Search

US-12622971-B2 - Linear polysaccharide based film products

US12622971B2US 12622971 B2US12622971 B2US 12622971B2US-12622971-B2

Abstract

Film products, especially suitable for oral delivery, which can be formed during manufacture in the form of large and/or heavy film strips or sheets and subsequently cut into uniform dosage units, each dosage unit being uniform in content and having distributed therein a linear polysaccharide, such as pullulan, a plasticizer, and an active component.

Inventors

  • Garry L. Myers
  • Michael Li
  • Beuford Arlie Bogue
  • Eric Dadey

Assignees

  • AQUESTIVE THERAPEUTICS, INC.

Dates

Publication Date
20260512
Application Date
20210929

Claims (16)

  1. 1 . A cast film product comprising: a self-supporting film composition comprising a matrix from which self-supporting unit doses can be formed, said matrix comprising: (a) at least one linear polysaccharide film-forming polymer comprising pullulan in amounts of about 10% to about 35% by weight of the film composition; (b) an active present in amounts of about 6% to about 65% by weight of the film composition; and (c) a plasticizer composition present in an amount of about 10% to about 45% by weight based on the combined weight of the plasticizer composition and a total polymer content in the film product; said plasticizer composition comprising xylitol and glycerin, wherein the glycerin is present in an amount that is equal to or less than the amount of the xylitol by weight; and said matrix further comprising a resin; wherein substantially uniformly sized unit doses of the film composition exhibit a disintegration value in the range of about 1 second to about 60 seconds as measured by suspending the unit dose film such that half of the unit dose film is submerged in water at 37° C. and determining the time for the submerged half of the unit dose film to separate from the suspended half.
  2. 2 . The cast film product of claim 1 , wherein the plasticizer composition further comprises a plasticizer selected from the group consisting of propylene glycol, triacetin and sorbitol.
  3. 3 . The cast film product of claim 1 , further comprising a sugar alcohol selected from the group consisting of sorbitol and maltitol.
  4. 4 . The cast film product of claim 1 , wherein the amount of the glycerin is equal to the amount of xylitol by weight.
  5. 5 . The cast film product of claim 1 , wherein the xylitol is present in an amount of about 10% to about 45% by weight based on the combined weight of the xylitol and the total polymer content.
  6. 6 . The cast film product of claim 1 , wherein the plasticizer composition is present in an amount of about 15% to about 22.5% by weight based on the combined weight of the plasticizer composition and the total polymer content.
  7. 7 . The cast film product of claim 1 , wherein the plasticizer composition is present in an amount of about 18% to about 21% by weight based on the combined weight of the plasticizer composition and the total polymer content.
  8. 8 . The cast film product of claim 1 , wherein the unit dose film has a thickness of from about 3 μm to about 500 μm.
  9. 9 . The cast film product of claim 1 , wherein the active is a neuromuscular drug.
  10. 10 . The cast film product of claim 1 , further comprising an additional polymer.
  11. 11 . The cast film product of claim 10 , wherein the additional polymer is selected from the group consisting of hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, sodium alginate, polyethylene glycol, xanthan gum, tragancanth gum, guar gum, acacia gum, arabic gum, starch, gelatin, and combinations thereof.
  12. 12 . The cast film product of claim 1 , further comprising an acid.
  13. 13 . The cast film product of claim 12 , wherein the acid is selected from the group consisting of citric acid, formic acid, acetic acid, propionic acid, ascorbic acid, lactic acid, malic acid, tartaric acid, and combinations thereof.
  14. 14 . The cast film product of claim 1 , wherein the unit doses exhibit a disintegration value in the range of about 2 to about 10 seconds as measured by suspending the unit dose film such that half of the unit dose film is submerged in water at 37° C. and determining the time for the submerged half of the unit dose film to separate from the suspended half.
  15. 15 . The cast film product of claim 1 , wherein the film product has a tensile strength of about 0.8 N/mm 2 .
  16. 16 . The cast film product of claim 1 , wherein the film product has a tensile strength of about 1 N/mm 2 .

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 16/830,448, filed Mar. 26, 2020, which is a continuation of U.S. application Ser. No. 16/002,643, filed Jun. 7, 2018, which is a continuation of U.S. application Ser. No. 15/534,630, filed Jun. 9, 2017, which is a National Stage of International Application No. PCT/US2015/064806, filed Dec. 9, 2015, which claims the benefit of U.S. Provisional Application No. 62/089,676, filed Dec. 9, 2014; the entire contents of each of the foregoing applications is incorporated by reference herein. FIELD OF THE INVENTION The invention relates to pharmaceutical film products, especially suitable for oral delivery, which can be formed during manufacture in the form of large and/or heavy film strips or sheets and subsequently cut into uniform dosage units, each dosage unit being uniform in active content and having distributed therein a linear polysaccharide as the polymer platform, such as pullulan, a plasticizer, other film forming excipients, and an active component. BACKGROUND OF RELATED TECHNOLOGY Pullulan is a relatively high molecular weight polymer yet has low viscosity and high solids loading due to its high water solubility. For example, a 10% solids solution of pullulan with an average molecular weight of 200,000 Daltons in 30° C. water has a viscosity of 130-180 centipoise. Films made with Pullulan tend to dissolve quickly. However, Pullulan also has some negative properties when it is manufactured on high speed mixing equipment. Used alone, it is brittle and shock sensitive and if plasticized, it is difficult to incorporate sufficient plasticizer into the formulation to decrease or eliminate shock sensitivity without the film becoming tacky. To get around these adverse properties, water is often used as a plasticizer with and without starch, xanthan and gellan gum. The films are dried with relatively high amounts of moisture left in the film, as much as 5-10%. However, high moisture content can increase the water activity of the film strips and thus become a breeding ground for microbial growth. Also, water (moisture content) tends to evaporate from such formulations over time and the loss of the plasticizer (water) leads to brittleness of the finished film as the film ages. Low tackiness, lack of shock sensitivity and lack of brittleness are all important physical attributes of a robust “production quality” polymer formulation for oral soluble films. The manufactured oral soluble film web undergoes many unit operations during the drying, slitting, storing and packaging production steps. Film webs with improper adhesion or release characteristics can result in jamming of the packaging line which brings the manufacturing process to a halt. The same jamming occurs with any film web that is brittle. Shock sensitivity is also important attribute of the film web, especially during the film slitting process, as a shock sensitive film web will experience crazing, and shatter like a broken glass, rather than propagating the failure in the direction of the knife, which results in a clean and even cut like paper. This leads to unusable product and a stalled low-yield manufacturing process. Self-supporting linear polysaccharide (e.g., glucan) films, such as those made from pullulan and elsinan, are known as being useful for the delivery of edible or ingestible components (e.g., commercial breath films), for packaging and wrapping as well as other uses. For example, U.S. Pat. No. 4,562,020 to Haijiya, et al. discloses a continuous process for producing such self-supporting glucan films formed from aqueous glucan solutions whereby the solution is deposited on a corona-treated plastic conveyor belt and air dried to form films. U.S. Pat. No. 4,927,636 to Haijiya, et al. discloses pullulan films which have decreased solubility in water. These films are made from a combination of pullulan and polyethylene glycol (PEG) which form an “association complex” to produce this effect. Polyethylene glycols within the molecular weight range of 400 to 10,000 Daltons are disclosed as useful. The ratio of pullulan to PEG is disclosed as being 1 part by weight (pbw) pullulan to 0.01 to 100 part by weight (pbw) PEG. This patent discloses that pullulan in combination with other water-soluble polymers does not form such an association complex useful for decreasing solubility and reducing adhesive and stickiness properties of aqueous pullulan. U.S. Pat. No. 5,411,945 to Ozaki, et al. discloses a pullulan binder composition made from a combination of pullulan and a mono-saccharide or lower molecular weight oligo-saccharide in a ratio of 85:15 to 65:35 pullulan/saccharide. These films are disclosed as being gradually dissolvable. U.S. Pat. No. 5,518,902 to Ozaki, et al. discloses high pullulan content products made by cultivating micro-organisms capable of producing pullulan at a pH exceeding 2.0 but not higher than 4.0 in a nutrient culture medi