US20230158051A1

US20230158051A1 - Pharmaceutical paste formulations for site specific application

Info

Publication number: US20230158051A1
Application number: US18/099,520
Authority: US
Inventors: Manesh A Dixit; Partha S Sen; Rahul Botkar; Ashim K Sarkar
Original assignee: Uspharma Ltd
Current assignee: First Time Us Generics LLC; Uspharma Ltd
Priority date: 2019-08-30
Filing date: 2023-01-20
Publication date: 2023-05-25
Also published as: US20210060045A1; US11590151B2

Abstract

A pharmaceutical paste formulation containing an active ingredient, an API solubilizer, a cross-linking agent, a consistency improver, a rheology modifier, a humectant, and a liquid base.

Description

RELATED APPLICATIONS

The present application is a continuation of U.S. patent application Ser. No. 17/002,183 filed Aug. 25, 2020, entitled Pharmaceutical Paste Formulations for Site Specific Application, which claims the benefit of U.S. Provisional Patent Application Ser. No. 62/893,952, filed Aug. 30, 2019, entitled Pharmaceutical Paste Formulations for Site Specific Application, each of which is hereby incorporated in its entirety by reference herein.

BACKGROUND

1. Field

The present invention relates to improved pharmaceutical gel formulations having enhanced spreadability and that can be applied using a wide range of devices for site specific application (e.g., single-and-multi-use squeezable tubes, syringes, etc.).

2. Discussion of Prior Art

Recurrent aphthous stomatitis (commonly referred to as canker sores, hereinafter referred to as “RAS”) is a common oral disorder affecting over half of the population of the United States where painful circular yellowish sores develop on the oral mucosa. RAS typically affects the softer parts of the mouth that move, such as the tongue, soft palate, cheeks, and lips. RAS is said to be “recurrent” because a sore usually reappears in the same or a new location after healing. In some cases, multiple ulcers are present, some of which may be healing while others are just starting to appear. There are three main subtypes of RAS: (1) minor aphthous stomatitis; (2) major aphthous stomatitis; and (3) herpetiform aphthous stomatitis. Minor aphthous stomatitis is the most common subtype, constituting more than 80% of RAS cases, and is generally characterized by small (i.e., less than 1 cm in diameter) sores that heal in approximately 1-week and do not typically result in the formation of scar tissue. Major aphthous stomatitis is the second most common form of RAS, constituting approximately 15% of RAS cases, and is generally characterized by slightly larger (i.e., greater than 1 cm in diameter) sores that take longer to heal (i.e., two or more weeks) and are extremely painful and often result in the formation of scar tissue. Herpetiform aphthous stomatitis is the least common subtype of RAS, occurring in less than 5% of RAS cases, and is generally characterized by clusters of very small ulcers (i.e., less than 1 mm) that typically heal in approximately 1-week.
The treatment of RAS with sucralfate is generally known. For instance, ProThelial™ “is polymerized sucralfate malate paste that forms a protective layer over the oral mucosa by adhering to the mucosal surface” marketed by Mueller Medical International LLC. ProThelial™ is a thick gel packaged in a wide mouth bottle. ProThelial™ users are instructed to remove the product from the bottle using a spoon and to apply the product to the affected area using the “tongue to apply paste throughout the mouth (as if using tongue to remove peanut butter from teeth).” Known sucralfate formulations for treating RAS require broad range application to the entire mouth by swishing/gargling and tend to dry-up quickly in storage due to high solid content and sucralfate's high water absorbing capacity.
Thus, there is a need for sucralfate formulations that can be applied to ulcers on a site specific basis using an applicator, such as a squeezable tube, and that will not dry and harden in storage.
The foregoing background discussion is intended to provide information related to the present invention which is not necessarily prior art.

SUMMARY OF THE INVENTION

Pharmaceutical gel formulations according to the present invention provide several advantages over the prior art. For instance, certain embodiments relate to soothing mucoadhesive pharmaceutical gels for treating RAS that: can be provided to patients in site specific applicators (such as a squeezable tube), which enable direct application on the lesions; spread easily and adhere better (relative to the prior art) to the affected area; will not exhibit increased viscosity over a longer shelf-life due to moisture loss and/or reactions between excipients; provide reduced irritability and improved taste; do not require the patient or physician to perform additional processing steps prior to application; and/or are free of preservatives. It should be understood that the present invention is not limited to the foregoing advantages and that other technical advantages may become readily apparent to one of ordinary skill in the art after review of the description.
Pharmaceutical gel formulations according to certain aspects of the present invention have Bingham plastic rheology, which means the inventive formulations behave as viscoplastic (i.e., behaves as a rigid body at low stresses but flows as a viscous fluid at high stress). This rheological property enables users to accurately deliver the pharmaceutical gel directly on the ulcerative lesions using a site specific applicator (such as a squeezable tube having an applicator tip). Such pharmaceutical gel formulations can be described as a congealed base having a high proportion of solids in a finely dispersed form.
Pharmaceutical gel formulations according to the present invention retain moisture; for instance, by inclusion of one or more humectants and/or rheology modifiers. Moisture retention facilitates fluidity by, among other things, reducing resistance to movement of solid particles in the dispersed phase. Known sucralfate products do not retain adequate moisture, and solids in the dispersed phase tend to aggregate, which contributes to their higher viscosity and limited application.
Certain aspects of the present invention relate to a medical device consisting of a ready-to-use topical pharmaceutical formulation contained within functional packaging designed to enable the user to apply the formulation directly on the treatment location.
The foregoing summary is provided to introduce a selection of concepts in a simplified form that are further described below in the detailed description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter. Other aspects and advantages of the present invention will be apparent from the following detailed description, working examples, and the accompanying drawing figures.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

Certain aspects of certain embodiments of the invention are described in detail below with reference to the attached figures, wherein:

FIG. 1 is a side perspective view of a medical device configured to contain a pharmaceutical gel formulation manufactured in accordance with certain embodiments of the present invention; and

FIG. 2 is an enlarged, partially sectioned cross-sectional view of the medical device of FIG. 1 .

The figures do not limit the present invention to the specific embodiments disclosed and described herein. The emphasis instead being placed upon clearly illustrating certain principles of a preferred embodiment.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In addition to the other terms expressly defined herein, for the purposes of this disclosure and claims, the following terms, units, symbols, words, abbreviations, acronyms, phrases, and/or other things shall have the respective meanings assigned to them as follows (and cognate expressions shall bear corresponding meanings): the symbol “%” means percent; the unit symbol “% w/w” means percent-by-weight, the amount/concentration of one or more components in a group of components, which can be calculated by dividing the numerical value for the mass of one or more components in a group of components by the numerical value for the mass of all of the components in the group and multiplying the quotient by 100; the unit symbol “° C.” means degree(s) in Celsius, a unit of temperature on the Celsius scale; the unit symbol “cfu” means colony-forming unit, the number of viable microorganisms in a sample; the unit symbol “cfu/g” means colony-forming units per gram, the number of viable microorganisms per gram of a sample; the unit symbol “cm” means centimeter, a unit of length equal to one hundredth of a meter; the acronym “EAA” means ethylene acrylic acid copolymers; the acronym “EDTA” means the compound sodium ethylenediaminetetraacetic acid; the unit symbol “g” means gram(s), a unit of mass equal to 0.001 kg; the unit symbol “mm” means millimeter, a unit of length equal to one thousandth of a meter; the acronym “NMT” means not more than; the symbol “pH” refers to a measure of the hydrogen ion concentration in solution and is also referred to as the degree of acidity or alkalinity; the phrases “pharmaceutical gel”, “sucralfate gel”, and “paste/gel” refer to the dosage form (i.e., the physical form in which a drug is produced and dispensed) gel and/or paste as defined by the U.S. Food and Drug Administration; the unit symbol “RH” means relative humidity; the acronym “rpm” means rotations per minute; and the unit symbol “μ” means micron, which is equal to 0.001 mm.
Certain aspects of the present invention are directed to pharmaceutical gel formulations. In certain embodiments, pharmaceutical gel formulations preferably include one or more: active pharmaceutical ingredients; crosslinking agents; rheology modifiers; liquid bases; taste modifiers; and other excipients. However, those having ordinary skill in the art will understand that other formulations are within the scope of the present invention.
In certain embodiments, the active pharmaceutical ingredient is sucralfate. Sucralfate is a disaccharide polysulfate-aluminum compound, more specifically referred to as alpha-D-glucopyranoside, beta-D-fructofuranosyl, catkins (hydrogen sulfate), aluminum complex having the structure shown below:
Sucralfate has been used to manage lesions in the oral cavity (e.g., aphthous ulcers, stomatitis, etc.). Sucralfate adheres to the mucosal surface and forms a protective layer over the oral mucosa to reduce irritation and pain caused by lesions in the oral cavity. Sucralfate is an oral “anti-ulcer” and gastrointestinal drug, which has been used to treat or prevent the recurrence of ulcers by protecting stomach or duodenal lining from the effects of various irritants (e.g., alcohol, acetylsalicylic acid, hydrochloric acid, sodium hydroxide, sodium taurocholate, etc.). Sucralfate has also been considered as a first-line drug therapy in the management of heartburn during pregnancy. Sucralfate is used as a topical drug for the healing of several types of epithelial wounds such as ulcers, inflammatory dermatitis, mucositis, and burn wounds.
In certain embodiments of the present invention, the pharmaceutical gel formulation includes sucralfate at a concentration ranging from about 3% w/w to about 15% w/w. In certain preferred embodiments, the pharmaceutical gel formulation includes sucralfate at a concentration of about 10% w/w.
In certain embodiments, the pharmaceutical gel formulation includes one or more API solubilizers. For instance, sucralfate is practically insoluble in water, so an API solubilizer may be incorporated in the formulation to decrease the pH of water and to solubilize sucralfate, which facilitates the polymerization of sucralfate. A wide range of API solubilizers can be used in the pharmaceutical gel formulations of the present invention, including, but not limited to, one or more API solubilizers selected from the group consisting of citric acid, lactic acid, malic acid, and tartaric acid. It should be understood that certain embodiments are not limited to the use of the foregoing API solubilizers. Furthermore, other ingredients may be used that function as API solubilizers without departing from the spirit of the present invention.
In certain embodiments, the pharmaceutical gel formulation includes one or more API solubilizers at a concentration ranging, preferably, from about 0.001% w/w to about 15% w/w. More preferably, the pharmaceutical gel formulation includes one or more API solubilizers at a concentration ranging from about 0.05% w/w to about 10% w/w.
In certain embodiments, preferred API solubilizers improve the solubility of the active ingredient in water. In certain embodiments, malic acid is used to improve the solubility of sucralfate in water, with the compositional ratio of malic acid to sucralfate in at least one preferred embodiment being approximately one-to-two (1:2). In certain embodiments, malic acid also helps facilitate water retention in the pharmaceutical gel throughout its shelf life. It should be understood that certain embodiments of the present invention are not limited to the use of malic acid as an API solubilizer. Furthermore, other ingredients may be used without departing from the spirit of the present invention.
In certain embodiments, the pharmaceutical gel formulation includes one or more rheology modifiers. Rheology modifiers facilitate manufacture of a pharmaceutical gel that is soft, spreadable, and will stay hydrated for longer periods of time, which enables packaging of the inventive pharmaceutical gels in site specific applicators. A wide range of rheology modifiers can be used in the pharmaceutical gel formulations of the present invention, including, but not limited to, one or more rheology modifiers selected from the group consisting of: carboxymethyl cellulose; cellulose derivatives; ethyl cellulose; hydroxypropyl cellulose; hydroxypropyl methylcellulose; methylcellulose; microcrystalline cellulose; natural polysaccharides such as chitosan, pectin, guar gum, etc.; polyvinyl alcohol; povidone; propyl cellulose; sodium carboxymethyl cellulose; and xanthan gum. It should be understood that certain embodiments are not limited to the use of the foregoing rheology modifiers. Furthermore, other ingredients that function as rheology modifiers may be used without departing from the spirit of the present invention.
In certain embodiments, the pharmaceutical gel formulation includes one or more rheology modifiers at a concentration ranging, preferably, from about 0.05% w/w to about 30% w/w. More preferably, the pharmaceutical gel formulation includes one or more rheology modifiers at a concentration ranging from about 1% w/w to about 25% w/w.
Preferred rheology modifiers according to certain embodiments are nontoxic and compatible with other pharmaceutical ingredients. Furthermore, preferred rheology modifiers enable certain preferred characteristic properties of pharmaceutical gel formulations of the present invention; more particularly, preferred rheology modifiers: provide consistency to the formulation; provide increased viscosity in low concentrations; exhibit good stability and viscosity properties over a wide range of pH levels and temperatures; maintain the preferred texture properties of the formulation; and maintain the thickness and stability of the pharmaceutical gel during long-term storage at elevated temperatures. One such preferred rheology modifier according to certain embodiments is xanthan gum. Xanthan gum is a hydrophilic polymer. Xanthan gum is nontoxic and is compatible with a wide range of pharmaceutical ingredients. Xanthan gum shows high viscosity at low concentrations, provides consistency to the pharmaceutical gel formulation, and helps maintain preferred textural properties of the inventive paste/gel formulations. Aqueous solutions of xanthan gum are stable over a wide range of pH levels (i.e., pH levels ranging from about three (3) to about twelve (12)). Xanthan gum remains stable in both acidic as well as in alkaline conditions due to its rigid structure and resistance to changes in pH. Xanthan gum gels show pseudo plastic behavior, the shear thinning is directly proportional to the shear rate; viscosity turns to normal immediately on release of shear stress. It should be understood that certain embodiments are not limited to the use of xanthan gum as a rheology modifier. Furthermore, other ingredients may be used as rheology modifiers without departing from the spirit of the present invention.
In certain embodiments, pharmaceutical gel formulations include one or more humectants. A wide range of humectants can be used in the pharmaceutical gel formulations of the present invention, including, but not limited to, one or more humectants selected from the group consisting of propylene glycol, polyethylene glycol, glycerin, sorbitol, hexylene glycol, and butylene glycol. It should be understood that certain embodiments are not limited to the use of a specific humectant. Furthermore, other ingredients that function as humectants may be used without departing from the spirit of the present invention.
Preferred humectants according to certain embodiments facilitate water retention in the inventive pharmaceutical gels, which enables such pharmaceutical gels to be packaged in site specific applicators by preventing drying and hardening of the pharmaceutical gel within such applicators. One such preferred humectant according to certain embodiments is propylene glycol. Propylene glycol facilitates water retention in the pharmaceutical gel formulation over a sufficient period of time, which enables such pharmaceutical gels to be packaged in site specific applicators. Furthermore, propylene glycol hydrates the mucosa and may help reduce irritation associated with lesions in the oral cavity, and can also improve palatability given its sweet taste. It should be understood that certain embodiments are not limited to the use of propylene glycol as a humectant. Furthermore, other ingredients may be used without departing from the spirit of the present invention.
In certain embodiments, the pharmaceutical gel formulation includes one or more humectants at a concentration ranging, preferably, from about 0.05% w/w to about 30% w/w. More preferably, the pharmaceutical gel formulation includes one or more humectants at a concentration ranging from about 1% w/w to about 25% w/w.
In certain embodiments, one or more crosslinking agents are used to facilitate polymerization of the active ingredient in the presence of organic acids, acting as a cross-linker for the active ingredient and the acid. A wide range of crosslinking agents can be used in the pharmaceutical gel formulations of the present invention, including, but not limited to, one or more crosslinking agents selected from the group consisting of bicarbonates, calcium carbonate, magnesium carbonate, and magnesium oxide. It should be understood that certain embodiments of the present invention are not limited to the use of a specific crosslinking agent. Furthermore, other ingredients that function as crosslinking agents may be used without departing from the spirit of the present invention.
In certain embodiments, the pharmaceutical gel formulation includes one or more crosslinking agents at a concentration ranging, preferably, from about 0.001% w/w to about 10% w/w. More preferably, the pharmaceutical gel formulation includes one or more crosslinking agents at a concentration ranging from about 0.05% w/w to about 5% w/w.
In certain embodiments, the pharmaceutical gel formulations have a pH value of approximately 5 to about 7. At pH levels of less than about 4, sucralfate undergoes extensive polymerization and becomes a sticky, viscid gel. At pH levels of greater than about 4, a cross-linking agent facilitates the desired characteristics of spreadability, adhesion, and mucosal affinity. In certain embodiments, calcium carbonate is a preferred cross-linking agent based on the chelation formation between the calcium ions (Ca2+) of calcium carbonate and the aluminum ions (A13+) of the sucralfate complex. In certain embodiments, calcium carbonate also acts as a buffering agent; maintaining the pH level of sucralfate paste/gel at a range of about 5 to about 7, which is approximately the same as the pH of saliva. In certain embodiments, calcium carbonate is used as a crosslinking agent at a concentration ranging, preferably, from about 1% w/w to about 5% w/w. It should be understood that certain embodiments are not limited to the use of calcium carbonate as a crosslinking agent. Furthermore, other ingredients may be used without departing from the spirit of the present invention.
In certain embodiments, where the pharmaceutical gel formulation includes sucralfate and malic acid (as an API solubilizer), it may be preferable to include malic acid and calcium carbonate in a specific ratio of one-to-two (1:2) to avoid phase separation during the processing stage, which can cause sucralfate to precipitate-out of the final composition. It should be understood that certain embodiments are not limited to the use of calcium carbonate as a crosslinking agent and/or malic acid as an API solubilizer. Furthermore, other ingredients may be used without departing from the spirit of the present invention.
In certain embodiments, the pharmaceutical gel formulation includes one or more consistency improvers. Consistency improvers reduce lumping of the pharmaceutical gel formulation and improve the paste/gel's overall consistency. In certain embodiments, calcium sulphate dihydrate is used as a consistency improver to reduce lumping of sucralfate and calcium carbonate and improve the pharmaceutical gel's consistency. It should be understood that certain embodiments of the present invention are not limited to the use of a consistency improver. Furthermore, other ingredients that function as consistency improvers may be used without departing from the spirit of the present invention.
In certain embodiments, the pharmaceutical gel formulation includes one or more consistency improvers at a concentration ranging, preferably, from about 0.001% w/w to about 10% w/w. More preferably, the pharmaceutical gel formulation includes one or more consistency improvers at a concentration ranging from about 0.01% w/w to about 1% w/w.
In certain embodiments, the pharmaceutical gel formulation includes one or more stabilizers. Stabilizers are used to help the active pharmaceutical ingredient maintain desirable properties of the pharmaceutical product until it is used by the patient; for example, stabilizers can be used to control degradation of the active ingredient. Suitable stabilizers include, but are not limited to, organic acids and inorganic acids. In certain embodiments, preferred stabilizers include ethylenediaminetetraacetic acid (hereinafter referred to as “EDTA”) and/or sodium edetate; however, it should be understood that certain embodiments are not limited to the use of a stabilizer. Furthermore, other ingredients that function as stabilizers may be used without departing from the spirit of the present invention.
In certain embodiments, the pharmaceutical gel formulation includes one or more liquid bases, which act as a vehicle for other ingredients. In certain embodiments, the liquid base will, preferably, serve as both a vehicle and a hydrating agent. In certain embodiments, the polymerization of sucralfate with malic acid and calcium carbonate takes place in the presence of purified water (as the liquid base). It should be understood that certain embodiments are not limited to the use of a specific liquid base. Furthermore, other ingredients that function as a vehicle may be used without departing from the spirit of the present invention.
In certain embodiments, the pharmaceutical gel formulation includes a liquid base at a concentration ranging, preferably, from about 1% w/w to about 95% w/w. More preferably, the pharmaceutical gel formulation includes a liquid base at a concentration ranging from about 10% w/w to about 90% w/w.
In certain embodiments, the pharmaceutical gel formulation includes one or more taste modifiers that function to improve the palatability of the formulation. Taste modifiers may include one or more sweetening agents, flavor enhancers, and/or flavoring agents. In certain preferred embodiments of the present invention, the pharmaceutical gel formulation includes one or more taste modifiers selected from the group consisting of stevia, aspartame, sucralose, neotame, acesulfame potassium, saccharin, and advantame; however, it should be understood that the present invention is not limited to the use of the foregoing taste modifiers. Furthermore, other ingredients that function as taste modifiers may be used without departing from the spirit of the present invention.
In certain embodiments, the pharmaceutical gel formulation includes one or more taste modifiers at a concentration ranging, preferably, from about 0.005% w/w to about 10% w/w. More preferably, the pharmaceutical gel formulation includes one or more taste modifiers at a concentration ranging from about 0.01% w/w to about 5% w/w.
Pharmaceutical gels manufactured in accordance with preferred embodiments of the present invention are capable of being packaged in a squeezable tube having a site specific applicator nozzle. For instance, pharmaceutical gels manufactured in accordance with preferred embodiments of the present invention are capable of being packaged in a primary packaging tube similar to that described in Table 1 below and shown in FIGS. 1 and 2 .

TABLE 1

Parameter	Description

Package Type	Laminated tube
Length with shoulder (mm)	100
Length without shoulder (mm)	83.5
Tube diameter (mm)	16
Inner Nozzle Diameter (mm)	0.61
Outer Nozzle Diameter (mm)	3.51
Nozzle length (mm)	14.25
Tube wall thickness (mm)	0.18
Total Thickness (μ)	175 ± 10%
Total GSM	186.96 ± 10%
Shelf Life	2 years in tube form or without filled product
Barrier layer	Aluminum Foil
	Thickness 9 μ
TIE layer	EAA
	Thickness 20.5 μ
Outer white film	Polyethylene
	Thickness 75 μ
Joint type	Butt joints (no overlapping) with heat
	resistant adhesive tapes on both sides.
Manufacturer	Essel Propack Ltd.

Similar primary packaging may be used without departing from the spirit of the present invention. For instance, a wide range of squeezable reservoirs configured to contain the pharmaceutical gel formulation are within the ambit of the present invention, including pouches, bags, balls, cylinders, and others. In certain preferred embodiments, with reference to the drawing figures, the medical device 1 includes a squeezable reservoir 3 configured to contain the pharmaceutical gel formulation (not shown) and a site specific applicator 5 projecting from the reservoir 3. The reservoir 3 includes a wall 7, which facilitates containment of the formulation. In certain embodiments, it may be preferable for a shoulder 9 to be formed in wall 7 to facilitate flow to applicator 5 when reservoir 3 is squeezed by the user. The site specific applicator 5 includes a wall 11 defining an inner margin 13 that extends from the proximal end 15 of applicator 5 to the outlet/opening 17 at the distal end 19 of applicator 5. Margin 13 is arranged in fluid communication with reservoir 3 so that when the user squeezes reservoir 3, the pharmaceutical gel formulation is expelled from reservoir 3, through margin 13, and out opening 17. Margin 13 has a width 21 in the range of about 0.5 mm to about 2 mm. In certain embodiments, the width 21 of margin 13 is substantially the same between end 15 and end 17. In other embodiments, it may be preferable for the width 21 of margin 13 to decrease from end 15 to end 17. In certain preferred embodiments, device 1 includes a closure (not shown), such as a cap, to prevent drying and/or contamination of the pharmaceutical gel formulation.
Additional advantages of the various embodiments will be apparent to those skilled in the art upon review of the disclosure herein and the working examples below.

EXAMPLES

The following working examples set forth preferred embodiments in accordance with the present invention. It is to be understood, however, that these examples are provided by way of illustration and nothing therein should be taken as a limitation upon the overall scope of the invention.
Ingredients corresponding to Example 1 (10% sucralfate pharmaceutical gel) are tabulated in Table 2, with the amount of each ingredient given in respective percent weight-by-weight (% w/w). In Example 1, the active ingredient is sucralfate. In Example 1, the active strength of sucralfate is about 10%.

TABLE 2

Ingredient	Type	% w/w

Sucralfate	Active Ingredient	10.000
Malic acid	API Solubilizer	5.000
Calcium carbonate	Crosslinking Agent	1.000
Polyvinylpyrrolidone K-30	Rheology Modifier	3.820
Polyvinylpyrrolidone K-90	Rheology Modifier	3.820
Calcium sulfate dihydrate	Consistency Improver	0.100
EDTA	Stabilizer	0.020
Sucralose	Taste Modifier	0.020
Propylene glycol	Humectant	7.000
Purified water	Liquid Base	69.220

	TOTAL	100.00

Procedure—Example 1

Step 1: triturate the batch quantity of malic acid to a fine powder by using a mortar pestle.
Step 2: add the batch quantities of calcium carbonate and sucralfate, simultaneously, to the triturated malic acid of Step 1 under continuous trituration until a uniform mixture is formed.
Step 3: add approximately 12% of the batch quantity of purified water to the mixture of Step 2 under continuous trituration, mix well until a thick, sticky gel is formed, and allow the mixture to soak for approximately 30-minutes.
Step 4: add approximately 40% of the batch quantity of purified water to a container, and add the batch quantities of polyvinylpyrrolidone K-30 and polyvinylpyrrolidone K-90 to the purified water under continuous stirring at about 800-rpm for approximately 10-minutes.
Step 5: add the batch quantities of EDTA, calcium sulfate dihydrate, and sucralose to the mixture of Step 4 under continuous stirring at about 800-rpm for approximately 15-minutes.
Step 6: add and mix the paste of Step 3 to the mixture of Step 5 under continuous high speed stirring at about 1500-rpm for approximately 120-minutes to form a uniform mixture.
Step 7: add and mix the batch quantity of propylene glycol to the mixture of Step 6 under continuous high speed stirring at about 1500-rpm.
Step 8: add the remaining batch quantity of purified water to the mixture of Step 7 and stir continuously.
Step 9: let the mixture of Step 8 set for approximately 12-hours — a paste/gel should begin to form after approximately 5 to 6 hours.
Table 3: Characterization of the pharmaceutical gel formed in accordance with Example 1.

	TABLE 3

	Appearance	Opaque
	Texture	Smooth
	Color	White
	Assay (percentage)	93.4

Ingredients corresponding to Example 2 (10% sucralfate pharmaceutical gel) are tabulated in Table 4, with the amount of each ingredient given in respective percent weight-by-weight (% w/w). In Example 2, the active ingredient is sucralfate. In Example 2, the active strength of sucralfate is about 10%.

TABLE 4

Ingredient	Type	% w/w

Sucralfate	Active Ingredient	10.000
Malic acid	API Solubilizer	5.000
Calcium carbonate	Cross Linking Agent	2.500
Xanthan gum	Rheology Modifier	0.500
Calcium sulfate dihydrate	Consistency Improver	0.100
Sucralose	Taste Modifier	0.020
Propylene glycol	Humectant	7.000
Purified water	Liquid Base	74.880

TOTAL	100.00

Procedure—Example 2

Step 1: add approximately 65% of the batch quantity of purified water to a vessel and add and dissolve the batch quantity of malic acid under continuous stirring at about 1200-rpm for approximately 10-minutes.
Step 2: add the batch quantity of sucralfate to the mixture of Step 1 under continuous stirring at about 1800-rpm for approximately 30-minutes (a uniform dispersion should be observed).
Step 3: add the batch quantity of calcium carbonate to the mixture of Step 2 under continuous stirring until a uniform mixture is formed (approximately 40-minutes).
Step 4: add the batch quantities of calcium sulfate dihydrate and sucralose to the mixture of Step 3 under continuous homogenization at about 2500-rpm, until a uniform dispersion is formed.
Step 5: slowly add and dissolve the batch quantity of xanthan gum to the dispersion of Step 4 under continuous homogenization at about 2500-rpm.
Step 6: add and mix the batch quantity of propylene glycol to the mixture of Step 5 under continuous stirring at about 1500-rpm for approximately 10-minutes.
Table 5: Characterization of the pharmaceutical gel formed in accordance with Example 2.

TABLE 5

Sample	Appearance	Texture	Color

EX 2	Opaque	Smooth	White
EX 2¹	Opaque	Smooth	White
EX 2²	Opaque	Smooth	White
EX 2³	Opaque	Smooth	White

¹one-month stability at 40° C. and 75% relative humidity (“RH”).
²three-month stability 40° C. and 75% RH.
³three-month stability 25° C. and 60% RH.

Table 6: pH value and water content of the pharmaceutical gel formed in accordance with Example 2.

TABLE 6

		Water Content
Sample	pH	(percentage)

EX 2	6.38	69.1908
EX 2¹	5.65	59.6283
EX 2²	5.86	60.7621
EX 2³	5.75	62.0086

¹one-month stability at 40° C. and 75% RH.
²three-month stability 40° C. and 75% RH.
³three-month stability 25° C. and 60% RH.

Analysis results concerning the chemical characterization and acid neutralizing capacity (performed as given in United States Pharmacopeia (USP) general chapter <301>Acid-neutralizing capacity) of the pharmaceutical gel formed in accordance with Example 2 are tabulated in Table 7.

TABLE 7

	Assay
Sample	(percentage)	Acid Neutralizing Capacity

EX 2	106.2	13.51
EX 2¹	100.3	13.21
EX 2²	99.2	13.03
EX 2³	104.1	13.2

¹one-month stability at 40° C. and 75% RH.
²three-month stability 40° C. and 75% RH.
³three-month stability 25° C. and 60% RH.

The results of a microbial enumeration analysis (conducted in accordance with USP general chapter <61>microbiological examination of nonsterile products: microbial enumeration tests) of the pharmaceutical gel formed in accordance with Example 2 are tabulated in Table 8.

TABLE 8

Test	Result	Specification

Total aerobic microbial count	<10 cfu/g	NMT 10²cfu/g
Total combined yeast and mold count	<10 cfu/g	NMT 10¹cfu/g
Escherichia coli	Absent/g	Absent/g
Pseudomonas aeruginosa	Absent/g	Absent/g
Staphylococcus aureus	Absent/g	Absent/g
Salmonella species	Absent/10 g	Absent/10 g

Modifications, additions, and/or omissions may be made to the compositions, methods, and steps described herein without departing from the scope of the disclosure. For example, the ingredients of the composition and method for manufacture may be integrated or separated. Moreover, the method for manufacture disclosed herein may be prepared by more, fewer, or other ingredients and the methods described may include more, fewer, or other steps. Additionally, steps may be performed in any suitable order.

Additional Considerations

As used herein, the term “specification” refers to all parts of the written description, including the working examples, and the claims of the present patent application.
As used in this specification, the phrase “and/or,” when used in a list of two or more items, means that any one of the listed items can be employed by itself or any combination of two or more of the listed items can be employed. For example, if a composition is described as containing or excluding components A, B, and/or C, the composition can contain or exclude A alone; B alone; C alone; A and B in combination; A and C in combination; B and C in combination; or A, B, and C in combination.
As used in this specification, the terms “comprises,” “comprising,” “includes,” “including,” “has,” “having” or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
Approximating language, as used in this specification, may be applied to modify any quantitative representation that could permissibly vary without resulting in a change in the basic function to which it is related. Accordingly, a value modified by a term or terms, such as “about,” “approximately,” and “substantially” are not to be limited to the precise value specified. In at least some instances, the approximating language may correspond to the precision of an instrument for measuring the value. In this specification, range limitations may be combined and/or interchanged. Such ranges are identified and include all the sub-ranges contained therein unless the context or language indicates otherwise.
With respect to the use of substantially any plural and/or singular terms used in this specification, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for the sake of clarity.
In this specification, a numerical range indicated by using “to” or “to about” shows a range including numerical values written before and after “to” or “to about” as a minimum value and a maximum value, respectively. In this specification numerical ranges are used to quantify certain parameters relating to various embodiments. It should be understood that when numerical ranges are provided, such ranges are to be construed as providing literal support for claim limitations that only recite the lower value of the range as well as claim limitations that only recite the upper value of the range. For example, a disclosed numerical range of “about 10 to about 100” provides literal support for a claim reciting greater than about 10 (with no upper bounds) and a claim reciting less than about 100 (with no lower bounds). Furthermore, in the case of all the relative or percentage amount information, particularly weight-related amount information, that this information is to be selected by a person having ordinary skill in the art, within the scope of the present invention, in such a manner that the sum of the respective ingredients, active ingredients, additives or ancillary substances, or the like always come up to 100% or 100% w/w.
With respect to the claims below, if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the claims in this specification may contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (e.g., “a” and/or “an” should be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, it should be understood that such recitation means at least the recited number (e.g., the bare recitation of “two recitations,” without other modifiers, means at least two recitations, or two or more recitations). In those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having ordinary skill in the art would understand the convention (e.g., “a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). In those instances where a convention analogous to “at least one of A, B, or C, etc.” is used, in general such a construction is intended in the sense one having ordinary skill in the art would understand the convention (e.g., “a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.).
In this written description, references to “one embodiment”, “an embodiment”, or “embodiments” mean that the feature or features being referred to are included in at least one embodiment of the present invention. Separate references to “one embodiment”, “an embodiment”, or “embodiments” in this written description do not necessarily refer to the same embodiment and are also not mutually exclusive unless so stated and/or except as will be readily apparent to those having ordinary skill in the art from the description. For example, a feature, structure, act, etc. described in one embodiment may also be included in other embodiments, but is not necessarily included. Thus, the present invention encompasses a variety of combinations and/or integrations of the specific embodiments described in the specification and any suitable combination of the previously described embodiments may be made without departing from the spirit of the present invention.
This disclosure is to be construed as exemplary only and does not describe every possible embodiment since describing every possible embodiment would be impractical. Numerous alternative embodiments may be implemented, using either current technology or technology developed after the filing date of this patent application, which would still fall within the scope of the present invention.
The inventors hereby state their intent to rely on the Doctrine of Equivalents to determine and assess the reasonably fair scope of the present invention as pertains to any process, machine, manufacture, or composition of matter not materially departing from but outside the literal scope of the invention as set forth in the following claims.

Claims

1. (canceled)

2. A medical device comprising:

a squeezable reservoir containing a pharmaceutical gel formulation; and

a site-specific applicator projecting from the reservoir,

said site specific applicator presenting a proximal end and a distal end,

said site-specific applicator including a wall defining an inner margin extending between the proximal end and the distal end,

said inner margin having a width ranging from 0.5 mm to 2 mm,

said inner margin defining an opening at the distal end,

said inner margin being arranged in fluid communication with the reservoir such that the sucralfate formulation is expelled therethrough and out of the opening when the reservoir is squeezed,

wherein said pharmaceutical gel formulation has a sucralfate concentration ranging from 3% w/w to about 15% w/w.

3. The medical device as claimed in claim 2, said squeezable reservoir being in the shape of a tube.

4. The medical device as claimed in claim 2, wherein said pharmaceutical gel formulation is capable of being stored in said squeezable tube for a period of time of 1-year, and wherein said pharmaceutical gel formulation is capable of being expelled from the squeezable reservoir through the inner margin throughout the period of time.

5. The medical device as claimed in claim 4, said period of time is 2-years.

6. The medical device as claimed in claim 2, said site-specific applicator having a conical shape.

7. The medical device as claimed in claim 2, said inner margin having a circular shape.

8. The medical device as claimed in claim 7, said inner margin presenting a diameter in the range from 0.5 mm to 2 mm.

9. The medical device as claimed in claim 2, said width being about the same along the inner margin.

10. The medical device as claimed in claim 2, wherein said site-specific applicator is removably fixed to the reservoir.

11. The medical device as claimed in claim 2, further comprising a removable closure arranged at the distal end of the site-specific applicator.

12. The medical device as claimed in claim 2, said pharmaceutical gel formulation further comprising:

malic acid, as an API solubilizer, in a concentration ranging from about 4.8% w/w to about 5.2% w/w;

calcium carbonate, as a cross-linking agent, in a concentration ranging from about 2.4% w/w to about 2.6% w/w;

calcium sulfate dihydrate, as a consistency improver, in a concentration ranging from about 0.05% w/w to about 1.5% w/w;

xanthan gum, as a rheology modifier, in a concentration ranging from about 0.1% w/w to about 1.0% w/w; and

propylene glycol, as a humectant, in a concentration ranging from about 2% w/w to about 10% w/w.

13. The medical device as claimed in claim 2, wherein said pharmaceutical formulation has a water content ranging from an about 56% w/w to about 85% w/w.

14. The medical device as claimed in claim 2, said pharmaceutical gel formulation further comprising sucralose, as a sweetener.

15. The medical device as claimed in claim 2, wherein said reservoir and said site-specific applicator being formed from a copolymer.

16. The medical device as claimed in claim 2, said reservoir comprising an inner layer and an outer layer.

17. The medical device as claimed in claim 16, said inner layer comprising an aluminum alloy.

18. The medical device as claimed in claim 16, said outer layer comprising polyethylene.

19. The medical device as claimed in claim 16, said reservoir further comprising a tie-layer arranged between the inner layer and the outer layer.

20. The medical device as claimed in claim 19, said tie-layer comprising an ethylene acrylic acid copolymer.