or 3.2%, or 3.5%, or 3.8%, or 4%, or 4.2%, or 4.5% by weight, and nifedipine and salts thereof in a concentration of 0.15%, or 0.18%, or 0.2%, or 0.22%, or .25%, or .28%, or .3%, or 0.32%, or 0.35%, or 0.38%, or 0.4%, or 0.42%, or 0.45% by weight.

[0010] In some embodiments, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of at least 1.5% by weight, and nifedipine and its salts in a concentration of at least 0.3% by weight.

[0011] In some embodiments, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of at least 1.5% by weight, and nifedipine and its salts in a concentration of at least 0.2% by weight.

[0012] In some embodiments, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of at least 1.5% by weight, and nifedipine and its salts in a concentration of at least 0.1% by weight.

[0013] In some embodiments, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of at least 1.5% by weight, and nifedipine and its salts in a concentration of at least 0.15% by weight.

[0014] In some embodiments, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of at least 1.5% by weight, and nifedipine and its salts in a concentration of at least 0.25% by weight.

[0015] In some embodiments, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of at least 1.5% by weight, and nifedipine and its salts in a concentration of at least 0.35% by weight.

[0016] In some embodiments, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of at least 1.5% by weight, and nifedipine and its salts in a concentration of at least 0.4% by weight.

[0017] In some embodiments, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of at least 1.5% by weight, and nifedipine and its salts in a concentration of at least 0.45% by weight.

[0018] In some embodiments, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of at least 1.5% by weight, and nifedipine and its salts in a concentration of at least 0.5% by weight.

[0019] In some embodiments, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of at least 1.5% by weight, and nifedipine and its salts in a concentration of at least 1% by weight.

[0020] In some embodiments, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of at least 1.5% by weight, and nifedipine and its salts in a concentration of at least 1.5% by weight.

[0021] In some embodiments, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of at least 0.15% by weight, and nifedipine and its salts in a concentration of at least 0.3% by weight.

[0022] In some embodiments, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of at least 0.2% by weight, and nifedipine and its salts in a concentration of at least 0.3% by weight.

[0023] In some embodiments, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of at least 0.4% by weight, and nifedipine and its salts in a concentration of at least 0.3% by weight.

[0024] In some embodiments, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of at least 0.6% by weight, and nifedipine and its salts in a concentration of at least 0.3% by weight.

[0025] In some embodiments, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of at least 0.8% by weight, and nifedipine and its salts in a concentration of at least 0.3% by weight.

[0026] In some embodiments, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of at least 1% by weight, and nifedipine and its salts in a concentration of at least 0.3% by weight.

[0027] In some embodiments, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of at least 1.5% by weight, and nifedipine and its salts in a concentration of at least 0.3% by weight.

[0028] In some embodiments, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of at least 2% by weight, and nifedipine and its salts in a concentration of at least 0.3% by weight.

[0029] In some embodiments, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of at least 2.5% by weight, and nifedipine and its salts in a concentration of at least 0.3% by weight.

[0030] In some embodiments, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of at least 3% by weight, and nifedipine and its salts in a concentration of at least 0.3% by weight.

[0031] In some embodiments, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of at least 4% by weight, and nifedipine and its salts in a concentration of at least 0.3% by weight.

[0032] In some embodiments, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of at least 4.5% by weight, and nifedipine and its salts in a concentration of at least 0.3% by weight.

[0033] In some embodiments, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of at least 5% by weight, and nifedipine and its salts in a concentration of at least 0.3% by weight.

[0034] In some embodiments, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of at least 6% by weight, and nifedipine and its salts in a concentration of at least 0.3% by weight.

[0035] In some embodiments, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of at least 6.5% by weight, and nifedipine and its salts in a concentration of at least 0.3% by weight.

[0036] In some embodiments, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of at least 7% by weight, and nifedipine and its salts in a concentration of at least 0.3% by weight.

[0037] In some embodiments, the present disclosure provides a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of at least 7.5% by weight, and nifedipine and its salts in a concentration of at least 0.3% by weight.

[0038] In some embodiments of any of the wipes described herein, a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of about 0.15-7.5% by weight, and nifedipine and its salts in a concentration of about 0.3-1.5% by weight, can treat anal fissures.

[0039] In some embodiments of any of the wipes described herein, a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine and its salts (e.g., lidocaine HCl) in a concentration of about 1.5-5% by weight, and nifedipine and its salts in a concentration of about 0.15-0.45% by weight, can treat anal fissures.

[0040] In some embodiments of any of the wipes described herein, the topical wipe further comprises a preservative. In some embodiments, the topical wipe further comprises an antioxidant. In some embodiments, the topical wipe further comprises at least one excipient. In some embodiments, the excipient is selected from the group consisting of an antioxidant, a penetration enhancer, a preservative, a humectant, a dispersant, a wetting agent, an emulsifier, a plasticizer, a surfactant, a viscosity modifier, an emollient, a film former, a tailing solvent, a co-solvent, and / or an oil. In some embodiments, the topical wipe further comprises an alcohol solvent.

[0041] Some embodiments of any of the wipes described herein further comprise a penetration enhancer selected from the group consisting of benzyl alcohol, dimethyl isosorbide (DMI), propylene glycol, hexylene glycol, isopropyl alcohol, ethanol, phenoxyethanol, oleic acid, oleyl alcohol, isopropyl myristate, medium chain triglycerides (MCT), and transcutol.

[0042] Some embodiments of any of the wipes described herein further comprise a humectant, wherein the humectant is selected from the group consisting of propylene carbonate, glycerin, pentylene glycol, butylene glycol, aloe vera juice, extract, hexylene glycol, hyaluronic acid, and lactic acid.

[0043] Some embodiments of any of the wipes described herein further comprise an emulsifier, wherein the emulsifier is selected from the group consisting of polysorbate (20-80), Span-80, PEG-40, hydrogenated castor oil, sodium lauryl sulfate (SLS), poloxamer, sorbitan (20-85), and glyceryl monooleate (GMO).

[0044] Some embodiments of any of the wipes described herein further comprise a surfactant, wherein the surfactant is selected from the group consisting of PEG400, tween-80, oleyl alcohol, glycerin, hexylene glycol, and propylene glycol.

[0045] Some embodiments of any of the wipes described herein further comprise an antioxidant, wherein the antioxidant is selected from the group consisting of butylated hydroxytoluene (BHT), alpha-tocopherol, propyl gallate, squalene ascorbate, ascorbyl palmitate, sodium thiosulfate, and sodium metabisulfate.

[0046] Some embodiments of any of the wipes described herein further comprise a bioadhesive polymer selected from the group consisting of carbomer homopolymer types A, B and C, carbomer copolymers, interpolymers, polycarbophil, pemulene, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), and hydroxypropyl methylcellulose (HPMC).

[0047] In some embodiments of any of the wipes described herein, the solution comprises a solvent selected from the group consisting of water, propylene glycol, and hexylene glycol.

[0048] In some embodiments of any of the wipes described herein, the wipe further comprises one or more of benzyl alcohol, transcutol, propylene carbonate, polysorbate 80, BHT, PEG 400, glycerin, and hexylene glycol.

[0049] In some embodiments of any of the wipes described herein, the wipe comprises benzyl alcohol in a concentration of at least 2%.

[0050] In some embodiments of any of the wipes described herein, the wipe comprises Transcutol in a concentration of 30-40%, particularly Transcutol in a concentration of 30%, 35%, or 40%.

[0051] In some embodiments of any of the wipes described herein, the wipe comprises a concentration of at least 4% propylene carbonate.

[0052] In some embodiments of any of the wipes described herein, the wipe comprises polysorbate 80 at a concentration of at least 2%.

[0053] In some embodiments of any of the wipes described herein, the wipe comprises a concentration of at least 0.2% BHT.

[0054] In some embodiments of any of the wipes described herein, the wipe comprises propylene glycol in a concentration of 30-60%, particularly propylene glycol in a concentration of 30%, 35%, 40%, 45%, 50%, 55%, or 60%.

[0055] In some embodiments of any of the wipes described herein, the wipe comprises glycerin at a concentration of at least 15%.

[0056] In some embodiments of any of the wipes described herein, the wipe comprises hexylene glycol in a concentration of at least 10%.

[0057] In some embodiments of any of the wipes described herein, the wipe comprises a formulation selected from the group consisting of formulation I, formulation II, formulation III, formulation IV, formulation V, and formulation VI.

[0058] In some embodiments of any of the wipes described herein, the topical wipe is made from fibers. In some embodiments, the topical wipe is made from nonwoven fibers. In some embodiments, the topical wipe is made from woven fibers.

[0059] In some embodiments of any of the wipes described herein, the topical wipe is generally rectangular in shape. In some embodiments, the topical wipe is individually packaged for single use.

[0060] In another aspect, the present disclosure provides a container comprising a plurality of topical wipes as described herein. In some embodiments, the container comprises a soft pack. In some embodiments, the container comprises a hard pack.

[0061] In another aspect, the present disclosure provides a kit comprising a plurality of topical wipes as described herein in separate individual single-use packs or in a bulk of at least 30 wipes each.

[0062] In another aspect, the present disclosure provides a method of treating or ameliorating anal fissure in a subject in need thereof, the method comprising applying a topical wipe comprising a fibrous substrate moistened with a solution comprising lidocaine HCl in a concentration of at least 1.5% and nifedipine in a concentration of at least 0.3% to the perianal area of ​​the subject, thereby providing therapeutic relief.

[0063] In another aspect, the present disclosure provides a method of treating or ameliorating anal fissure in a subject in need thereof, the method comprising applying a formulation comprising lidocaine HCl in a concentration of 1.5% to 5%, preferably at least 1.5%, and nifedipine in a concentration of 0.15 to 4.5%, preferably at least 0.15%, to anal tissues within 1 cm of the anal canal of said subject, thereby providing therapeutic relief.

[0064] In another aspect, the present disclosure provides a method of treating or ameliorating anal fissure in a subject in need thereof, the method comprising applying a formulation comprising lidocaine HCl in a concentration of 1.5% to 5%, preferably at least 1.5%, and nifedipine in a concentration of 0.15 to 0.45%, preferably at least 0.15%, to the external anal sphincter of the subject, thereby providing therapeutic relief.

[0065] In another aspect, the present disclosure provides a method of making a topical wipe comprising nifedipine in a concentration of 0.15-0.45%, preferably at least 0.3%, and lidocaine HCl in a concentration of 1.5-5%, preferably at least 1.5% lidocaine HCl, the method comprising providing a wipe, applying a formulation comprising at least 0.15% nifedipine and at least 1.5% lidocaine HCl, drying the wipe for a sufficient period of time, and packaging the wipe in an airtight container or pouch.

[0066] In another aspect, the disclosure provides a method of using a topical wipe, the wipe comprising a formulation of nifedipine at a concentration of 0.15-0.45%, preferably at least 0.15% nifedipine and at least 1.5% lidocaine HCl, the method comprising applying the wipe to the perianal area of ​​a subject such that the formulation contacts the external anal sphincter or anal tissue within 1 cm of the anal canal of the subject, the subject having an anal fissure.

[0067] In some embodiments, upon application of the wipe to the perianal area, a formulation comprising at least 0.15% nifedipine and at least 1.5% lidocaine HCl, preferably 0.3% nifedipine and 1.5% lidocaine, contacts the external anal sphincter.

[0068] In some embodiments, upon application of the wipe to the perianal area, a formulation comprising at least 0.15% nifedipine and at least 1.5% lidocaine HCl, preferably 0.3% nifedipine and 1.5% lidocaine, contacts the external and internal anal sphincter muscles.

[0069] In some embodiments, upon application of the wipe to the perianal area, the formulation comprising at least 0.15% nifedipine and at least 1.5% lidocaine HCl, preferably 0.3% nifedipine and 1.5% lidocaine, contacts the external anal sphincter but not the internal anal sphincter.

[0070] In some embodiments, upon application of the wipe to the perianal area, a formulation comprising at least 0.15% nifedipine and at least 1.5% lidocaine HCl, preferably 0.3% nifedipine and 1.5% lidocaine, contacts the anal tissue within 1 cm of the anal canal.

[0071] Certain exemplary embodiments are now described to provide a general understanding of compositions of matter (e.g., formulations of nifedipine and lidocaine HCl) and methods of making the same. The present disclosure provides various ingredients and / or combinations thereof for formulating compositions of matter, and further provides various steps that may be used to combine various ingredients and / or combinations thereof to arrive at compositions of matter. Those skilled in the art will understand that the compositions and methods described herein are non-limiting and exemplary embodiments, and the scope of the present disclosure is defined only by the claims. Features illustrated or described in connection with an exemplary embodiment may typically be combined with features of other embodiments, unless otherwise indicated. For example, those skilled in the art will understand, in light of the present disclosure, one or more steps provided as part of a method for making compositions of matter as provided herein, and such steps can be used in other methods for making compositions of matter as provided herein or otherwise known in the art. Similarly, one of ordinary skill in the art will recognize various steps that may be interchangeable among various methods disclosed herein or otherwise known to those of ordinary skill in the art, or that may be otherwise modified in light of various methods disclosed herein or otherwise known to those of ordinary skill in the art, without departing from the spirit of the present disclosure. As a non-limiting example, one of ordinary skill in the art will recognize in light of the present disclosure that the use of alternative techniques, whether explicitly disclosed in the present application or known to those of ordinary skill in view of the present disclosure, will typically still maintain the inventive concepts associated with the present disclosure.

[0072] In this disclosure, many different terms may be used interchangeably and would still be understood by one of ordinary skill in the art. As a non-limiting example, phrases such as "selected from the group consisting of," "chosen from," and the like include mixtures of the specified materials. When numerical limits or ranges are stated herein, the endpoints are included. Also, all values ​​and subranges within a numerical limit or range are specifically included as if expressly stated. Reference to an element in the singular is not intended to mean "one and only one," unless otherwise specified, but rather "one or more." Unless otherwise specified, terms such as "some" refer to one or more, and singular terms such as "a," "an," and "the" refer to one or more.

[0073] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS In one aspect, the present disclosure relates to methods and compositions for treating anal fissures by providing a medicated wipe containing a therapeutic agent and a local anesthetic that can be applied to the anus, which can, among other things, accelerate or facilitate healing, locally numb pain to aid comfort, and relax local muscles to increase blood flow to the affected area, thereby facilitating healing of the anal fissure.

[0074] The wipes provide improvements over the prior art, including an easier-to-use and more comfortable delivery mechanism for therapeutic compounds and local anesthetics, a cooling, soothing, and comfortable reduction of pain, irritation, and other discomforts, and a chemical composition that results in better and accelerated healing. Also, unlike prior art ointments that are not always practical or comfortable, the wipes ensure better compliance with topical medication application. Prior art ointments are generally spread in and / or around the anal cavity and require finger insertion, whereas the topical wipes used herein spread therapeutic compounds externally. This promotes patient comfort and ease of use, because the mechanism of the wiping action mimics everyday bathroom hygiene and does not require insertion. This in turn promotes compliance with treatment regimens and improved outcomes. Additionally, the compounds can be safely exposed to the skin. And because use of the wipes does not require finger insertion, patients may simply wash their hands properly after use without using disposable gloves or other sanitary covers.

[0075] In some embodiments, the active pharmaceutical compounds in the wipe achieve an effective permeation profile to the target tissue to provide therapeutic relief. The permeation profile of each compound is based on, among other things, the physical and chemical properties of each compound, the microstructural properties of each compound, the loading dose of the topical wipe, and the characteristics of the target tissue, which may vary substantially in different anatomical regions. That is, formulations and prior art products known to be suitable for use in certain areas, such as the scalp, abdomen, or hands, may not be suitable for use with the topical wipes described herein. An additional consideration is sensory, in that compound formulations may be selected or optimized taking into account attributes such as viscosity or sensory sensations that may affect the "messiness" of product use (e.g., overly saturated application compounds may drip excessively from the wipe before and after use, or transfer excessive amounts of the formulation to the affected area, which do not permeate the skin and must be removed manually).

[0076] In some embodiments, the topical wipes are treated with one or more topical agents having therapeutic properties effective in relaxing the external anal sphincter and increasing blood flow. By way of example and without limitation, one such family of compounds is calcium channel blockers. By way of further example and without limitation, one such calcium channel blocker is nifedipine, C, as illustrated below. 17 H 18 It is N2O6. [ka]

[0077] Nifedipine is soluble in organic solvents such as EtOH (3 mg / ml), DMSO (30 mg / ml), and dimethylformamide (30 mg / ml), which can be removed by inert gas. One of the challenges of using nifedipine is that it is highly lipophilic and soluble in alcohol, but is poorly soluble in aqueous buffers.

[0078] In another embodiment, the topical wipes are additionally or alternatively treated with one or more topical agents having pain or itch relieving properties effective in reducing discomfort in the affected area. By way of example and without limitation, one such compound is lidocaine (illustrated below) and its salts, e.g., lidocaine HCl, C 14 H 22 N2O (illustrated below), etc. [ka]

[0079] Lidocaine and its salts are local anesthetics with a rapid onset of action, highly soluble in alcohol (4 mg / ml EtOH) and chloroform, freely soluble in ether, benzene, and soluble in oils.

[0080] In another embodiment, the topical wipes are pre-moistened with a solution containing the desired compound, such as muscle relaxants and / or pain relievers, and then packaged in a ready-to-use form, such as a soft pack or hard cover container, with a slit top opening, which inhibits the intake of oxygen and other decomposition agents, retains moisture to inhibit evaporation, and protects the wipe from external contaminants.The wipes may be removed from the container for immediate use, one at a time, as prescribed or required, and the container may then be resealed.Alternatively or additionally, the wipes may be packaged individually in a single-use container or flexible packaging.

[0081] In some embodiments, the wipe is pre-moistened with a solution containing about 1.5% lidocaine and about 0.3% nifedipine by weight. In some embodiments, the wipe is pre-moistened with a solution containing about 2% lidocaine and about 0.3% nifedipine by weight. In some embodiments, the wipe is pre-moistened with a solution containing about 2.5% lidocaine and about 0.3% nifedipine by weight. In some embodiments, the wipe is pre-moistened with a solution containing about 3% lidocaine HCl and about 0.3% nifedipine by weight. In some embodiments, the wipe is pre-moistened with a solution containing about 3.5% lidocaine and about 0.3% nifedipine by weight. In some embodiments, the wipe is pre-moistened with a solution containing about 4% lidocaine and about 0.3% nifedipine by weight. In some embodiments, the wipes are pre-moistened with a solution containing about 4.5% lidocaine and about 0.3% nifedipine by weight. In some embodiments, the wipes are pre-moistened with a solution containing about 5% lidocaine and about 0.3% nifedipine by weight. In some embodiments, the wipes are pre-moistened with a solution containing lidocaine HCl in the range of 1.5-5% by weight and about 0.3% nifedipine by weight.

[0082] These concentrations may be modified by the addition of other compounds discussed elsewhere herein. Such compounds include, but are not necessarily limited to, preservatives and antioxidants. The concentrations may also vary depending on other factors, such as the amount and concentration at which the compound in question may be synthesized and / or packaged, shipped, and stored, subject to applicable practical constraints, such as typical formulation amounts, storage interval requirements, expected sealed shelf life in typical detailed environments, shelf life upon opening and use, and typical transport conditions. In particular, attention should be paid to the inclusion of impurities or compound-related decomposition products that may be formed during synthesis or storage.

[0083] In some embodiments, the topical wipes further comprise suitable excipients and / or solvents that are typically selected to achieve the desired concentration. For example, both nifedipine and lidocaine are highly soluble in alcohol. One or more excipients or classes of excipients may be included. Such agents may include, but are not necessarily limited to, antioxidants, penetration enhancers, humectants, dispersants, viscosity modifiers, emollients, film formers, preservatives, tailing solvents, co-solvents, oils, and the like. The mass and / or volume of therapeutic compound used may be modified or adapted to achieve the desired concentration as described elsewhere herein, taking into account the excipients contained in any given formulation. Excipients may be selected based on many factors. Such factors include, but are not necessarily limited to, stability and potential interactions with the therapeutic compound that result in inhibition of degradation or other inhibition of function at the dose levels envisaged.

[0084] In some embodiments, the topical wipes include fibrous substrates, such as natural or synthetic fibers or fabrics, which preferably have a smooth, low-friction surface and / or finish that is gentle on sensitive skin. In some embodiments, nonwoven fibers may be used that have effective absorption properties to be loaded with the desired combination of pharmaceuticals, as well as desirable storage properties (e.g., ability to load and preserve the pharmaceutical compounds for the desired shelf-stable period without excessive spoilage or degradation), usage properties (resistance to tearing and breakage), and desirable disposal properties (e.g., biodegradable, compostable, flushable, safe for spoilage, etc.). In some embodiments, the components of the topical wipes are effective to provide a shelf-stable product for approximately two years.

[0085] In some embodiments, the wipes include one or more preservatives and / or antioxidants. The classes and amounts or concentrations of these compounds are preferably effective to ensure the desired shelf life of the topical wipes under normal shipping, retail, and consumer conditions. Techniques for determining suitable compounds and amounts thereof through routine experimentation and testing are known in the art.

[0086] In some embodiments, the topical wipes are generally rectangular, preferably rectangular, so that they can be easily stored and retrieved. The wipes may be individually or multi-packaged, such as in a sealed single-unit packet or pouch. The packaging is preferably resealable, such as by use of a zipper or adhesive.

[0087] In some embodiments, the topical wipes are abrasive-free and gentle on sensitive skin.

[0088] In some embodiments, the topical wipes are flushable, disposable, and spoilage-safe.

[0089] In some embodiments, the topical wipes are storage stable for at least two years.

[0090] It will be readily appreciated that although the topical wipes described above have been described with respect to specific compounds for the treatment of anal fissures in humans, the same considerations and principles apply in other areas and may be used to treat similar types of injuries in the tissues of non-human mammals or other animals, and in other anatomical areas with similar medical characteristics, anatomical geometries, or social attitudes that would inhibit full patient compliance with a self-administered therapy.

[0091] Although the present invention has been disclosed in conjunction with a description of specific embodiments, including what are currently considered to be preferred embodiments, the detailed description is intended to be illustrative and should not be understood as limiting the scope of the disclosure. As will be understood by those skilled in the art, embodiments other than those specifically described herein are encompassed by the present invention. Modifications and variations of the described embodiments may be made without departing from the spirit and scope of the present invention. [Brief description of the drawings]

[0092] [Figure 1] FIG. 1 shows the process of testing different combinations of excipients and varying concentrations to arrive at a formulation of nifedipine and lidocaine suitable for impregnating wipes for therapeutic use. [Diagram 2]FIG. 2 shows different impregnation methods to produce topical wipes containing formulations of nifedipine and lidocaine with selected excipients. A) Take the required amount of lidocaine HCl+nifedipine solution in a container. B) Immerse or soak the wipe in the active solution for t minutes. C) Dry the wipe after immersion for t minutes. D) Take the required amount of lidocaine HCl+nifedipine solution in a spray bottle. E) Spray the wipe with the active solution for t minutes. F) Dry the wipe after spraying for t minutes. G) Take the required amount of lidocaine HCl+nifedipine solution with a pipette. H) Wet the wipe with the active solution by pipetting for t minutes (add the formulation to the wipe in stages using a pipette). I) Dry the wipe after pipetting for t minutes. The saturation loading is the final weight of the wipe / dry weight of the wipe, the percentage of saturation is the final weight of the wipe / dry weight of the wipe x 100, and the weight of the impregnating formulation is the weight of the dry wipe after loading and drying - the tare weight of the dry wipe. [Diagram 3] FIG. 3 shows the drying method used consistently to dry all wipes impregnated with different methods. [Figure 4] Figure 4 shows a graph of the weight of impregnation solution, saturation loading, and % saturation loading at each incremental addition step. After each addition step, the wipes were allowed to dry for 45 minutes. [Diagram 5] Figure 5 shows a graph of the weight of impregnation solution, saturation loading, and % saturation loading at each incremental addition step. After each addition step, the wipes were allowed to dry for 15 minutes. [Figure 6] Figure 6 shows the calibration curves obtained with different wipe weights / sizes. [Figure 7] FIG. 7 shows the mean cumulative permeation of lidocaine HCl in each type of formulation F1-F3 (solution, wipe, and ointment, respectively). [Figure 8] FIG. 8 shows the average flux of lidocaine HCl in each type of formulation F1-F3 (solution, wipe, and ointment, respectively). [Figure 9]FIG. 9 shows the mean cumulative permeation of nifedipine in each type of formulation F1-F3 (solution, wipe, and ointment, respectively). [Figure 10] FIG. 10 shows the average flux of nifedipine in each type of formulation F1-F3 (solution, wipe, and ointment, respectively). [Figure 11] FIG. 11A shows the average retention of lidocaine HCl in tissue for each type of formulation F1-F3 (solution, wipe, and ointment, respectively), the total lidocaine HCl recovered from tissue (amount in ng / cm2 square), FIG. 11B shows the corresponding recovery of the applied dose of lidocaine HCl as % recovery, and FIG. 11C shows the total tissue retention in the three formulations. [Figure 12] FIG. 12A shows the average retention of nifedipine in tissue for each type of formulation F1-F3 (solution, wipe, and ointment, respectively), the total nifedipine recovered from tissue (amount in ng / cm2 square), FIG. 12B shows the corresponding recovery of the applied dose of nifedipine as % recovery, and FIG. 12C shows the total tissue retention in the three formulations. [Figure 13] Figure 13A shows the anal canal and various tissues associated therewith. The topical wipe is preferably applied to tissues within the first cm of the anal canal. Application of the topical wipe by the patient delivers the API (nifedipine and lidocaine HCl) to the external anal sphincter and aids in the treatment of the anal fissure. Figure 13B shows the structure of human skin, including multiple layers. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0093] definition As used herein, the term "wipe" refers to a small to medium sized moistened piece of plastic or cloth that is folded and individually rolled for convenience or in the case of a dispenser. Wipes are generally used for cleaning purposes such as personal hygiene, but may be used for therapeutic purposes when impregnated with ethyl alcohol (sterile wipes), or medicamentously active compounds such as witch hazel (hemorrhoid wipes). The topical wipes of the present disclosure are impregnated with a formulation of nifedipine (at least 0.3% by weight) and lidocaine HCl (at least 1.5% by weight) for use in treating anal fissures. The dimensions of the wipes can vary depending on the nature of the use, with portable wipes often being smaller, such as about 6 inches by 3 inches. Conventional wipes range, for example, from about 6 inches by 4 inches, about 8 inches by 8 inches, or 9 inches by 7 inches. The thickness of the wipes ranges from 0.5 mm to 1 mm. Preferably, the wipes are 6 by 4 inches and are made of nonwoven fabric made from cellulose.

[0094] Wipes are made of materials such as polyester, polypropylene, cotton, wood pulp, or rayon fibers formed into sheets. Wipes may be individually packaged or in small or bulk packages. Wipes can be made of woven and nonwoven fibers. Wipes are moistened with water and other inactive ingredients, such as surfactants and humectants, to help the active ingredients work better and ensure user compliance. They may contain other ingredients, such as preservatives to prevent the growth of bacteria and mold. Wipes can be biodegradable and flushable to be safe for aseptic use.

[0095] As used herein, the term "woven fabric" refers to a fabric made by interweaving two or more yarns at right angles to one another. Woven fabrics or wipes can be made from both natural and synthetic fibers, and are often made from a mixture of both. For example, 100% nylon or 80% nylon and 20% polyester.

[0096] As used herein, the term "nonwoven fibers" refers to fibers that do not contain interwoven twists but have an organized internal structure. They are made by placing fibers together and then using heat, chemicals, or pressure to coalesce them into a cohesive cloth-like material. In contrast to traditional materials such as cotton, wool, and silk, nonwovens do not require weaving. They are made by stirring the fibers in a solution until they interlock into a dense fabric. Cellulose is commonly used to make nonwoven fibers.

[0097] As used herein, the term "lidocaine" refers to a monocarboxylic acid amide resulting from the formal condensation of N,N-diethylglycine with 2,6-dimethylaniline. It acts as a local anesthetic and antiarrhythmic agent. An example of a lidocaine salt is lidocaine HCl, and other salts of lidocaine are also contemplated for use in the topical wipes described herein.

[0098] As used herein, the term "lidocaine hydrochloride" or "lidocaine HCl" or "2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide; hydrochloride" refers to the hydrochloride salt derived from lidocaine, a prototypic member of the aminoethylamide, and amide class of anesthetic agents. Lidocaine interacts with voltage-gated Na+ channels in nerve cell membranes and blocks the transient increase in excitable membrane permeability to Na+. This prevents the generation and conduction of nerve impulses and results in reversible sensory loss. Lidocaine hydrochloride also exhibits class IB antiarrhythmic effects. The agent reduces the flow of sodium ions into myocardial tissue during phase 0 of the action potential, particularly on the Purkinje network, thereby reducing depolarization, automaticity, and excitability.

[0099] As used herein, the term "nifedipine" or "dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate" refers to a dihydropyridine calcium channel blocker. Nifedipine inhibits the transmembrane influx of extracellular calcium ions into cardiac myocytes and vascular smooth muscle cells, causing dilation of major coronary and systemic arteries and reducing myocardial contractility. The agent also inhibits the drug efflux pump P-glycoprotein, which is overexpressed in some multidrug-resistant tumors, and may improve the efficacy of some antineoplastic agents. Nifedipine base and nifedipine salts are also contemplated for use in the topical wipes described herein.

[0100] As used herein, the term "anal canal" refers to the most distal portion of the lower GI tract / large intestine, which lies between the perianal verge (anal opening, anus) below and the rectum above.

[0101] As used herein, the term "anal fissure" refers to a cut or tear in the thin, delicate lining of the anus. The tear often exposes the muscle around the anus called the anal sphincter. The injury can cause the muscle to spasm, pulling the edges of the fissure further apart. This spasm can cause pain and slow healing. Bowel movements can also prevent the fissure from healing better.

[0102] As used herein, the term "external anal sphincter" refers to a layer of voluntary (striated) muscle that surrounds the outer wall of the anal canal and the anal opening. The external anal sphincter is approximately 8-10 cm long from its anterior to posterior end, approximately 1-2.5 cm facing the anus, and the sphincter contracts during defecation. It consists of two layers, the superficial and the deep. The superficial layer constitutes the major part of the muscle and arises from a narrow band of tendons called the anococcygeal raphe, which extends from the tip of the coccyx to the posterior margin of the anus. The superficial layer forms two flat planes of muscle tissue that surround the anus and meet in front to insert into a tendon center of the perineum that connects with the superficial transverse perineal muscle, the levator ani muscle, and the bulbocavernosus muscle, also known as the bulbocavernosus. The deeper layer forms the complete sphincter for the anal canal.

[0103] As used herein, the term "internal anal sphincter" refers to a ring of smooth muscle that surrounds the anal canal. Its lower edge is in contact with but completely separate from the external anal sphincter. The internal sphincter is made of smooth muscle and is innervated by the autonomic nervous system, whereas the external sphincter is made of striated muscle and has somatic (voluntary) innervation provided by a nerve called the pudendal nerve.

[0104] As used herein, the terms "perianal" or "perirectal" refer to the area surrounding the rectal opening or the opening of the anal canal. Generally, wipes are used to clean or reach the perianal area.

[0105] As used herein, the term "endorectal" refers to the area deep inside the rectum or anal canal. Generally, digital penetration or an applicator wand is required to access the intrarectal area.

[0106] As used herein, the term "excipient" refers to an inactive pharmaceutical ingredient used in a pharmaceutical formulation. Excipients can play various functional roles in a pharmaceutical product. Each excipient serves a specific purpose (e.g., binder, disintegrant, or pH adjustment) for the proper performance of the dosage form. The properties (i.e., stability) of the final dosage form are in most cases highly dependent on the selected excipients, their concentrations, and their interactions with the active compound and with each other. The majority of excipients used in product formulations are compendial (United States Pharmacopoeia (USP), European Pharmacopoeia (EP), Japanese Pharmacopoeia (JP)).

[0107] As used herein, the term "API" refers to "active pharmaceutical ingredient." Any substance or combination of substances used in a finished pharmaceutical product (FPP) provides pharmacological activity or otherwise has a direct effect on the diagnosis, cure, mitigation, treatment or prevention of disease, or is intended to have a direct therapeutic effect. In this disclosure, the term API refers to nifedipine and lidocaine HCl.

[0108] As used herein, the term "preservative" refers to a substance that prevents or inhibits the growth of microorganisms and extends the shelf life of a pharmaceutical product. Commonly used preservatives in these systems include sodium benzoate, EDTA, sorbic acid, and parabens.

[0109] As used herein, the term "antioxidant" refers to a substance that reduces damage to an active ingredient due to oxidation, such as that caused by free radicals. Common examples of antioxidants include butylated hydroxytoluene (BHT), alpha-tocopherol, propyl gallate, beta hydroxy acids (BHA), squalene, ascorbyl palmitate, sodium thiosulfate, and sodium metabisulfate.

[0110] As used herein, the term "penetration enhancer" or "penetration enhancer" refers to an agent that penetrates the skin and interacts with skin components to enhance drug flux or reversibly reduce barrier resistance. Common examples include benzyl alcohol, dimethyl isosorbide (DMI), propylene glycol, hexylene glycol, isopropyl alcohol (IPA), ethanol, phenoxyethanol, oleic acid, oleyl alcohol, isopropyl myristate, medium chain triglycerides (MCT), and transcutol. Combinations of ethanol or IPA with one or more of oleic acid, oleyl alcohol, medium chain triglycerides (MCT), or isopropyl myristate can also be used.

[0111] As used herein, the term "humectant" or "emollient" refers to a substance that forms a barrier around the surface of the skin and prevents loss of moisture from the skin cells. Common examples include shea butter, cocoa butter, mineral oil, lanolin, petrolatum, paraffin, beeswax, and squalene.

[0112] As used herein, the term "dispersant" refers to a substance that disperses another substance in a medium such as water to form a colloidal solution. Their main function is to reduce adhesion between particles and prevent flocculation or agglomeration. Common examples include cetrimonium chloride, PEG-10 dimethicone, PEG-7 glyceryl cocoate, and Glycereth-26.

[0113] As used herein, the term "humectant" refers to a hygroscopic substance that absorbs water vapor and binds water to the skin. Aqueous solutions of humectants can reduce the rate of water loss. They are commonly added to cosmetics such as oil-in-water type creams (vanishing creams) to prevent drying. Common examples of humectants include propylene carbonate and glycerin, pentylene glycol, butylene glycol, aloe vera juice / extract, hexylene glycol, hyaluronic acid and its salts, and lactic acid and its salts.

[0114] As used herein, the term "emulsifier" refers to a compound or substance that acts as a stabilizer for an emulsion and prevents liquids that normally do not mix from separating. Common examples include polysorbate 80, Span-80 sodium stearoyl lactylate, mono- and diglycerol, ammonium phosphatide, PEG-40 hydrogenated castor oil, sodium lauryl sulfate (SLS), poloxamers (coblock polymers), hydrogenated castor oil, polysorbate (20-80)-TWEENS, sorbitan (SPANS(20-85)), and glyceryl monooleate (GMO).

[0115] As used herein, the term "surfactant" refers to a substance, such as a detergent, that when added to a liquid reduces its surface tension, thereby increasing its spreading and wetting properties. Surfactants have several uses in medicine, including i) for solubilizing hydrophobic agents in aqueous media, ii) as components of emulsions, iii) as surfactant-based self-assembling vehicles for oral and transdermal drug delivery, iv) as plasticizers for semi-solid delivery systems, and v) as agents to improve drug absorption. Common examples include PEG400, tween-80, oleyl alcohol, glycerin, hexylene glycol, and propylene glycol.

[0116] As used herein, the term "viscosity modifier" refers to a substance that can change the thickness or texture of a pharmaceutical ingredient. Viscosity modifiers can include products such as thickeners, toning agents, gelling agents, and stiffening agents. Numerous viscosity modifiers can be used to transform liquids into gels, pastes, or powders, helping formulators create the ideal product for end users. Viscosity modifiers can reduce the viscosity of liquids to improve pourability and spreadability on surfaces.

[0117] As used herein, the term "film former" refers to a compound that, when applied to a surface, leaves a flexible, adhesive, and continuous coating over hair or skin. This film has strong hydrophilic properties and leaves a smooth feel on the skin. Common examples include polyvinylpyrrolidone (PVP), acrylates, acrylamides, and copolymers. Bioadhesive polymers can be used as excipients to create a film to reduce friction between the medicated wipe and the anal skin and improve retention after wiping. Common examples of such bioadhesive polymers include carbomer homopolymer types A, B, and C, carbomer copolymers and interpolymers (polycarbophil and pemulene), cellulose derivatives such as hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), and hydroxypropyl methylcellulose (HPMC).

[0118] As used herein, the term "IVPT" refers to an in vitro release test (IVRT) involving the measurement of a drug released from a vehicle into a receptor medium, separated by an inert membrane, and used to quantify the amount of active pharmaceutical ingredient (API) released from a semi-solid dosage form or wipe and to determine its release rate. Details of how to perform IVPT can be found in Rath S, Kanfer IA Validated IVRT Method to Assess Topical Creams Containing Metronidazole Using a Novel Approach.Pharmaceutics.2020;12(2):119.Published 2020 Feb 3.doi:10.3390 / pharmaceutics12020119.

[0119] As used herein, the term "TEWL" is the amount of water that passively evaporates through the skin to the external environment due to the water vapor pressure gradient across the skin barrier, and is used to characterize skin barrier function. The average TEWL in humans is approximately 300-400 mL / day, but can be influenced by environmental and intrinsic factors. Transepidermal water loss (TEWL) can serve as a measure of the effectiveness of the barrier properties of the stratum corneum.

[0120] Wipe Manufacturing The material used for topical wipes can be nonwoven, similar to the type used for diapers and dryer sheets or woven fabrics. Traditional woven fabrics (woven fabrics) are made by weaving together fibers of silk, cotton, polyester, wool, and similar materials to form an interlocking matrix of loops called woven fabrics. Nonwoven fabrics (nonwoven fabrics), on the other hand, are made by a process in which a single sheet of material is extruded from a mass of separate fibers. Fibers such as cotton and rayon are used in this process, as well as plastic resins such as polyester, polyethylene, and polypropylene. The wipes are preferably made of nonwoven 100% cellulose (wood pulp) available from commercial sources. (https: / / pdicontract.com / ).

[0121] The topical wipes may optionally contain mild detergents mixed with moisturizers, fragrances, and preservatives. The wipes may optionally contain amphoteric surfactants, such as sodium diaminoacetate and cocophosphatidyl PG-dimonium chloride, used in the wipes. These chemicals do not strip the skin of its natural oils and also reduce the possibility of skin irritation. Gentleness is a major consideration, considering that the wipes come into contact with the delicate skin around the anus and genitals. Humectants, such as propylene glycol and glycerin, may optionally be added to prevent the solution from drying out prematurely and contribute to moisturizing the skin.

[0122] Additionally, oils such as mineral oil, lanolin, or silicones may be incorporated into the desired formulation (lidocaine HCl and nifedipine and suitable excipients) to aid in softening the skin. Thickeners, such as cellulose derivatives such as hydroxymethylcellulose, control the viscosity of the final product and keep it at the proper consistency. Other ingredients include preservatives such as methyl and propyl parabens to ensure that the solution does not support microbial growth. Fragrances may also be added to increase consumer appeal and help control body odor. Natural ingredients known to be gentle on the skin, such as aloe vera and oatmeal extracts, may also be added to further nourish the skin.

[0123] There are two main methods for constructing nonwoven fabrics: wet-laid and dry-laid. The dry-laid process is a "melt-blown" method used to make nonwoven fabrics from plastic resins. In this method, plastic pellets are melted and then extruded or forced through small holes by air pressure. When the stream of fibers cools, it condenses to form a sheet. Hot metal rollers are used to flatten and bond the fibers together.

[0124] The wet laid process is typically used for softer fabrics that use cotton blends, such as diaper wipes. In this wet process, the fibers are made into a liquid slurry with water and other chemicals. The resulting paste is compressed by rollers into a flat sheet and then dried to form long rolls of woven fabric. These rolls are then further processed and cut into narrow widths, and then perforated or cut into individual sheets. The finished fabric is classified with a dry weight of at least 1.4 oz / in2 (40 g / m2). The absorbency of the wipe is also an important requirement (a high quality wipe can absorb 200%-600% of its weight in solution).

[0125] Once the nonwoven fabric is prepared, it is fed from a storage roll onto a coating machine where the desired formulation (lidocaine HCl and nifedipine and appropriate excipients) is applied. Several methods can be used in this process. The formulation can be added by passing the fabric through a container containing the solution, or the formulation can be sprayed onto a sheet of fabric through a series of nozzles.

[0126] Alternatively, individual napkins may be packaged in sealed foil pouches. In this process, sheets of laminated foil are fed into an automated machine that folds the foil into small pouches and heat seals three sides to form an open-ended bag. At the same time, a separate conveyor line feeds nonwoven fabric into the pouch. A liquid delivery mechanism, including a conduit extending through the stuffing bar, injects a wetting liquid into the stack of napkins while simultaneously stuffing the napkin material. The pouch is then heat sealed to maintain wetness.

[0127] The dimensions of the wipes can vary depending on the nature of the use, with carry-on wipes often being smaller, such as about 6 inches by 3 inches. Conventional wipes, for example, range from about 8 inches by 8 inches, or 9 inches by 7 inches. The thickness of the wipes ranges from 0.5 mm to 1 mm. The wipes are made of materials such as polyester, polypropylene, cotton, wood pulp, or rayon fibers formed into sheets. The wipes may be individually packaged or in small or bulk packages. To help the active ingredients work better and ensure user compliance, the wipes are moistened with water and other inactive ingredients, such as surfactants and humectants. They may contain other ingredients, such as preservatives to prevent bacterial and mold growth. The wipes can be biodegradable and flushable so that they are safe for aseptic use. EXAMPLES

[0128] Example 1 - Solvent Screening Using Solubility Assays To identify a suitable solvent system, experiments were performed to evaluate the visual solubility of nifedipine and lidocaine HCl in a series of excipients. Solvent systems capable of dissolving both components were identified by this process. The solvents used in the analysis are listed in Table I. An aliquot of lidocaine HCl (e.g., 20-30 mg) was added to each of the scintillation vials containing solvent. The vials were then closed, placed on a multi-position stir plate at ambient conditions, and mixed for at least 15 minutes. The vials were then visually inspected periodically (1 hour) for the presence of turbidity, and if the drug had solubilized, additional aliquots of lidocaine HCl were added until saturation was achieved. The process was repeated separately with an aliquot of nifedipine following the same protocol described above.

[0129] The test was carried out for 24 hours while the samples were kept under stirring and visually inspected the following day. The final weight of each vial was obtained to determine the approximate solubility in each excipient. The results of the visual solubility assay are listed in Table II.

[0130] The solubility assay analysis showed that nifedipine is lipophilic in nature. Nifedipine does not partition easily into aqueous and oil phases, but can partition into solvent systems such as benzyl alcohol, DMI, propylene carbonate, transcutol (diethylene glycol monoethyl ether), and polysorbate 80. It also showed that lidocaine HCl is hydrophilic in nature and partitions easily into aqueous and glycol phases, such as propylene glycol, hexylene glycol, glycerin, PEG 400, along with benzyl alcohol, propylene carbonate, and transcutol (diethylene glycol monoethyl ether).

[0131] Transcutol-P and propylene glycol stabilized lidocaine HCL and enhanced the wettability of the dose from the nonwoven fabric. They also enhanced the transmucosal delivery of lidocaine HCL to the perianal tissues and improved its efficiency in functioning as a local anesthetic. Polysorbate 80 was found to reduce the surface tension of the formulations, such that the formulations containing the active pharmaceutical ingredients (nifedipine and lidocaine) could be easily impregnated onto the surface of the wipe. Polysorbate 80 also enhances delivery by increasing the wettability of the medicated wipe to the application site. Benzyl alcohol also acted as a preservative for the active pharmaceutical ingredients (nifedipine and lidocaine HCl). Propylene carbonate was useful in solubilizing nifedipine. Butylated hydroxytoluene (BHT) acted as an antioxidant and stabilizer for lidocaine HCl and nifedipine.

[0132] [Table 1]

[0133] [Table 2]

[0134] Example 2 - Drug excipient compatibility and stability testing Drug-excipient compatibility testing is generally performed with the primary objective of selecting dosage form components that are compatible with the therapeutic ingredients nifedipine and lidocaine HCl. Various classes of excipients, such as antioxidants, penetration enhancers, humectants, dispersants, viscosity modifiers, emollients, film formers, preservatives, tailing solvents, co-solvents, etc., were tested in combination with the therapeutic ingredients (nifedipine and lidocaine HCl) to evaluate any possible incompatibility of the formulation when exposed to the excipients. Figure 1 shows a schematic process of optimizing each category of excipients and optimal concentration to arrive at a formulation containing the APIs (lidocaine HCl and nifedipine) and then impregnating the wipe with this formulation to create a topical therapeutic wipe capable of treating anal fissures.

[0135] Most excipients have no direct pharmacological action, but are important in facilitating administration, regulating the release of the active ingredient, and stabilizing the drug against degradation. Potential interactions between the drug and excipients affect the chemical, physical, bioavailability, and stability of the therapeutic ingredient. Drug-excipient mixtures were prepared by making solutions consisting of drug substance dissolved in a suitable solvent (benzyl alcohol, propylene carbonate, transcutol) at a strength of 1.5% by weight and at target concentrations of 0.3% by weight for nifedipine and / or lidocaine HCl.

[0136] Four sample sets were prepared for testing. Each sample set had 17 vials, one per excipient tested and one control vial containing the active compound without excipient. The first sample set (I) had only nifedipine (0.3% by weight) as the therapeutic compound, and each of the excipients shown in Table III were added individually to form a solution, which was mixed and stored in a vial. The second sample set (II) had only lidocaine HCl (1.5% by weight) as the therapeutic compound, and each of the excipients shown in Table III were added to form a solution, which was mixed and stored in a vial. The third sample set (III) had both nifedipine (0.3% by weight) and lidocaine HCl (1.5% by weight) as the therapeutic compound, and each of the excipients shown in Table III were added to form a solution, which was mixed and stored in a vial. A fourth sample set (IV) served as a placebo control that contained neither lidocaine HCl nor nifedipine, but only the solvent was mixed with each of the excipients shown in Table III to form a solution and stored in a vial. A vial from each sample set was divided into two equally sized smaller vials (A and B). Vial A from each sample set was then subjected to analysis after storage at room temperature, and vial B from each sample set was subjected to analysis after storage under elevated temperature (40° C. and 75% relative humidity) conditions. The vials were stored for four weeks, and the vials were analyzed at two and four weeks.

[0137] [Table 3]

[0138] A vial from each batch was (a) monitored for visual turbidity, (b) monitored under a microscope for signs of precipitation or crystallization, (c) measured for pH, and (d) performed HPLC to see if there were any degradation product peaks (T0 measurement). Vials from each batch were then stored at room temperature (25°C and 60% relative humidity) for 2 weeks and then checked for visual turbidity, analysis under a microscope, and pH measurement as above (T-2 measurement). Vials from each batch were then stored at room temperature for another 2 weeks (4 weeks total) and the same analysis was repeated (T-4 measurement). The experiment was repeated in duplicate to determine if the added excipients were compatible with the active ingredients (nifedipine and lidocaine HCl) and if they had a stable shelf life at room temperature after 2-4 weeks of storage.

[0139] The B vials of each batch were (a) monitored for visual turbidity, (b) monitored under a microscope for signs of precipitation or crystallization, (c) measured for pH, and (d) performed HPLC to see if there were any degradation product peaks (T0 measurement). Vials from each batch were then stored at elevated temperature (40°C and 75% relative humidity) for 2 weeks and then checked for visual turbidity, analysis under a microscope, and pH measurement as above (T-2 measurement). Vials from each batch were then stored at elevated temperature for an additional 2 weeks (4 weeks total) and the same analysis was repeated (T-4 measurement). The experiment was repeated in duplicate to determine if the added excipients were compatible with the active ingredients (nifedipine and lidocaine HCl) and if they had a stable shelf life when stored at elevated temperature conditions for 2-4 weeks.

[0140] T0 measurements of the first samples set up at both temperatures (RT and 40°C) showed that the control sample (only nifedipine) appeared to be stable at T0 weeks without impurities. No significant degradation (>5%) was observed for any of the excipient combinations at T0. T4 measurements of the first samples set up at both temperatures (RT and 40°C) showed that the control sample (only nifedipine) appeared to be stable at T4 weeks without impurities. Significant degradation (>5%) was observed for the DEC combination of Transcutol, DMI, benzyl alcohol, oleyl alcohol, PEG400, and ascorbic acid, indicating incompatibility. Slight degradation was also observed with the Tween 80 combination. Degradation was significantly reduced when the antioxidant BHT was added to the formulation.

[0141] T0 measurements of the second sample set at both temperatures (RT and 40°C) showed that the control sample (lidocaine HCl only) appeared to be stable at T0 weeks without impurities. No significant degradation (>5%) was observed in any of the excipient combinations at T0. T4 measurements of the second sample set at both temperatures (RT and 40°C) showed that the control sample (lidocaine HCl only) appeared to be stable at T4 weeks without impurities. Significant degradation (>5%) was observed in the DEC combination of Transcutol, DMI, and PEG400, indicating incompatibility. Slight degradation was also observed in the combinations with benzyl alcohol and oleyl alcohol.

[0142] T0 measurements of the third sample set at both temperatures (RT and 40°C) showed that the control sample (nifedipine and lidocaine HCl) appeared stable at T0 weeks without impurities. No significant degradation (>5%) was observed for any of the excipient combinations at T0. T4 measurements of the second sample set at both temperatures (RT and 40°C) showed similar results to the first and second sample sets. Based on the results of the sample sets, six formulations with specific concentrations of excipients were selected for further analysis.

[0143] Example 3 - Stability analysis of formulations The following six formulations were selected for further stability analysis:

[0144] [Table 4]

[0145] [Table 5]

[0146] [Table 6]

[0147] [Table 7]

[0148] [Table 8]

[0149] [Table 9]

[0150] Each formulation was subjected to three different temperature conditions (25° C. / RH60%, 30° C. / RH65%, 40° C. / RH75%) and four different storage time points (T0, 1 month, 2 months, and 3 months), and the formulations were then (a) monitored for visual turbidity, (b) monitored under a microscope to check for signs of precipitation or crystallization, (c) measured pH, and (d) performed HPLC to check for the presence of degradation product peaks after each time point mentioned in Example 2.

[0151] T-0 measurements showed that all six formulations were stable and no degradation profile was observed on HPLC even when exposed to different temperatures (25°C, 30°C, and 40°C).

[0152] T-1 month measurements showed that all formulations were stable except for Formulation-1. Three impurities (RRT 0.293, RRT 2.630, and RRT 2.796) were observed in the FI formulation at a total concentration of approximately 0.75% and were not observed in the other formulations.

[0153] The T-2 month measurements showed that the FI formulation showed some degradation. Three impurities (RRT 0.293, RRT 2.630, and RRT 2.796) were observed in the FI formulation at a total of about 1.1% at 40°C and about 0.5% at 25°C, and were not observed in the other formulations. Similarly, the F6 formulation showed impurities of 0.1-0.2% total at 40°C and RRT 2.672.

[0154] The T-3 month measurement showed that the FI and F-II formulations showed some degradation. The impurities at RRT 0.106 observed in the FI and F-II formulations were still consistent with the previous time points. In the FI formulation, three impurities (RRT 0.293, RRT 2.630, and RRT 2.796) were observed totaling about 1.4% at 40°C and about 0.8% at 25°C, and were not observed in the other formulations. No impurities were observed in the F-III formulation. The F-IV, FV, and F-VI formulations did not show a significant increase in impurities from the previous time points.

[0155] Example 4 - Saturation Loading Capacity of Wipes Formulation III was selected to be tested for its ability to be loaded onto wipes.The protocol described in this example can be applied to any formulation disclosed herein.A placebo solution using formulation composition 3 without active substance was used to establish saturation loading content.

[0156] As shown in FIG. 2, the formulations were applied to the wipes by either dipping, pipetting, or spraying techniques.

[0157] immersion For immersion, the tare dry weight of an approximately 6×4 inch wipe was measured in a tared container and then added to a container containing approximately 30 g of placebo formulation for each addition time. After the wipe was immersed in the formulation for approximately 1 minute, the wipe was allowed to dry as shown in FIG. 3. Each drying step took approximately 15 minutes. Drying times were estimated based on the amount of dripping, with very little dripping observed at 15 minutes, assumed to be the point at which at least 50% of drying had occurred. The wipe was then re-weighed to determine the dry weight of the wipe after one formulation addition step.

[0158] Pipetting For pipetting, a 6×4 inch wipe was tared dry weight in a tared container and then approximately 5 g of placebo formulation was pipetted onto the wipe for each addition time. The 5 g addition was determined based on previous studies that showed that adding more than 5 g of formulation each time showed dripping. After the wipe was immersed in the formulation for approximately 1 minute, the wipe was allowed to dry as shown in FIG. 3. The wipe was then weighed again to determine the dry weight of the wipe after one formulation addition step.

[0159] spray For spraying, the dry tare weight of an approximately 6×4 inch wipe was measured in a tared container, and then approximately 5 g of placebo formulation was sprayed onto the wipe for each addition time using a spray bottle. After the wipe was immersed in the formulation for approximately 1 minute, the wipe was allowed to dry as shown in FIG. 3. The wipe was then weighed again to determine the dry weight of the wipe after one formulation addition step.

[0160] This study shows that drying time, dosing times, and application process do not play a significant role in controlling or limiting the ability of the formulation to saturate the wipes. The following tables and figures (Figures 4 and 5) provide study details and their respective calculations for weight of impregnated formulation, saturation loading, and % saturation loading.

[0161] Figure 4 shows that the weight of the impregnated formulation ranged from 4.8g to 6.05g with no trend with respect to the number of additions or application process. The wipes were allowed to dry for 45 minutes before weighing. The saturation loading was found to be 5.5-6.5 with no trend with respect to the number of additions or application process. The saturation loading percentage was found to be in the range of 550-650 with no trend with respect to the number of additions or application process. Thus, the results showed that the number of additions and application process did not have any effect on the amount of formulation impregnated or the saturation loading of the wipes.

[0162] The same experiment was repeated with an increased drying time of 15 minutes. The results of the experiment are shown in Figure 5. As with the 45 minute drying time, the weight of the impregnated formulation ranged from 3.6 g to 5.8 g, with no trends in terms of the number of additions or application process. The saturation loading was found to be 4.2 to 6.2, with no trends in terms of the number of additions or application process. The saturation loading percentage was found to be in the range of 420 to 620, with no trends in terms of the number of additions or application process. Thus, the results show that the number of additions and application process have no effect whatsoever on the amount of formulation impregnated or the saturation loading of the wipes.

[0163] To further establish the uniformity of loading, calibration tests were carried out using wipes of different weights and sizes by immersing them in the formulation and subjecting them to the same process parameters. The weight of the wipes was measured before and after loading the formulation. The following table shows the results obtained.

[0164] [Table 10]

[0165] The calibration curve in Figure 6 shows that this loading is consistent with the different wipe sizes, indicating that the formulation is evenly distributed within the wipe.

[0166] Example 5 - In vitro permeation testing of therapeutic wipes In vitro permeation testing (IVPT) is designed to determine the in vitro permeation profile of a specific active pharmaceutical ingredient (API) formulated into a well-defined topical product into target human tissues. The permeation profile of a specific API is not only determined by the physical and chemical properties of the API (size, solubility, lipophilicity, logP, etc.), but is also influenced by the microstructural properties of the topical product (viscosity, selected permeation enhancers, emulsifiers, etc.) and the dosage form. Thus, IVPT is an important tool that not only provides information and understanding on the viability of nifedipine HCl and lidocaine HCl in a single formulation, but also shows the effect of various formulation prototypes on the ability of the API to reach the desired target site of action.

[0167] The IVPT test protocol is disclosed in Santos et al. (Santos LL, Swofford NJ, Santiago BG. In Vitro Permeation Test (IVPT) for Pharmacokinetic Assessment of Topical Dermatological Formulations. Curr Protoc Pharmacol. 2020 Dec;91(1):e79).

[0168] In vitro permeation studies (IVPT) were performed ex vivo across human cryopreserved cadaveric perianal tissue to compare the skin penetration of a topical solution containing formulation III containing 1.5% lidocaine HC1 and 0.3% nifedipine, its corresponding solution on wipes, and an ointment formulation. The experiment can be repeated with other formulations (I-II and IV-VI) following the same procedures disclosed herein.

[0169] Reagents and materials a) Formulation III of 1.5% lidocaine HCl and 0.3% nifedipine i. Formulation III (F1) as a solution ii. Formulation III impregnated on wipes (according to the protocol of Example 4) (F2) iii. Formulation III as an ointment (F3) b) Cryopreserved human cadaveric perianal tissue (thickness 500±250μm) c) Quadruplicates were used per formulation. d) 1x phosphate buffered saline (PBS, pH 7.4) e) Homogenization solution (50 / 50 methanol / LCMS grade water) f) 20mL scintillation vial g) 6.0 mL homogenization vial containing ceramic beads h) 96-well plates for mass spectrometry i) Washing solvent (70% by volume ethanol)

[0170] device a) Automated vertical in-line flow-through cell (PermeGear collector FC 33, version 3.1) b) Positive Displacement Pipette c) Calipers / Measuring Gauges d) Water evaporation meter (Delphin Technologies) e) Infrared / Laser Thermometer f) Probe thermometer g) Tissue homogenizer h) Laboratory oven at 60°C i) Mass spectrometer j) Centrifuge

[0171] Cryopreserved human cadaveric perianal tissue was obtained from a commercial source and stored at -80 °C upon arrival. Skin tissue was thawed at room temperature and examined for visible holes, damage, extensive stretching, or scarring. Transepidermal water loss (TEWL or TWL) is commonly used to characterize skin tissue barrier function. The TEWL value of each skin tissue sample was measured to estimate tissue integrity using a water transpiration meter. A low TEWL value is generally characteristic of intact tissue barrier function. Measure and record the TEWL of each diffusion cell (Franz diffusion cell) prior to application of formulations (F1-F3).

[0172] An automated in-line flow-through diffusion cell system (PermeGear collector FC 33, version 3.1) was used to evaluate the drugs / APIs in tissue permeation experiments. An ambient environmental controlled laboratory temperature range of 21°C ± 2°C and humidity range of 50% ± 20% relative humidity was maintained throughout the IVPT studies. The flow-through diffusion cell system was equilibrated with receptor media.

[0173] The heater and circulator were adjusted to maintain the skin sample at 32°C ± 1°C. The diffusion cell was placed and heated while supporting the movable arm of the system to maintain the skin surface temperature (32°C ± 1°C). The cell was connected to a multichannel peristaltic pump and the outlet of the diffusion cell was directed to drip into a 20 mL scintillation vial. The skin tissue slices were cut into 1.5 x 1.5 cm slices and mounted on the diffusion cell with the epidermis / stratum corneum facing up. The donor compartment block was placed on the skin tissue (donor chamber above the stratum corneum) and secured with stainless steel clamps to seal without leakage. Air bubbles were removed by inverting the diffusion cell and visually confirmed through the glass window below the diffusion cell. The pump was adjusted to maintain a flow rate of 30 μL / min (1.8 mL / h) to provide adequate sink conditions.

[0174] The diffusion cells were allowed to equilibrate for approximately 30 minutes. Any cells that showed water accumulation on top of the tissue were excluded from the analysis. After equilibration, the temperature of each cell was measured using infrared or a suitable thermometer. The skin surface temperature was maintained stable at 32° C.±1° C. T "0" samples were collected at 30 μL / min (1.8 mL / hr) for 30 minutes prior to dosing.

[0175] Using a positive displacement pipette set to deliver a volume of 10 μL appropriately, each formulation (F1, F2, F3) was evenly dispensed onto the skin tissue surface in alternating order on the continuous diffusion cell. The donor chamber was kept at near ambient conditions. Fractions were collected at intervals marked in the protocol for up to 24 hours. At the end of the study, untreated skin samples were collected, followed by treated skin.

[0176] The cleaned and taped skin was placed dermis side down on aluminum foil. If applicable, the perianal tissue sample was placed in an oven set at 60°C for approximately 2.0 minutes. Forceps were used to separate the epidermis from the dermis. The cleaned tissues were placed into their respective pre-weighed labeled vials and the weight of the tissue was recorded. The untreated skin sample was placed into the vials first, followed by the treated skin.

[0177] Clean epidermal and dermal tissues were placed into respective pre-weighed labeled vials and the weight of the tissue was recorded. Epidermal and dermal tissue samples were homogenized using an Omni Prep homogenizer according to the following protocol. a) Using a new scalpel, the tissue was minced properly and evenly. b) 2000 μL of homogenization solvent (50:50 by volume methanol / LC-MS grade water) was added to the labeled tube containing the skin sample. c) The tissue was homogenized at 4.5 m / s for 3×30 sec with a 45 sec pause. d) After homogenization was completed, 200 μL of this aliquot was used for API (Nifedipine and Lidocaine HCl) extraction with 800 μL of acetonitrile, vortexed briefly, and then sonicated in a water bath for 10 minutes. e) Centrifuge the vial at 10,000 RPM for 5 minutes at 5°C. f) The supernatant shall be used for mass spectrometry to confirm the presence of API and to quantify the amount of API (LC / MS).

[0178] Recovery of the formulation on the surface of the skin tissue was performed by wiping with one dry swab, one wet swab soaked in a cleaning solvent of 70% ethanol (v / v), and one dry swab, followed by one continuous tape strip. The swabs and tape strips were collected in labeled vials for analysis. The tissue was then subjected to homogenization and protein disruption to extract the adsorbed formulation. Untreated skin samples were first washed, and then the skin was placed on a clean dissection board. a) 10 mL of ACN was added to the tape and swab samples, the samples were collected, placed on a stir plate and stirred at 600 RPM overnight. b) A 200 μL aliquot of the supernatant was used for mass spectrometry.

[0179] All samples were stored at 2-8°C for short-term storage (<1 week) and at -20°C for long-term storage (>1 week) until analysis by LC-MS / MS. Analysis showed that cumulative permeation of lidocaine HCl throughout tissue was higher in the solution-based delivery formulation (F1) compared with the wipe-based (F2) and ointment-based delivery formulations (F3).

[0180] The formula for calculating the cumulative permeation is the concentration of the analyte x the volume of the sample, where the volume of the sample is added after each collection to the same collected at the previous time point. Jmax is the calculated maximum flux achieved by each train over the study period. The formula for mathematically calculating Jmax is the partition coefficient Kp, expressed in cm / hr, multiplied by the diffusive properties of the analyte by the water saturation solubility Csat-max, expressed in mg / L. Jmax=Kp x Csat-max.

[0181] Interestingly, the cumulative permeation of lidocaine HCl throughout the tissue was higher for the wipe-based delivery formulation (F2) compared to the ointment-based delivery formulation (F3) (see Figure 7). A similar trend was seen where the mean flux measurements were higher for F1 compared to F2 and F3. Similarly, the mean flux for F2 was higher than that for F3 (see Figure 8).

[0182] The analysis also showed that the cumulative permeation of nifedipine through the tissue was higher for the solution-based delivery formulation (F1) compared to the wipe-based delivery formulation (F2) and the ointment-based delivery formulation (F3). Interestingly, the cumulative permeation of nifedipine through the tissue was higher for the wipe-based delivery formulation (F2) compared to the ointment-based delivery formulation (F3). (See Figure 9). A similar trend was seen when the average flux measurements were higher for F1 compared to F2 and F3. Similarly, the average flux for F2 was higher than that for F3. (See Figure 10).

[0183] Lidocaine HCl retention in tissue for the three delivery formulations is shown in Figure 11. Lidocaine HCl retention in tissue was higher for the solution-based delivery formulation (F1) compared to the wipe-based delivery formulation (F2) and the ointment-based delivery formulation (F3). Similarly, lidocaine HCl retention in tissue was higher for the wipe-based delivery formulation (F2) than the ointment-based delivery formulation (F3).

[0184] The retention of nifedipine in tissue for the three delivery formulations is shown in Figure 12. The retention of nifedipine in tissue was higher for the solution-based delivery formulation (F1) compared to the wipe-based delivery formulation (F2) and the ointment-based delivery formulation (F3). Similarly, the retention of nifedipine in tissue was higher for the wipe-based delivery formulation (F2) than the ointment-based delivery formulation (F3).

[0185] Experiments have shown that wipe-based delivery is more effective than ointment-based delivery of nifedipine and lidocaine HCl. Wipe-delivered formulations of nifedipine and lidocaine HCl can penetrate through perianal tissues for up to 24 hours, as observed in IVPT studies. Topical solutions provide absolute availability of drug molecules at the site of action, but are impractical to apply in terms of patient use and compliance.

[0186] Incorporation by Reference All publications and patents mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.

[0187] Other embodiments While specific embodiments of the subject matter have been discussed, the above specification is illustrative and not limiting. Many variations will become apparent to those skilled in the art upon review of this specification and the following claims. The full scope of the invention should be determined by reference to the claims, along with such variations, along with their full scope of equivalents, and this specification.

Claims

1. A topical wipe comprising a fibrous substrate containing lidocaine at a concentration of 0.15% to 7.5% by weight and nifedipine at a concentration of 0.15% to 1.5% by weight.

2. The topical wipe of claim 1, wherein the fibrous substrate comprises lidocaine at a concentration of 1.5% to 5% by weight and nifedipine at a concentration of 0.3% to 1% by weight.

3. The topical wipe of claim 1 or 2, wherein the wipe further comprises at least one excipient.

4. The topical wipe of claim 3, wherein the excipient is selected from the group consisting of antioxidants, penetration enhancers, preservatives, humectants, dispersants, humectants, emulsifiers, plasticizers, surfactants, polymers, viscosity modifiers, softeners, film formers, tailing solvents, co-solvents, and / or oils.

5. The topical wipe of claim 1 or 2, wherein the wipe further comprises an alcohol solvent.

6. The topical wipe of claim 1 or 2, wherein the wipe further comprises a solvent selected from the group consisting of water, propylene glycol, and hexylene glycol.

7. The topical wipe of claim 1 or 2, wherein the wipe further comprises one or more of benzyl alcohol, transcutol, propylene carbonate, polysorbate 80, BHT, PEG 400, glycerin and hexylene glycol.

8. A topical wipe as described in claim 1 or 2, wherein the wipe is made from fibers.

9. The topical wipe of claim 4, wherein the penetration enhancer is selected from the group consisting of benzyl alcohol, dimethyl isosorbide (DMI), propylene glycol, hexylene glycol, isopropyl alcohol, ethanol, phenoxyethanol, oleic acid, oleyl alcohol, isopropyl myristate, medium chain triglycerides (MCT), and transcutol.

10. The topical wipe of claim 4, wherein the humectant is selected from the group consisting of propylene carbonate, glycerin, pentylene glycol, butylene glycol, aloe vera juice, extract, hexylene glycol, hyaluronic acid, and lactic acid.

11. The topical wipe of claim 4, wherein the emulsifier is selected from the group consisting of polysorbate (20-80), Span-80, PEG-40, hydrogenated castor oil, sodium lauryl sulfate (SLS), poloxamer, sorbitan (20-85), and glyceryl monooleate (GMO).

12. The topical wipe of claim 4, wherein the surfactant is selected from the group consisting of PEG 400, tween-80, oleyl alcohol, glycerin, hexylene glycol, and propylene glycol.

13. The topical wipe of claim 4, wherein the antioxidant is selected from the group consisting of butylated hydroxytoluene (BHT), alpha-tocopherol, propyl gallate, squalene ascorbate, ascorbyl palmitate, sodium thiosulfate, and sodium metabisulfate.

14. The topical wipe of claim 4, wherein the polymer is selected from the group consisting of carbomer homopolymer types A, B and C, carbomer copolymers, interpolymers, polycarbophil, pemulen, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), and hydroxypropyl methylcellulose (HPMC).

15. A container containing a plurality of the topical wipes according to claim 1 or 2, preferably comprising a soft pack or a hard pack.

16. A topical wipe as described in claim 1 or 2 for use in the treatment or amelioration of anal fissure in a subject in need thereof, wherein said use in treating or ameliorating comprises the step of applying the topical wipe to the perianal area of ​​the subject, thereby providing therapeutic relief.

17. The topical wipe of claim 16, wherein the topical wipe is applied to anal tissue within 1 cm of the subject's anal canal, thereby providing therapeutic relief, or is applied to the subject's external anal sphincter, thereby providing therapeutic relief.

18. A topical wipe comprising a fibrous substrate, the fibrous substrate comprising lidocaine in a concentration of 5% and nifedipine in a concentration of 1%.

19. The topical wipe of claim 18, wherein the wipe further comprises at least one excipient selected from the group consisting of antioxidants, penetration enhancers, preservatives, humectants, dispersants, humectants, emulsifiers, plasticizers, surfactants, polymers, viscosity modifiers, emollients, film formers, tailing solvents, co-solvents, and / or oils; the penetration enhancer is selected from the group consisting of benzyl alcohol, dimethyl isosorbide (DMI), propylene glycol, hexylene glycol, isopropyl alcohol, ethanol, phenoxyethanol, oleic acid, oleyl alcohol, isopropyl myristate, medium chain triglycerides (MCT), and transcutol, and / or said humectant is selected from the group consisting of propylene carbonate, glycerin, pentylene glycol, butylene glycol, aloe vera juice, extract, hexylene glycol, hyaluronic acid, and lactic acid; and / or said emulsifier is selected from the group consisting of polysorbates (20-80), Span-80, PEG-40, hydrogenated castor oil, sodium lauryl sulfate (SLS), poloxamer, sorbitan (20-85) and glyceryl monooleate (GMO); and / or said surfactant is selected from the group consisting of PEG 400, tween-80, oleyl alcohol, glycerin, hexylene glycol and propylene glycol; and / or said antioxidant is selected from the group consisting of butylated hydroxytoluene (BHT), alpha-tocopherol, propyl gallate, squalene ascorbate, ascorbyl palmitate, sodium thiosulfate, and sodium metabisulfate; and / or - topical wipes, wherein the polymer is selected from the group consisting of carbomer homopolymer types A, B and C, carbomer copolymers, interpolymers, polycarbophil, pemulene, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), and hydroxypropyl methylcellulose (HPMC).

20. The topical wipe of claim 18 or 19, wherein the fibrous substrate further comprises a solvent selected from the group consisting of water, propylene glycol, hexylene glycol and alcohol solvents, preferably a solvent selected from the group consisting of water, propylene glycol and hexylene glycol.

21. A topical wipe as described in claim 18 or 19, wherein the wipe is made from fibers, preferably from nonwoven or woven fibers.

22. The topical wipe of claim 18 or 19, wherein the wipe is generally rectangular.

23. The topical wipe of claim 18 or 19, wherein the wipe is individually packaged for single use.

24. The topical wipe of claim 18 or 19, wherein the wipe further comprises one or more of benzyl alcohol, transcutol, propylene carbonate, polysorbate 80, BHT, glycerin and hexylene glycol.

25. The topical wipe of claim 24, comprising: benzyl alcohol in a concentration of at least 2% by weight, or Transcutol at a concentration of 30% to 40% by weight, or Propylene carbonate in a concentration of at least 4% by weight, or Polysorbate 80 at a concentration of at least 2% by weight, or BHT at a concentration of at least 0.2% by weight, or Propylene glycol in a concentration of 30% to 60% by weight, or Glycerin at a concentration of at least 15% by weight, or A topical wipe comprising: hexylene glycol in a concentration of at least 10% by weight.

26. A container containing a plurality of the topical wipes of claim 18 or 19, preferably said container containing a soft pack or a hard pack.

27. A kit comprising the topical wipe of claim 18 or 19 as a plurality of individually rolled topical wipes.

28. A method for producing a topical wipe comprising nifedipine at a concentration of at least 0.3% to 1.5% by weight and lidocaine at a concentration of at least 0.15% to 0.7% by weight, the method comprising the steps of providing a wipe; applying a formulation comprising at least 0.3% nifedipine and at least 0.15% lidocaine by weight; drying the wipe for a sufficient period of time; and packaging the wipe in an airtight container or pouch.

29. A composition comprising a soluble formulation, comprising: The soluble formulation comprises: Nifedipine in a concentration of at least 1.5%, 1%, 0.5%, or 0.4%, or 0.3%, or 0.2%, or 0.1% and lidocaine in a concentration of at least 0.15%, or Nifedipine in a concentration of at least 0.3% and lidocaine in a concentration of at least 0.5%, 0.8%, 1%, 1.2%, 1.5%, or 2%, or 2.5%, or 3%, or 3.5%, or 4%, or 4.5%, or 5%, or 6%, or 7%, or 7.5%, or Nifedipine in a concentration of at least 1.5%, 1%, 0.5%, or 0.4%, or 0.3%, or 0.2%, or 0.1%, and lidocaine in a concentration of at least 0.15%, 0.3%, 0.5%, 1%, 1.2%, 1.5%, or 2%, or 2.5%, or 3%, or 3.5%, or 4%, or 4.5%, or 5%, or 6%, or 7%, or 7.5%, or A composition comprising nifedipine in a concentration of 0.3-1.5% and lidocaine in a concentration of 1.5-7.5%.

30. Nifedipine is selected from the group consisting of anhydrous nifedipine, nifedipine monohydrate, and nifedipine dihydrate, or 30. The composition of claim 29, wherein the lidocaine is selected from the group consisting of anhydrous lidocaine, lidocaine monohydrate, and lidocaine dihydrate.

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