Details for Patent: 5,643,602

US Patent 5,643,602: Scope, Claims, and Patent Landscape for Controlled-Release Budesonide Pellets for Inflammatory Bowel Disease

What does US 5,643,602 actually claim?

US 5,643,602 claims controlled-release oral pellet formulations for inflammatory bowel diseases (IBD) built on a common three-part architecture:

1) Non-pareil or drug-loaded seed core sized 0.3 to 5 mm diameter
2) Drug layer (budesonide or a defined glucocorticosteroid) and polymer layer surrounding the core
3) Release-controlling membrane containing a film-forming anionic carboxylic polymer that resists dissolution at gastric pH and dissolves at intestinal pH about 4 to 7.5, producing a defined in vitro dissolution profile that maps to in vivo release time 1 to 50 hours

This is not a broad “budesonide MR formulation” patent. It is a formulation and performance claim set that locks down specific steroid identity, pellet geometry, polymer classes, polymer fractions, release behavior by dissolution testing, and membrane composition constraints.

Claim 1: The independent formulation scaffold (full scope anchor)

Claim 1 is the broad independent claim (with multiple embodiments inside the claim). Its scope can be reduced to the following claim-limiting elements.

1) Device form and size

• Oral controlled-release pellet formulation for IBD
• Pellet diameter: 0.3 mm to 5 mm

2) Core options (two embodiments)

(A) Core is a non-pareil seed, with drug in an external “layer”

• Core: non-pareil seed

(B) Core is a seed with glucocorticosteroid homogeneously distributed

• Core: seed containing glucocorticosteroid homogeneously distributed

3) Glucocorticosteroid identity (budesonide family list)

If the core is the non-pareil seed embodiment, the surrounding layer contains a glucocorticosteroid selected from the listed group. The list spans:

• Budesonide-like corticosteroids expressed via stereochemistry and fluorination/difluorination/acetoxy modifications
• Includes (22R,S) forms and their 22R epimers
• Includes methyl esters for androstane/pregnane derivatives with corresponding stereochemical descriptors

In practice, this list functions as a structured genus of specific glucocorticosteroids, not “any steroid.”

4) Layer polymer selection and fraction

For the layer:

• Layer polymer is a pharmaceutically acceptable film-forming polymer
• The layer polymer can be water-insoluble or water-soluble (or mixtures), depending on embodiment
• Layer comprises about 0.5% to 30% by weight of the pellet

5) Membrane (release gate) composition

A membrane surrounding the core and the layer contains:

• film-forming anionic carboxylic polymer
• polymer is difficult to dissolve at low pH but soluble at higher pH about 4 to 7.5
• membrane also can include water-insoluble polymer in combination

The membrane weight contribution is:

• membrane comprises about 1% to 50% by weight of the pellet

6) Performance limits tie back to specific dissolution testing conditions

Claim 1 includes a detailed in vitro dissolution release-time window in a flow-through cell:

• 8 mL/min
• 37 °C
• dissolution measured in simulated gastric and intestinal fluids
• and the measured dissolution corresponds to in vivo release time 1 to 50 hours

Claim 1 then splits performance into intended tract location.

Small intestine release profile (percent released of total glucocorticosteroid)

• (a) Not more than 10% released after 2 hours in simulated gastric fluid
• (b) 15% to 55% released after 2 hours in simulated intestinal fluid
• (c) 35% to 80% released after 4 hours in simulated intestinal fluid
• (d) Not less than 60% released after 8 hours in simulated intestinal fluid
• (e) Not less than 80% released after 12 hours in simulated intestinal fluid

Large intestine release profile (percent released of total glucocorticosteroid)

• (f) Not more than 10% released after 2 hours in simulated gastric fluid
• (g) 5% to 30% released after 4 hours in simulated intestinal fluid
• (h) 20% to 65% released after 12 hours in simulated intestinal fluid
• (i) 40% to 95% released after 24 hours in simulated intestinal fluid
• (j) Not less than 70% released after 48 hours in simulated intestinal fluid

Net effect: even if a competitor uses the correct steroid and polymer class, they must hit the stated dissolution windows to fall within Claim 1.

How does Claim 2 narrow or expand compared to Claim 1?

Claim 2 is also an independent formulation claim but adds more detailed performance constraints and tightens the testing language. Compared to Claim 1, Claim 2:

• retains the same pellet size range (0.3 to 5 mm)
• repeats the same core/layer/membrane architecture
• explicitly binds dissolution testing to flow-through cell at 8 mL/min and 37 °C
• sets a more specific small/large intestinal dissolution schedule, with different numeric ranges than Claim 1

Claim 2 key tightening: location-matched dissolution windows

Small intestine:

• After 2 hours (gastric): not more than 5% released
• After 2 hours (intestinal): 20% to 50%
• After 4 hours: 40% to 70%
• After 8 hours: 60% to 90%
• After 12 hours: ≥ 80%

Large intestine:

• After 2 hours (gastric): not more than 5%
• After 4 hours (intestinal): 10% to 30%
• After 12 hours: 35% to 55%
• After 24 hours: 55% to 85%
• After 48 hours: ≥ 80%

Net effect: Claim 2 is a narrower performance envelope than Claim 1 and is therefore harder to design around without changing the system materially.

How does Claim 3 differ from Claims 1 and 2?

Claim 3 is structurally similar but changes some threshold numbers again.

Small intestine:

• Gasric 2 hours: not more than 5%
• Intestinal 2 hours: 20% to 50%
• Intestinal 4 hours: 40% to 70%
• Intestinal 8 hours: 60% to 90%
• Intestinal 12 hours: ≥ 80%

Large intestine:

• Gastric 2 hours: not more than 5%
• Intestinal 4 hours: 10% to 30%
• Intestinal 12 hours: 35% to 65%
• Intestinal 24 hours: 55% to 85%
• Intestinal 48 hours: ≥ 80%

Net effect: Claim 3 provides an alternative set of dissolution limits, including a larger upper range at 12 hours for large-intestine targeting (up to 65% vs up to 55% in Claim 2).

Where are the claim-limiting material constraints in dependent claims?

The patent then breaks down the independent claim scaffold into explicit design constraints that can drive freedom-to-operate (FTO) outcomes.

Polymer composition and fraction constraints

• Claim 4: anionic carboxylic polymer ranges 25% to 100% by weight of total polymer content in membrane
• Claim 8: membrane ranges 1 to 50% of total pellet weight (consistent with independent claim)
• Claim 21: layer comprises 1% to 15% (w/w) of total pellet weight

Specific polymer species called out (harder to design around)

• Claim 5 (anionic carboxylic polymer examples):

  • cellulose acetate phthalate
  • cellulose acetate trimellitate
  • polyvinyl acetate phthalate
  • hydroxypropyl-methylcellulose phthalate
  • methacrylic acid copolymer

• Claim 6 (water-insoluble polymer examples):

  • ethyl-cellulose
  • cellulose acetate
  • polyvinyl acetate
  • ethylene-vinyl acetate copolymer
  • amino methacrylate copolymers
  • polymethacrylic acid esters

• Claim 7: membrane can include one additional component among plasticizer, antiadhesive, surfactant

Drug identity narrowing

• Claim 9: glucocorticosteroid is budesonide or the 22R epimer
• Claim 24: in the pharmaceutical composition, disease is ulcerative colitis and drug is budesonide or 22R epimer
• Multiple dependent claims preserve the same scaffold but tighten drug species for enforcement strength.

Layer composition and embedded polymer selection

• Claim 10: layer beneath membrane contains budesonide/22R epimer plus water-soluble or water-insoluble film-forming polymer

• Claim 12: layer beneath membrane is film-forming water-insoluble polymer(s) or mixtures including water-soluble and water-insoluble film-forming polymers

• Claim 13: embedded polymeric material selection list includes:

  • polyvidone acetate
  • methylcellulose
  • hydroxypropyl cellulose
  • polyvinylpyrrolidone
  • hydroxypropylmethylcellulose
  • ethylcellulose
  • cellulose acetate
  • polyvinyl acetate
  • ethylene-vinylacetate copolymer
  • amino methacrylate copolymer
  • polymethacrylic acid ester

• Claims 14-15: layer can include plasticizer/antiadhesive/surfactant; polymer list is reiterated with minor phrasing differences.

Core and seed parameters

• Claim 16: core comprises budesonide/22R epimer distributed in excipients OR budesonide/22R epimer in a layer on a non-pareil seed; seed diameter 0.2 to 1.5 mm

Release time mapping (in vivo ranges)

• Claim 17: release time is 5 to 10 hours for treating small intestine or 25 to 50 hours for large intestine

Dissolution profile constraints restated for claims 2 and 3

• Claims 18-19: restate dissolution targets in further detail for small vs large intestine, corresponding to the respective independent claim performance sets.

Formulation composition exclusions

• Claim 20: pellet is substantially free of precipitating electrolyte salts or cross-linking additives

Dosage forms and use claims

• Claim 22: pharmaceutical composition for IBD by oral route; disease list includes:

  • ulcerative colitis
  • Crohn’s colitis in active phase
  • Crohn’s colitis chronic relapse-preventing therapy
  • Crohn’s disease in small intestines as relapse-preventing treatment

• Claim 25: capsule comprising formulation of pellets

Manufacturing process (composition-to-process protection)

• Claim 26: process includes forming drug-loaded cores or coating non-pareil seeds with steroid+polymer, then coating with membrane polymer system that yields the defined release behavior.

What is the practical “patent landscape” implied by this claim structure?

US 5,643,602 is positioned as a formulation-performance patent for budesonide-based enteric controlled-release pellets using:

• layered seed pellet engineering
• anionic carboxylate polymer membranes designed for pH-triggered solubility
• tight dissolution windows in simulated GI fluids in a specified flow-through test

Enforceability is likely strongest where competitors overlap all three:

1) Budesonide or 22R-budesonide (or one of the enumerated glucocorticosteroids)
2) same pellet and layer/membrane architecture (core and surrounding layer plus anionic carboxylic polymer membrane)
3) same dissolution windows in gastric and intestinal fluids in flow-through cell conditions

If even one axis is shifted (different steroid species, different membrane polymer family, or different dissolution profile), the coverage can fall outside the independent claims.

Likely FTO pressure points

• Membrane polymers: cellulose acetate phthalate, cellulose acetate trimellitate, PVAc phthalate, HPMCP phthalate, methacrylic acid copolymer are explicitly listed. A design using these exact polymers with the same polymer fraction constraints and pH solubility behavior is likely to be higher risk.
• Fraction constraints: membrane includes 1 to 50% pellet weight; membrane polymer composition requires anionic carboxylic polymer 25 to 100% of membrane polymer content.
• Release performance: the independent claims and dependent claims define release percentages at multiple timepoints. Competitors often tune dissolution, but doing so to satisfy multiple target sites (small vs large intestine) within tight windows becomes a design constraint.

How to interpret scope beyond the independent claims

Functional claim language still bites

Even though polymer species are named, the claims also include functional language:

• “difficult to dissolve at a low pH but soluble at higher pH of about 4 to 7.5”
• “effective to prevent release in gastric fluids but permit release in intestinal fluids”
• dissolution windows in simulated fluids under specified test conditions

That combination can capture “equivalents” within the same functional performance envelope.

Dependent claims build multiple narrow combinations

The dependent claims provide fallback positions:

• polymer species (claims 5-6)
• drug identity to budesonide/22R epimer (claim 9)
• specific embedded polymers (claims 13 and 15)
• dissolution profile recitations (claims 18-19)
• seed diameter (claim 16)
• pellet salt/excipient restrictions (claim 20)

These increase infringement risk against “near-miss” products that try to avoid one aspect but still share the rest.

Design-around logic implied by the claim language

A product that aims to avoid coverage would need to change at least one of these claim anchors:

• Steroid identity: use a corticosteroid not in the enumerated list, or not budesonide/22R if the dependent claims are asserted.
• Membrane polymer family: move away from the anionic carboxylic film-forming membrane that is pH 4 to 7.5 soluble and low pH insoluble.
• Tested dissolution profile: change dissolution kinetics such that the formulation fails one or more percentage/time constraints (especially at 2, 4, 8, 12, 24, 48 hours depending on small vs large intestine intent).
• Geometry/material constraints: pellet size and seed diameter and mass fractions are specific; changing pellet engineering may move outside.

Claims set summary table (scope at a glance)

Key Takeaways

• US 5,643,602 covers budesonide-family controlled-release pellet formulations built from a seed core, a polymer-drug layer, and a pH-responsive anionic carboxylic polymer membrane.
• The independent claims enforce coverage through tight dissolution windows measured in a flow-through cell at 8 mL/min and 37 °C with explicit percent-release targets for small vs large intestine delivery.
• Dependent claims add enforcement leverage by locking in membrane polymer species, polymer fractions, pellet/seed size, budesonide/22R-budesonide drug identity, and additional composition exclusions (no precipitating electrolyte salts or cross-linkers).
• A competitive product must avoid coverage by changing at least one of: steroid identity, membrane polymer class/chemistry and fraction, or the tested dissolution profile such that the formulation fails one or more percentage/time windows.

FAQs

1. Does US 5,643,602 claim a specific commercial product name or brand?
   No. It claims a pellet-based controlled-release formulation architecture and performance profile for IBD.

2. What are the most enforceable claim elements in US 5,643,602?
   The combination of (i) budesonide (or listed glucocorticosteroids), (ii) a membrane with a film-forming anionic carboxylic polymer that dissolves at intestinal pH, and (iii) the specified dissolution windows in simulated GI fluids in a flow-through cell.

3. Can a competitor avoid infringement by using a different buzdsonide epimer or steroid stereoisomer?
   Risk increases if the steroid is within the enumerated glucocorticosteroid list or budesonide/22R-budesonide as called out in dependent claims.

4. Is the scope limited to small intestine targeting only?
   No. Claims provide separate dissolution windows for small intestine and large intestine release behavior.

5. Does US 5,643,602 protect formulation process as well as composition?
   Yes. Claim 26 is a process claim describing manufacture steps to form cores/layers and apply the anionic carboxylic polymer membrane with the required release behavior.

References

[1] US Patent No. 5,643,602. Controlled release pellet formulation for oral administration in the treatment of inflammatory bowel diseases. (Claim text as provided in prompt).