Multicomponent biodegradable bioadhesive controlled release system for oral care products

• US 6,589,562 B1
• Filed: 10/25/2000
• Issued: 07/08/2003
• Est. Priority Date: 10/25/2000
• Status: Expired due to Term

• Current Assignee: Salvona LLC, Slavona, LLC
• Original Assignee: Salvona LLC
• Inventors: Shefer, Adi, Shefer, Shmuel David
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): TRAN, SUSAN T
• Application Number:
  US09/696,148
• Time in Patent Office: 986 Days
• Field of Search: 424/49, 424/52, 424/426, 424/439, 424/489, 424/490, 424/435, 424/484, 424/485, 424/486, 424/501, 424/502
• US Class Current: 424/490
• CPC Class Codes: A23G 1/54 Composite products, e.g. layered laminated, coated, filled
• CPC Class Codes: A23L 2/39 Dry compositions
• CPC Class Codes: A23L 27/72 Encapsulation
• CPC Class Codes: A23V 2002/00 Food compositions, function of food ingredients or processes for food or foodstuffs
• CPC Class Codes: A23V 2200/25 Nanoparticles, nanostructures
• CPC Class Codes: A61K 2800/412 Microsized, i.e. having sizes between 0.1 and 100 microns
• CPC Class Codes: A61K 2800/56 Compounds, absorbed onto or entrapped into a solid carrier, e.g. encapsulated perfumes, inclusion compounds, sustained release forms
• CPC Class Codes: A61K 8/0283 Matrix particles
• CPC Class Codes: A61K 8/11 Encapsulated compositions
• CPC Class Codes: A61K 8/27 Zinc; Compounds thereof
• CPC Class Codes: A61K 8/347 Phenols
• CPC Class Codes: A61K 8/4926 having six membered rings
• CPC Class Codes: A61K 8/922 of vegetable origin
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/0063 Periodont
• CPC Class Codes: A61K 9/5123 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61Q 11/00 Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses

Abstract

The present invention relates to a controlled release system useful for site'"'"'specific delivery of biologically active ingredients or sensory markers, over an extended period of time, targeting biological surfaces comprising the oral cavity and mucous membranes of various tissues, as well as the controlled release of the biological active ingredients or sensory markers. The controlled release system of the present invention is a nano-particle encapsulated in a moisture sensitive micro-particle. The nano-particle having an average particle diameter of from about 0.01 microns to about 10 microns, which comprises a biodegradable solid hydrophobic core and a bioadhesive/mucoadhesive positively charged surface. The invention also relates to the use of the nano-particles of the present invention in consumer oral hygiene products, such as toothpaste or mouthwash, for treatment and prevention of periodontal disease. The nano-particles of the present invention are particularly effective for targeted controlled delivery of biological active ingredients into the periodontal pocket. The present invention also provides synchronizing the release of the biologically active ingredient with that of the sensory markers to convey to the consumer the product performance and signal that a new application of the product is needed.

Claims

1. A multi-component moisture activated controlled release delivery system for delivery to biological surfaces comprising an oral cavity or mucous membranes of various tissues, said system comprising:

a plurality of solid nano-particles having a core formed of a biodegradable hydrophobic material selected from the group consisting of natural waxes, synthetic waxes, fatty acid esters, fatty alcohols, solid hydrogenated plant oils, biodegradable natural polymers and synthetic polymers, each of said solid nano-particles comprising a core and an effective amount of a first active agent contained therein and a bioadhesive positively charged surfactant surrounding said core, wherein said positively charged surfactant is selected from the group consisting of straight-chain alkylammonium compounds, cyclic alkylammonium compounds, petroleum derived cationics, and polymeric cationic materials, said plurality of nano-particles being encapsulated in a moisture sensitive microparticle, said microparticle is formed of a moisture sensitive material,

wherein said microparticle dissolves upon contact with said moisture to provide a burst of said nanoparticles or said microparticle swells or softens to slowly release said nanoparticles and said nanoparticles release said active agent continuously thereafter for an extended period of time.

2. The system of claim 1 wherein said hydrophobic material has a melting point between 50 degrees C. and 120 degrees C.

3. The system of claim 1 wherein said hydrophobic material comprises candelilla wax.

4. The system of claim 1 wherein said moisture sensitive matrix material is selected from the group consisting of a starch derivative, natural gum, polyvinyl alcohol, protein, hydrocolloid, polycarboxylate, and mixtures thereof.

5. The system of claim 4 wherein said hydrocolloid is selected from the group consisting of xanthan, maltodextrin, galactomanan, and tragacanth.

6. The system of claim 4 wherein said natural gum is gum arabic.

7. The system of claim 4 wherein said polyvinyl alcohol has a degree of hydrolysis from about 75% to about 99%.

10. The system of claim 1 wherein said first active agent is a sensory marker selected from the group consisting of a flavor, sweetener and cooling agent.

13. The system of claim 1 wherein said positively charged surfactant is cetylpyridinium chloride.

14. The system of claim 1 wherein said bioadhesive is a mucoadhesive.

15. The system of claim 1 wherein said system remains active for a period between about ten minutes and about 3 months.

16. The system of claim 1 wherein said nano-particles adhere to said oral cavity or mucous membranes of various tissues.

17. The system of claim 1 wherein said nano-particles provide one or more of the following site specific adhesion:

settling around the gumline;

settling subgingivally;

penetrating into periodontal pocket;

adhering to soft tissue; and

becoming immobilized over an extended period of time.

18. By The system of claim 1 wherein said nano-particles have an average particle diameter between about 0.01 microns and about 10 microns.

19. The system of claim 1 wherein said nano-particles further comprise a preservative.

20. The system of claim 1 wherein said positively charged surfactant includes hydrophobic ends and hydrophilic ends said hydrophobic ends of said positively charged surfactant are embedded in said core and said hydrophilic ends of said positively charged surfactant are exposed on a surface of said core.

27. An oral hygiene product comprising the system of claim 1.

8. A multi-component moisture activated controlled release delivery system for delivery to biological surfaces comprising an oral cavity or mucous membranes of various tissues, said system comprising:

a plurality of solid nano-particles having a core formed of a biodegradable hydrophobic material, each of said solid nano-particles comprising a core and an effective amount of a first active agent contained therein and a bioadhesive positively charged surfactant surrounding said core, said plurality of nano-particles being encapsulated in a moisture sensitive microparticle, said microparticle is formed of a moisture sensitive material,

wherein said first active agent is a biologically active agent selected from the group consisting of anti-septic materials, antibacterial materials, anti-inflammatory materials and active ingredients that interdict the attachment, propagation, growth and or colonization of bacteria on teeth.

9. The system of claim 8 wherein the first active agent is said antibacterial material selected from the group consisting of thimerosal, chloramine, boric acid, phenol, iodoform, chlorhexidine, oral antiseptic, beta-lactam antibiotic, cefoxitin, n-formamidoyl thienamycin, thienamycin derivatives, tetracycline, chloramphenicol, neomycin, gramicidin, kanamycin, amikacin, sismicin and tobramycin.

11. A multi-component moisture activated controlled release delivery system for delivery to biological surfaces comprising an oral cavity or mucous membranes of various tissues, said system comprising:

a plurality of solid nano-particles having a core formed of a biodegradable hydrophobic material, each of said solid nano-particles comprising a core and an effective amount of a first active agent contained therein and a bioadhesive positively charged surfactant surrounding said core, said plurality of nano-particles being encapsulated in a moisture sensitive microparticle, said microparticle is formed of a moisture sensitive material,

wherein said microparticle dissolves upon contact with said moisture to provide a burst of said nanoparticles or said microparticle swells or softens to slowly release said nanoparticles and said nanoparticles release said active agent continuously thereafter for an extended period of time,

wherein said first active agent is a biological active agent and further comprising a second active agent, said second active agent is a sensory marker.

12. The system of claim 11 wherein a release rate of said first active agent is synchronized with a release rate of said second active agent.

21. A multi-component moisture activated controlled release delivery system for delivery to biological surfaces comprising an oral cavity or mucous membranes of various tissues, said system comprising:

a plurality of solid nano-particles having a core formed of a biodegradable hydrophobic material, each of said solid nano-particles comprising a core and an effective amount of a first active agent contained therein and a bioadhesive positively charged surfactant surrounding said core, said plurality of nano-particles being encapsulated in a moisture sensitive microparticle, said microparticle is formed of a moisture sensitive material,

wherein said first active agent is a biologically active agent selected from the group consisting of anti-septic materials, antibacterial materials, anti-inflammatory materials and active ingredients that interdict the attachment, propagation, growth and or colonization of bacteria on teeth further comprising a second active agent in said moisture sensitive matrix wherein said matrix releases said second active agent upon contact with said moisture and continuously thereafter for an extended period of time.

22. The system of claim 21 wherein said composition releases an effective amount of said second active agent to provide a burst of said active agent.

23. The system of claim 22 wherein after said burst of said second active agent, said second active agent is continuously released for an extended period of time.

24. The system of claim 21 wherein said second active agent is a biologically active agent.

25. The system of claim 21 wherein said second active agent is a sensory marker.

26. A method for producing a system for delivery to biological surfaces comprising an oral cavity or mucous membranes of various tissues, said system comprising:

a plurality of solid nano-particles having a core formed of a biodegradable hydrophobic material, each of said solid nano-particles comprising a core and an effective amount of a first active agent contained therein and a bioadhesive positively charged surfactant surrounding said core, said plurality of nano-particles being encapsulated in a moisture sensitive microparticle, said microparticle is formed of a moisture sensitive material comprising the steps of;

(i) heating a core material forming said core to a temperature above said core material melting point to form a melt;

(ii) dispersing said first active agent or sensory marker into said melt;

(iii) dispersing said positively charged surfactant said first active agent or sensory marker and a water sensitive material in the aqueous phase;

(iv) heating the suspension to a temperature above the melting point of the mixture formed in step (ii) to form a hot melt;

(v) mixing said hot melt of step (ii) with the aqueous solution formed in step (iii) to form a suspension;

(vi) high shear homogenization of said suspension at a temperature above the melting temperature of said material mixture formed in step (v) until a homogeneous fine suspension is obtained;

(vii) rapidly cooling said suspension to ambient temperature to form a dispersion; and

(viii) spray drying said cooled dispersion to form a dry powder composition.